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13:["$","p",null,{"className":"mt-3 leading-relaxed","children":["Spike protein persistence describes continued antigen detection after SARS-CoV-2 infection or COVID-19 vaccination. Most individuals clear circulating spike within weeks, but ultra-sensitive assays (Simoa, high-sensitivity ELISA) detect low pg/mL levels in subsets for months to years. The 2026"," ",["$","a",null,{"href":"https://link.springer.com/article/10.1186/s43094-026-00939-2","className":"text-[#e64a19] underline hover:text-[#ff9800]","children":"systematic review"}]," ","synthesizes evidence across bodily fluids and autopsy tissues."]}]
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23:T5c5,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is initiated by the viral spike proteins, which are key structural components that mediate host cell binding and entry and alter downstream signaling through multiple interactions with endothelial surface receptors. Endothelial dysfunction is a central consequence of COVID-19, contributing to vascular inflammation, barrier disruption, thrombosis, and multi-organ injury affecting the pulmonary, cardiovascular, cerebral, and renal systems. Emerging evidence demonstrates that spike protein-mediated effects, independent of productive viral infection, disrupt endothelial homeostasis through angiotensin-converting enzyme 2 (ACE2) dysregulation, integrin engagement, altered calcium signaling, junctional protein remodeling, oxidative stress, and pro-inflammatory and pro-apoptotic pathways. This review is intentionally focused on spike (S) protein-driven mechanisms of endothelial dysfunction; pathogenic vascular effects attributed to other SARS-CoV-2 structural proteins, including the nucleocapsid (N) protein, are beyond the scope of this discussion. In this review, we synthesize current experimental and translational data detailing the molecular mechanisms by which the SARS-CoV-2 spike protein drives endothelial dysfunction across multiple organ systems and discuss potential therapeutic strategies aimed at preserving endothelial integrity in acute COVID-19 and its long-term vascular sequela.24:T7d9,AIMS: Interferon (IFN) alpha (IFNα) and lambda3 (IFNλ3) constitute first line responses of immunity against SARS-CoV-2 infection by increasing interferon-stimulated genes (ISGs). Prolonged IFN production may exacerbate inflammation, contributing to endotheliitis and vascular dysfunction in COVID-19. We investigated whether spike protein S1 (SP1) of SARS-CoV-2 via IFN influences inflammation in human vascular and lymphatic endothelial cells (EC) and whether these processes contribute to vascular dysfunction in the context of hypertension. We focused on ISG15, a crucial immune protein that is also implicated in hypertension-associated vascular injury. METHODS AND RESULTS: Exposure of microvascular ECs to SP1 of SARS-CoV-2 induced expression of ISGs: ISG15, MX1 and IFIT1. These effects were potentiated by IFNs and reduced by ADAM17 and STAT1 inhibition and genetic inhibition of IFN alpha and beta receptor subunit 1 (IFNAR1). In microvascular ECs IFNλ3 and IFNα increased expression of ISGs, TMPRSS2, ADAM17, production of pro-inflammatory mediators (TNFα, IL-6, PAI-1) and reduced phosphorylation of eNOS (Ser1177). In pulmonary, lymphatic and aortic ECs, IFNα, but not IFNλ3, increased expression of ISGs and IL-6. To explore the relevance in intact vessels, effects of IFNs were studied in isolated microvessels from wildtype (WT), hypertensive and ISG15-/- mice. IFNα, IFNλ3 and SP1 reduced endothelium-dependent relaxation in WT vessels, whereas IFNα increased contraction in vessels from hypertensive mice. Vascular dysfunction induced by IFNα, IFNλ3 or spike protein was abrogated in vessels from ISG15-/- mice. CONCLUSIONS: SP1 and IFNs synergically increase EC expression of ISGs through ADAM17. IFNλ3 and IFNα promote endothelial inflammation and vascular dysfunction through ISG15. These processes may play a role in the endotheliopathy and vascular damage associated with SP1 and might contribute to cardiovascular sequelae, including hypertension, of SARS-CoV-2 infection.25:T60b,Postacute sequelae of SARS-CoV-2 infection (PASC), or Long COVID, is estimated to affect over 60 million individuals globally, with almost half of COVID-19 survivors experiencing persistent symptoms such as neuropathic pain, fatigue, and autonomic dysfunction. Despite its prevalence, the pathophysiology of PASC remains poorly understood. This narrative review highlights activation of mast cells (MCs), the unique tissue immune cells as a central contributor to neuropathic manifestations in PASC. Mast cell locations near nerves and vessels allows them to regulate neuroimmune and neurovascular processes. Mast cell activation mirrors patterns seen in small-fiber neuropathy and myalgic encephalomyelitis/chronic fatigue syndrome, suggesting a shared immune-mediated etiology. The SARS-CoV-2 spike protein has been shown to activate MCs via angiotensin-converting enzyme 2 and toll-like receptor 4, triggering release of pro-inflammatory and neurotoxic mediators, including interleukin-1β, interleukin-6, tumor necrosis factor alpha, histamine, and tryptase. Such mediators sensitize peripheral nerves, disrupt the blood-brain barrier, and recruit microglia, ultimately contributing to small-fiber injury, neuroinflammation, and dysautonomia. Emerging reports suggest benefit from MC-directed treatments although responses remain variable. Understanding the role of MCs in PASC may offer a plausible mechanism of pathogenesis and guide targeted therapies. Future studies are needed to validate these findings and improve PASC patient outcomes.26:T71e,Coronavirus disease 2019 (COVID-19) patients have a 1.7-fold higher arrhythmia risk with rates of cardiac complications ranging from 2% non-ICU patients to 59% in non-survivors. Atrial fibrillation (AF), the most common arrhythmia, is a frequent complication of acute and long COVID-19. The high expression of ACE2 in the heart suggested that infectious virus may underlie cardiac complications. However, we recently reported in human cardiac tissue from fatal COVID-19 cases perivascular spike protein, elevated pro-inflammatory cytokines, vascular damage, and cardiac remodeling without evidence for direct infection of cardiac cells by SARS-CoV2. Mislocalization of intercalated disc (ID) components, connexin-43 (Cx43) gap junctions and NaV1.5 sodium channels, was also evident in patients' hearts, recapitulating structural remodeling we previously identified as providing a substrate for atrial arrhythmias following an acute inflammatory insult. Therefore, we hypothesized that the inflammatory response elicited by SARS-CoV2 spike protein is sufficient to provoke atrial arrhythmias. Structural and functional assessments of WT murine hearts were performed five days following a single bolus intravenous injection of the viral spike protein. In vivo ECGs demonstrated increased atrial arrhythmia burden in spike-injected mice vs. control. Immunohistochemistry studies revealed elevated expression of inflammatory markers and evidence of vascular damage in these mice. Additionally, we observed disruption of ID ultrastructure and mislocalization of Cx43 and NaV1.5 in the atria of spike protein-injected mice. Our results suggest that vascular-leak inducing inflammatory insult from viral spike protein, and not direct infection by SARS-CoV2 results in the pathophysiology of cardiac dysfunction in fatal COVID-19.27:T537,Therapeutic monoclonal antibodies can prevent severe disease in SARS-CoV-2 exposed individuals. However, currently circulating virus variants have evolved to gain significant resistance to nearly all neutralizing human immune system-derived therapeutic monoclonal antibodies that had previously been emergency-authorized for use in the clinic. Here, we describe the discovery of a panel of single-domain antibodies (VHHs) directed against the spike protein S2 subunit that broadly neutralize SARS-CoV-1 and -2 with unusually high potency. One of these VHHs tightly clamps the spike's monomers at a highly conserved, quaternary epitope in the membrane proximal part of the trimeric Heptad Repeat 2 (HR2) coiled-coil, thereby locking the HR2 in its prefusion conformation. Low dose systemic administration of a VHH-human IgG1 Fc fusion prevented SARS-CoV-2 infection in two animal models. Pseudovirus escape selection experiments demonstrate that the very rare escape variants are rendered almost non-infectious. This VHH-based antibody with a highly potent mechanism of antiviral action forms the basis for a new class of pan-sarbecovirus neutralizing biologics, which are currently under development. In addition, the unique quaternary binding mode of the VHHs to the prefusion HR2 could be exploited for other class I fusion proteins.28:T5c8,A major challenge during viral pandemics is the ability to develop therapeutics whose efficacy can withstand viral genetic evolution. During the COVID-19 pandemic, five SARS-CoV-2 monoclonal antibody (mAb) therapeutics were rendered ineffective within a period of 2 years, leading to the U.S. FDA revoking their emergency use authorization. Here, we describe ReconnAb-multimers, a new therapeutic design that broadly and potently neutralize all tested betacoronaviruses that use host ACE2 as their receptor to enter cells. These ReconnAb-multimers have potent neutralization efficacy via avidity, enhanced breadth via a new pan-betacoronavirus-binding antibody that targets a highly conserved epitope on SARS-CoV-2 spike protein, and the potential for clinical development by using a catalytically inactive ACE2 component. We demonstrate that ReconnAb-multimers neutralize all SARS-CoV-2 pseudoviruses and authentic viral variants of concern (VOC) tested, with similar or higher potency than mAbs previously approved by the FDA; neutralize related pandemic-potential betacoronaviruses, including SARS-CoV, WIV1-CoV, PRD-0038, and merbecovirus HKU5-CoV-2; and despite a short half-life, protect female mice against authentic viral challenge with Omicron variant XBB.1.5. Our results highlight ReconnAb-multimers as a broad and highly potent therapeutic that could potentially withstand viral escape against current and future betacoronaviruses that require host ACE2 as a receptor.29:T49f,The continued emergence of SARS-CoV-2 variants necessitates the development of immunogens that promote broad and durable immunity. The SARS-CoV-2 S2 fusion subunit drives viral entry and has sequence conservation among coronavirus spike proteins. Therefore, S2 could represent an immunogen to boost broadly reactive antibodies. However, when expressed without the S1 domain, metastable S2 irreversibly collapses into the post-fusion six-helix bundle conformation. Beyond well-characterized RBD/NTD shifts, biophysical measurements indicate that spike exhibits reversible "breathing" motions. Using an engineered S2-only antigen that retains the pre-fusion viral surface conformation, we isolated S2-specific antibodies from convalescent and vaccinated individuals. One mAb was used to solve a high-resolution cryo-EM structure of pre-fusion S2. Our structure reveals that, relative to intact spike, engineered S2 adopts a more "open" conformation with stabilizing intermolecular interactions at the trimer base and fusion peptide repositioning. This structure could advance next-generation "booster" immunogens and illuminate potential breathing adjustments of the coronavirus spike.2a:T428,SARS-CoV-2 infection has had a significant impact on global health through both acute illness, referred to as coronavirus disease 2019 (COVID-19), and chronic conditions (long COVID or post-acute sequelae of COVID-19, PASC). Despite substantial advancements in preventing severe COVID-19 cases through vaccination, the rise in the prevalence of long COVID syndrome and a notable degree of genomic mutation, primarily in the S protein, underscores the necessity for a deeper understanding of the underlying pathophysiological mechanisms related to the S protein of SARS-CoV-2. In this review, the latest part of this series, we investigate the potential pathophysiological molecular mechanisms triggered by the interaction between the spike protein and cellular receptors. Therefore, this review aims to provide a differential and focused view on the mechanisms potentially activated by the binding of the spike protein to canonical and non-canonical receptors for SARS-CoV-2, together with their possible interactions and effects on the pathogenesis of long COVID.2b:T6f4,BACKGROUND: The COVID-19 pandemic, caused by SARS-CoV-2, has led to the first approval of mRNA vaccines in humans. By producing the full-length SARS-CoV-2 Spike protein, they induce protective antiviral immunity. Acute myopericarditis (AMP) development after vaccination has repeatedly been reported; however, the pathogenesis of this complication remains elusive. METHODS: In-depth phenotyping of peripheral blood T cells was undertaken in cohorts of patients who developed AMP after mRNA vaccination, patients hospitalized for severe COVID-19, and healthy subjects with no cardiac side effects after mRNA vaccine. Validation studies were carried out using an experimental model of cardiac inflammation, in which a shared epitope elicits functional responses in patients and mice and induces AMP. RESULTS: We show that T cells from patients with AMP recognize vaccine-encoded Spike epitopes homologous to those of cardiac self-proteins. One of these epitopes, mimicking an amino acid sequence from a cardiomyocyte-expressed K+ channel, induced AMP in mice. When functional responses to the Kv2 were analyzed, patients with AMP after mRNA vaccination, but not patients with COVID-19, displayed an expanded pattern of cytokine production similar to that observed in AMP mice and in autoimmune myocarditis. Crucially, T-cell autoimmunity segregates to cardiotropic cMet (c-mesenchymal epithelial transition factor)-expressing T cells and is prevented by cMet inhibition, suggesting that heart homing imprinting, permitted by the unique mRNA vaccine biodistribution, is required for AMP development. CONCLUSIONS: AMP development after mRNA vaccines is mediated by distinct immune components, including molecular mimicry, T-cell receptor affinity, and, importantly, homing imprinting.2c:T5be,SARS-CoV-2 Spike - the sole neutralization target, is highly resilient to the immune pressure driving genetic evolution. While potency and breadth of neutralization are widely studied, the incomplete neutralization - the mechanism of resistance without needing genetic change - remains unexplored. Several monoclonal antibodies, although potent, showed incomplete neutralization of genetically homogeneous pseudovirus suggesting the existence of distinct spike conformations. The residual infectivity at high antibody concentration indicates a viral fraction with intrinsic resistance to the antibody. Although the published studies on spike glycosylation, structure, and conformations provide evidence of spike heterogeneity the precise mechanism for the incomplete neutralization has not been established. In this study, we devise a method to separate the un-neutralized virion population, called as persistent fraction of infectivity (PF), and characterize the viral spike protein. The neutralization resistance of PF is stable and unrelated to the conformational equilibrium that exists in the pseudovirus stock. The spike on the PF is highly cleaved between S1 and S2, adopts the closed conformation, and express more mannosidic glycans on RBD than the total virus population. Our study provides possible explanations for the incomplete neutralization by antibodies and delineates the association between furin cleavage of spike, its conformation and glycosylation.2d:T5b8,Post-acute sequelae of SARS-CoV-2 infection (long COVID) present with persistent fatigue, cognitive impairment, and autonomic and multisystem dysfunctions that often go unnoticed by standard diagnostic tests. Increasing evidence suggests that mitochondrial dysfunction and oxidative stress are central drivers of these post-viral sequelae. Viral infections, particularly SARS-CoV-2, disrupt mitochondrial bioenergetics by altering membrane integrity, increasing mitochondrial reactive oxygen species (mtROS), and impairing mitophagy, leading to sustained immune activation and metabolic imbalance. This review synthesizes an understanding of how mitochondrial redox signaling and impaired clearance of damaged mitochondria contribute to chronic inflammation and multisystem organ symptoms in both long COVID and post-vaccine injury. We discuss translational biomarkers and non-invasive techniques, exploring therapeutic strategies that include pharmacological, non-pharmacological, and nutritional approaches, as well as imaging modalities aimed at assessing and restoring mitochondrial health. Recognizing long COVID as a mitochondrial disorder that stems from redox imbalance will open new options for personalized treatment and management guided by biomarkers. Future clinical trials are essential to validate these approaches and translate mitochondrial resuscitation into effective care for patients suffering from long COVID and related post-viral syndromes.2e:T5cc,Vaccine-induced thrombotic thrombocytopenia (VITT) is a rare thrombotic disorder first identified in 2021 as a catastrophic syndrome associated with anti-SARS-CoV-2 adenoviral vector (AdV)-vaccine administration. It is characterized by the presence of oligo- or monoclonal anti-PF4 antibodies able to induce in vitro platelet activation in the presence of PF4. In addition to this immune-based pathomechanism, random splicing events of the Adv-vector DNA encoding for SARS-CoV-2 spike protein resulting in the secretion of soluble spike variants have been postulated as a possible pathophysiological mechanism. More recently, some novel clinical-pathological anti-PF4-associated entities also characterized by thrombosis, thrombocytopenia, and VITT-like antibodies but independent from heparin or AdV-vaccine administration have been identified. To date, these VITT-like disorders have been reported following the administration of vaccines different from anti-SARS-CoV-2 AdV-vaccines, like human papillomavirus (HPV) and mRNA-based COVID-19 vaccines, following a bacterial or viral respiratory infection, and in patients with a monoclonal gammopathy of undetermined significance. The purpose of this review is to provide an update on the knowledge on VITT pathogenesis, focusing on recent findings on anti-PF4 antibodies, on a possible genetic predisposition to VITT, on VITT-antibody intracellular activated pathways, on lipid metabolism alterations, and on new VITT-like disorders.2f:T69a,Long COVID, or postacute sequelae of COVID-19 from SARS-CoV-2 infection, is a persistent debilitating disease affecting multiple systems and organs. Long COVID pathophysiology is a complex and not fully established process. One prevailing theory is that the formation of fibrin amyloid microclots (fibrinaloids), due to SARS-CoV-2 infection, can induce persistent inflammation and capillary blockage. An association between the amyloidogenic Spike protein of SARS-CoV-2 and impaired fibrinolysis was made when it was observed that fibrin clots formed in the presence of a mixture of amyloid fibrils from the spike protein mediated resistance to plasmin lysis. Here, we use purified components from the coagulation cascade to investigate the molecular processes of impaired fibrinolysis using seven amyloidogenic SARS-COV-2 Spike peptides. Five of seven Spike amyloid fibrils appeared not to substantially interfere with the fibrinogen-fibrin-fibrinolysis process in vitro, while two spike fibrils were active in different ways. Spike601 amyloid fibrils (sequence 601-620) impaired thrombin-mediated fibrin formation by binding and sequestering fibrinogen but did not affect fibrinolysis. On the contrary, fibrin clots formed in the presence of Spike685 amyloid fibrils (sequence 685-701) exhibited a marked resistance to plasmin-mediated fibrinolysis. We conclude that Spike685 amyloid fibrils can induce dense fibrin clot networks as well as incorporate fibrin into aggregated structures that resist fibrinolysis. Our study proposes a molecular mechanism for how the Spike protein of SARS-CoV-2 could contribute to the formation of fibrinolysis-resistant microclots observed in long COVID.30:T702,COVID affects around 400 million individuals today with a strong economic impact on the global economy. The list of long COVID symptoms is extremely broad because it is derived from neurological, cardiovascular, respiratory, immune, and renal dysfunctions and damages. We review here these pathophysiological manifestations and the predictors of this multi-organ pathology like the persistence of the virus, altered endothelial function, unrepaired tissue damage, immune dysregulation, and gut dysbiosis. We also discuss the similarities between long COVID and vaccine side effects together with possible common immuno-inflammatory pathways. Since the spike protein is present in SARS-CoV-2 (and its variants) but also produced by the COVID vaccines, its toxicity may also apply to all mRNA or adenoviral DNA vaccines as they are based on the production of a very similar spike protein to the virus. After COVID infection or vaccination, the spike protein can last for months in the body and may interact with ACE2 receptors and mannan-binding lectin (MBL)/mannan-binding lectin serine protease 2 (MASP-2), which are present almost everywhere in the organism. As a result, the spike protein may be able to trigger inflammation in a lot of organs and systems similar to COVID infection. We suggest that three immuno-inflammatory pathways are particularly key and responsible for long COVID and COVID vaccine side effects, as it has been shown for COVID, which may explain in large part their strong similarities: the renin-angiotensin-aldosterone system (RAAS), the kininogen-kinin-kallikrein system (KKS), and the lectin complement pathway. We propose that therapeutic studies should focus on these pathways to propose better cures for both long COVID as well as for COVID vaccine side effects.31:T7d0,During the summer of 2024, coronavirus disease 2019 (COVID-19) cases surged globally, driven by variants derived from JN.1 subvariants of severe acute respiratory syndrome coronavirus 2 that feature new mutations, particularly in the N-terminal domain (NTD) of the spike protein. In this study, we report on the neutralizing antibody (nAb) escape, infectivity, fusion, and spike stability of these subvariants-LB.1, KP.2.3, KP.3, and KP.3.1.1. Our findings demonstrate that all of these subvariants are highly evasive of nAbs elicited by the bivalent mRNA vaccine, the XBB.1.5 monovalent mumps virus-based vaccine, or from infections during the BA.2.86/JN.1 wave. This reduction in nAb titers is primarily driven by a single serine deletion (DelS31) in the NTD of the spike, leading to a distinct antigenic profile compared to the parental JN.1 and other variants. We also found that the DelS31 mutation decreases pseudovirus infectivity in CaLu-3 cells, which correlates with impaired cell-cell fusion. Additionally, the spike protein of DelS31 variants appears more conformationally stable, as indicated by reduced S1 shedding both with and without stimulation by soluble ACE2 and increased resistance to elevated temperatures. Molecular modeling suggests that DelS31 enhances the NTD-receptor-binding domain (RBD) interaction, favoring the RBD down conformation and reducing accessibility to ACE2 and specific nAbs. Moreover, DelS31 introduces an N-linked glycan at N30, shielding the NTD from antibody recognition. These findings underscore the role of NTD mutations in immune evasion, spike stability, and viral infectivity, highlighting the need to consider DelS31-containing antigens in updated COVID-19 vaccines.IMPORTANCEThe emergence of novel severe acute respiratory syndrome coronavirus 2 variants continues to pose challenges for global public health, particularly in the context of immune evasion and viral stability. This study identifies a key N-terminal domain (NTD) mutation, DelS3132:T5b1,Background/Objectives: According to the World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC), an estimated 3-6% of people suffer from post-COVID condition or syndrome (PCS). A subset meets the diagnostic criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Studies have reported that SARS-CoV-2 proteins or RNA can persist after acute infection in serum or tissues, but their role in PCS is unclear. Methods: Here, SARS-CoV-2 spike protein was analyzed in the serum of 121 PCS patients with predominant fatigue and exertional intolerance, of whom 72 met diagnostic criteria for ME/CFS, 37 post-COVID recovered healthy controls, and 32 pre-pandemic healthy controls. Results: Spike protein was detected in the serum of 11% of recovered controls, 2% of PCS patients, and 14% of ME/CFS patients between 4 and 31 months after SARS-CoV-2 infection, but not in pre-pandemic samples. The occurrence and concentration of spike protein did not correlate with infection or vaccination timepoints. In ME/CFS patients, spike protein presence was not associated with the severity of symptoms or functional disability. In 5 out of 22 patients who under-went immunoglobulin depletion, spike protein levels were reduced or undetectable after treatment, indicating binding to immunoglobulins. Conclusions: In summary, this study identified serum spike protein in a subset of patients but found no association with ME/CFS.33:T446,Entry of seasonal human coronavirus HKU1 (HCoV-HKU1) into host cells is facilitated by sequential binding to sialoglycans and transmembrane serine protease 2 (TMPRSS2) receptors. However, the neutralizing capacity of antibodies disrupting these receptor interactions have not been examined. Here, we describe the isolation and characterization of a human monoclonal antibody (mAb) HKU1-2 that recognizes the HCoV-HKU1 spike protein and exhibits dose-dependent neutralization of the virus. Epitope mapping and structural analysis revealed that HKU1-2 mAb targets the sialoglycan binding site in the N-terminal domain of the spike protein. A cryo-electron microscopy (cryo-EM) structure of the spike-Fab complex further demonstrated the ability of HKU1-2 to mimic sialic acid binding thereby effectively blocking sialoglycan receptor engagement. HKU1-2 binding is primarily mediated by CDRH3 recognition of NTD residues K80 and W89 that are known to be critical for sialic acid engagement. Overall, our results demonstrate antibody recognition and neutralization of HCoV-HKU1 by receptor mimicry.34:T626,Long COVID, characterized by persistent symptoms following acute SARS-CoV-2 infection, has emerged as a significant public health challenge with wide-ranging clinical and socioeconomic implications. Developing an effective risk assessment strategy is essential for the early identification and management of individuals susceptible to prolonged symptoms. This study uses a quantitative approach to characterize the dose-response relationships between spike protein concentrations and effects, including Long COVID symptom numbers and the release of proinflammatory mediators. A mathematical model is also developed to describe the time-dependent change in spike protein concentrations post diagnosis in twelve Long COVID patients with a cluster analysis. Based on the spike protein concentration-Long COVID symptom numbers relationship, we estimated a maximum symptom number (~20) that can be used to reflect a persistent predictor. We found that among the crucial biomarkers associated with Long COVID proinflammatory mediator, CXCL8 has the lowest 50% effective dose (0.01 μg mL-1), followed by IL-6 (0.39), IL-1β (0.46), and TNF-α (0.56). This work provides a comprehensive risk assessment strategy with dose-response tools and mathematical modeling developed to estimate potential spike protein concentration. Our study suggests persistent Long COVID guidelines for personalized care strategies and could inform public health policies to support early interventions that reduce long-term disability and healthcare burdens with possible other post-infection syndromes.35:T60c,Despite safety concerns regarding the toxicity of tattoo ink, no studies have reported the consequences of tattooing on the immune response. In this work, we have characterized the transport and accumulation of different tattoo inks in the lymphatic system using a murine model. Upon quick lymphatic drainage, we observed that macrophages mainly capture the ink in the lymph node (LN). An initial inflammatory reaction at local and systemic levels follows ink capture. Notably, the inflammatory process is maintained over time, as we observed clear signs of inflammation in the draining LN 2 mo following tattooing. In addition, the capture of ink by macrophages was associated with the induction of apoptosis in both human and murine models. Furthermore, the ink accumulated in the LN altered the immune response against two different types of vaccines. On the one hand, we observed a reduced antibody response following vaccination with an messenger ribonucleic acid (mRNA)-based severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine, which was associated with a decreased expression of the spike protein in macrophages in the draining LN. In contrast, we observed an enhanced response when vaccinated with influenza vaccine inactivated by ultraviolet (UV) radiation. Considering the unstoppable trend of tattooing in the population, our results are crucial in informing the toxicology programs, policymakers, and the general public regarding the potential risk of the tattooing practice associated with an altered immune response.36:T7d2,BACKGROUND: The rapid deployment of mRNA vaccines for SARS-CoV-2, such as BNT162b2 (BioNTech-Pfizer) and mRNA-1273 (Moderna), provided a critical tool in combating the COVID-19 pandemic. While their short-term safety and efficacy were demonstrated in clinical trials, rare adverse events, including hemorrhagic strokes, have been reported after widespread use. However, the long-term biodistribution and effects of mRNA vaccines remain underexplored. This study aimed to investigate the long-term presence of SARS-CoV-2 spike protein in brain tissues of patients with hemorrhagic strokes, examining its potential association with mRNA vaccination. METHODS: A total of 19 cases of hemorrhagic stroke from 2023 to 2024 were retrospectively analyzed. Immunohistochemical staining for SARS-CoV-2 spike protein and nucleocapsid protein was performed on tissue samples. In situ hybridization was conducted in selected cases to confirm the origin of spike protein expression (vaccine or viral infection). Vaccination history and SARS-CoV-2 infection status were documented for all cases. RESULTS: Spike protein expression was detected in 43.8 % of vaccinated patients, predominantly localized to the intima of cerebral arteries, even up to 17 months post-vaccination. While no active inflammatory changes were identified, infiltration of CD4-, CD8- and CD68- positive cells was observed in the spike protein positive vessels. In situ hybridization confirmed the presence of both vaccine-derived mRNA and SARS-CoV-2 virus-derived mRNA, which encode the spike protein, in select cases. Notably, spike protein positivity was observed exclusively in female patients (P = 0.015). None of the cases showed nucleocapsid protein positivity, supporting the absence of active viral infection. CONCLUSION: Although the possibility of spike protein expression due to asymptomatic SARS-CoV-2 infection cannot be entirely excluded, this study demonstrated prolonged presence of SARS-CoV-2 spike protein in the cerebral ar37:T623,The COVID-19 pandemic has been driven by SARS-CoV-2 variants with enhanced transmission and immune escape. Apart from extensive evolution in the Spike protein, non-Spike mutations are accumulating across the entire viral genome and their functional impact is not well understood. To address the contribution of these mutations, we reconstructed genomes of recent Omicron variants with disabled Spike expression (replicons) to systematically compare their RNA replication capabilities independently from Spike. We also used a single reference replicon and complemented it with various Omicron variant Spike proteins to quantify viral entry capabilities in single-round infection assays. Viral entry and RNA replication were negatively correlated, suggesting that as variants evolve reduced entry functions under growing immune pressure on Spike, RNA replication increases as a compensatory mechanism. We identified multiple mutations across the viral genome that enhanced viral RNA replication. NSP6 emerged as a hotspot with a distinct L260F mutation independently arising in the BQ.1.1 and XBB.1.16 variants. Using mutant and revertant NSP6 viral clones, the L260F mutation was validated to enhance viral replication in cells and increase pathogenesis in mice. Notably, this mutation reduced host lipid droplet content by NSP6. Collectively, a systematic analysis of RNA replication of recent Omicron variants defined NSP6's key role in viral RNA replication that provides insight into evolutionary trajectories of recent variants with possible therapeutic implications.38:T79a,The soluble S1 subunit of Spike protein (SP) from the SARS-CoV-2 of different variants of concern (VOCs) may directly bind and activate human NK cells in vitro through the engagement of the toll-like receptor (TLR) 2 and TLR4. This mechanism revealed a novel pathogenic role played by NK cells not only in the different phases of disease but also in the post-acute sequelae of COVID-19 (PASC) and some post-vaccination side effects. In addition to its binding to angiotensin-converting enzyme 2 (ACE2), which mediates virus attachment and cell entry, soluble SP triggers several active receptors/molecules expressed by many cells, inducing, in turn, type I/III interferon decrease, altered autophagy and apoptosis, the release of inflammatory cytokines and chemokines, complement activation and endothelial damage, which favour clotting events. In this review, we discuss the hypothesis that circulating SP, exerting multiple biological activities, can explain the heterogeneity of the clinical outcomes of severe COVID-19, PASC and post-vaccine-related effects. Recent reports have clearly indicated that soluble SARS-CoV-2 and post-vaccination SP trigger the same cascade of events, acting on the immune response and promoting defined adverse events. Factors hindering the pathological activity of soluble SP are the SP plasma levels, the age of the infected/vaccinated people and the efficiency of protein synthesis of ectopic targets triggered by soluble SP, as well as the specificity, the titre and the affinity of anti-SP antibodies elicited by the infection. At present, the risk/benefit ratio is largely in favour of vaccination; however, the excessive and persistent ectopic production of synthetic SP should be systematically analysed. This would allow for the identification of subjects at risk for major adverse events and to answer the urgent need for efficient vaccines that provide long-lasting activity with minimal side effects.39:T6b0,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogenic agent responsible for the coronavirus disease 2019 (COVID-19) pandemic, uses the trimeric spike protein to gain entry into the host cell. Structural studies have revealed that the spike protein is comprised of the S1 and S2 subunits. The S1 subunit of the spike protein contains the receptor-binding domain (RBD), which binds to the human angiotensin-converting enzyme 2 (ACE2) receptor. The interaction between the RBD and ACE2 facilitates membrane fusion and host cell infection. The SARS-CoV-2 spike protein also contains a unique insertion of four amino acids that results in the 682-RRAR↓S-686 polybasic furin cleavage motif at the boundary of the S1 and S2 subunits. The furin cleavage motif contributes to the high infectivity and transmissibility of SARS-CoV-2. This review provides a comprehensive analysis of the molecular interactions of the spike protein, with a specific focus on the RBD and furin cleavage site. In addition to examining the binding characteristics with ACE2, the interactions with alternative receptors, such as neuropilin-1 (NRP1) and the nicotinic acetylcholine receptors (nAChRs) are highlighted. The ability of the spike protein to bind alternative receptors and host factors has been linked to the pathophysiology of COVID-19 and the persistence of symptoms in the post COVID-19 condition. Furthermore, we examine the impact of spike protein mutations on receptor affinity and disease severity. SARS-CoV-2 continues to evolve, with variants remaining an ongoing threat to public health. Understanding these molecular interactions is critical for the development of novel therapeutic interventions.3a:T43b,Pathogens, including bacteria, viruses and fungi, employ virulence genes to invade their hosts, circumvent immunity and induce diseases. The present review examines the categorization and regulatory mechanisms of virulence genes and their co‑evolution with antimicrobial resistance. The present review focused on the fimbrial adhesion H adhesion gene of Escherichia coli, the spike protein gene of severe acute respiratory syndrome coronavirus 2 and the enhanced filamentous growth protein 1 (EFG1) morphological transition gene of Candida albicans, as well as their roles in host adhesion, immune evasion and tissue damage. Application of technologies, including multi‑omics integration, artificial intelligence and CRISPR‑based genome editing, is discussed in the context of precision diagnostics, targeted therapy and vaccine development. By elucidating pathogen adaptation dynamics and host‑pathogen interactions, the present review offers a basis for reducing the global burden of drug‑resistant infections through improved surveillance and personalized interventions.3b:T624,The development of a globally effective COVID-19 vaccine faces significant challenges, particularly in redirecting the B-cell response from immunodominant yet variable regions of viral proteins toward their conserved domains. To address this, an integrated strategy is implemented that combines classical B-cell epitope prediction with protein-antibody cluster docking and antibody titer analysis from 30 vaccinated and convalescent individuals. This approach yields stable immunodominant and immunoprevalent B-cell epitopes capable of eliciting robust antibody responses in BALB/c mice and effectively neutralizing pseudoviruses expressing the Spike protein of SARS-CoV-2 variants of concern, including Alpha, Beta, Gamma, Delta, and Omicron. To achieve a broader T-cell-based immune response, promiscuous T-cell epitopes are identified by integrating classical T-cell epitope predictions, differential scanning fluorimetry, and peptide-MHC structural analysis. Unique peptides with conserved MHC-anchoring residues are identified, enabling binding to a spectrum of MHC-I and MHC-II haplotypes. These peptides elicit strong interferon gamma responses in human peripheral blood mononuclear cells and demonstrate cross-species efficacy by activating both CD4+ and CD8+ T-cells in BALB/c mice. Collectively, these findings highlight the significance of innovative vaccine strategies targeting immunodominant/immunoprevalent B-cell and promiscuous T-cell epitopes to drive broad and robust humoral and cellular immune responses against a wide range of SARS-CoV-2 variants.3c:T608,With the global rollout of COVID-19 vaccines, vaccine safety remains a priority. Emerging concerns have raised the potential risk of a long COVID-like syndrome following vaccination, informally called long Vax and provisionally termed post-COVID-19 vaccination syndrome (PCVS). Our narrative review describes the putative manifestation, pathophysiology, and therapeutic approaches of PCVS based on the available evidence, mostly from case reports/series and observational studies. Our review noted that PCVS typically manifests within days to weeks post-vaccination, with symptoms lasting months to years. PCVS may present as recognized diagnoses such as postural orthostatic tachycardia syndrome (POTS), small-fibre neuropathy (SFN), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), or as long-term sequelae of myocarditis, vaccine-induced thrombotic thrombocytopaenia (VITT), or immune thrombocytopaenia purpura (ITP). Symptomatically, PCVS overlaps with long COVID, such as fatigue and brain fog, but PCVS may involve more frequent paraesthesia and less dyspnoea. We also review pathophysiological hypotheses of PCVS, focussing on the vaccine-derived spike protein and related immune responses. Finally, we discuss potential therapies used to treat patients with PCVS or related conditions, primarily documented in case reports/series, which could guide future clinical research. Overall, PCVS remains a poorly understood condition that requires more research to elucidate its prevalence, prognosis, risk factors, and treatments.3d:T5ba,Despite over 13 billion SARS-CoV-2 vaccine doses administered globally, persistent post-vaccination symptoms, termed post-COVID-19 vaccine syndrome (PCVS), resemble post-acute sequelae of COVID-19 (PASC). Symptoms like cardiac, vascular, and neurological issues often emerge shortly after vaccination and persist for months to years, mirroring PASC. We previously showed the S1 subunit of the SARS-CoV-2 spike protein persists in CD16+ monocytes after infection, potentially driving PASC. Approved vaccines (Pfizer, Moderna, Janssen, AstraZeneca) deliver synthetic S1 to elicit immunity, suggesting a shared mechanism. We hypothesized that vaccine-derived S1 persistence in CD16+ monocytes sustains inflammation akin to PASC, contributing to PCVS. We studied 50 individuals with PCVS symptoms lasting over 30 days post-vaccination and 26 asymptomatic controls, using (1) machine learning-based immune profiling to compare cytokine signatures with PASC, (2) flow cytometry to detect S1 in CD16+ monocytes, and (3) LC-MS to confirm S1 across vaccine types. We correlated S1 persistence with symptom duration and inflammation. Prior infection was excluded via clinical history, anti-nucleocapsid antibody tests, and T-detect assays, though definitive tests are lacking. Preliminary findings suggest S1 persistence in CD16+ monocytes and an associated inflammatory profile may contribute to PCVS. Further studies are needed to confirm causality and prevalence.3e:T635,Severe COVID-19 is characterized by thrombo-inflammatory processes within the lung microvasculature. In pursuit of effective treatments, clinical studies explored mesenchymal stromal cells (MSCs) as a promising approach due to their anti-inflammatory, immunomodulatory, and regenerative properties, through their paracrine action.Here, we tested the conditioned medium (CM) derived from human umbilical cord (UC)-MSCs in acute lung injury induced by the spike protein subunit 1 (S1) in ACE2-humanized male mice. Injection of CM significantly limited S1-induced lung injury, edema, and fibrosis. This was associated with reduced vascular dysfunction, in terms of restored thrombomodulin levels and decreased von Willebrand (vWF) expression. By preserving endothelial glycocalyx, CM reduced complement C3 accumulation, favoring factor H binding on the lung microvasculature. Reduced oxidative stress, nuclear NF-κB p65 accumulation, and inflammatory cell infiltration were also observed in response to CM in S1-injected mice.In vitro, CM counteracted thrombo-inflammation by preserving thrombomodulin, as well as limiting vWF expression, due to endothelial glycocalyx recovery. CM reduced nuclear translocation of NF-κB p65 and its downstream targets, ICAM-1 and P-selectin, translating in decreased C3 deposits, platelet aggregation, and leukocyte adhesion on S1-challenged endothelial cells.Collectively, these data indicate that UC-MSC-derived secretome represents a promising therapy in COVID-19 due to its potent anti-thrombotic and anti-inflammatory effects on lung microcirculation.3f:T7d0,Since the end of 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected many people globally. Diagnosis and treatment of patients have a pivotal role in surviving them. Two units of virus namely, Nucleocapsid protein and Spike proteins play important roles in entering and affecting cells. These two substances can be good targets for producing monoclonal antibodies which can be useful in treatment, serological diagnosis tests, and even prevention by vaccination. In 2020, the nucleocapsid protein and spike proteins of SARS-CoV-2 were procured by the Razi Vaccine and Research Institute in Karaj. Subsequently, the proteins were injected into mice, with the injection dosage adjusted to ensure that the mice received an appropriate amount of the proteins. Subsequently, the spleen cells of the immunized mice were fused with myeloma cells. The most promising antibody-producing clones were selected for further evaluation. The immunoreactivity of the recombinant Np and S proteins was subsequently evaluated by implementing Western Blot and ELISA techniques. Finally, the most promising clones were cryopreserved using a nitrogen gas cryogenic method. The employment of an ELISA test resulted in the identification of eight clone antibodies, namely 3G1, 3G2, 3E7, H11, A11, F10, B11, and 2F6. These monoclonal antibodies were found to be against the S and Np antigens of SARS-CoV-2. Furthermore, the results of the western blot test indicated that each of these antibodies had antigenic sites against the Spike and Nucleocapsid protein independently, and the isotyping test revealed that they were from IgG (2a, 2b) or IgM class antibodies. The development of monoclonal antibodies has the potential to facilitate both diagnosis and treatment. The Nucleocapsid protein and Spike protein of SARS-CoV-2 show great promise in the creation of a new generation of monoclonal antibodies. Furthermore, a comprehensive approach to the early diagnosis of the disease can be fac40:T774,Since 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing COVID-19, has been spreading and mutating globally despite the expedited approval of many commercial vaccines. Therefore, developing safe, effective and affordable vaccines remains essential to meet the global demand, particularly in developing countries. Transgenic plants have emerged as a promising platform to express recombinant proteins for pharmaceutical and vaccine applications. Two binary vectors, pCAMBIA1300Gt1-S1 and pCAMBIA1300Actin-S1, containing distinct promoters, were constructed and transformed into rice via Agrobacterium. Overall, 56 independent transgenic rice lines were regenerated. Expression analysis revealed that the rice-derived S1 (rS1) protein could be expressed in pGt1::S1 transgenic rice seeds. rS1 protein expression levels reached up to 282 μg/g dry weight, with S1 gene insertion having no effect on grain size and weight. The rS1 protein exhibited a high affinity for human angiotensin-converting enzyme 2 (ACE2) in vitro. Moreover, the immunogenicity of purified rS1 protein co-administered with various adjuvants demonstrated that mice vaccinated with Alum-adjuvant rS1 generated enhanced humoral immune responses with high serum IgG, IgG1 and neutralizing antibody levels. Salmonella Typhimurium flagellin (FliC)-adjuvanted rS1 elicited stronger S1-specific IgG2a levels, promoted splenocyte proliferation and induced mixed Th1/Th2/Th17 cytokine responses. This was evidenced by increased proportions of antigen-specific interferon (IFN)-γ, interleukin-4 (IL-4) and IL-17A-positive CD4+ T lymphocytes, suggesting its potential to induce both humoral and cellular immune responses. These findings suggest that rS1 protein offers a promising approach for affordable COVID-19 subunit vaccine production, and this strategy can be universally applied to other viral vaccines.41:T603,Acute respiratory distress syndrome (ARDS) is a life-threatening condition characterized by acute lung inflammation, increased vascular permeability, and hypoxemic respiratory failure. Oxidative stress, driven by excessive reactive oxygen species (ROS), is a key contributor to ARDS pathogenesis, causing cellular damage, inflammation, and alveolar-capillary barrier disruption. This review elucidates the mechanisms of oxidative stress in ARDS, focusing on ROS production via NADPH oxidase (NOX) and mitochondria, which activate pathways like NF-κB and MAPK, promoting pro-inflammatory cytokine release. ROS-induced lipid and protein peroxidation, endothelial dysfunction, and programmed cell death (PCD), including apoptosis, pyroptosis, and ferroptosis, exacerbate lung injury. In COVID-19-related ARDS, SARS-CoV-2 spike protein amplifies mitochondrial ROS, worsening outcomes. Antioxidant therapies falter due to non-specific ROS suppression, patient heterogeneity (e.g., GSTP1 polymorphisms), and poor bioavailability. We propose a model where oxidative stress drives ARDS stages-early alveolar injury and late systemic dysfunction-suggesting targeted therapies like endothelial-specific nanoparticles or ferroptosis inhibitors. Precision medicine using biomarkers (e.g., mtDNA) and gender-specific approaches (e.g., estrogen-Nrf2 regulation) could enhance outcomes. This review bridges mechanistic gaps, critiques therapeutic failures, and advocates novel strategies like mitochondrial-targeted therapies to improve ARDS management.42:T6be,UNLABELLED: Post-Spike Syndrome (PSS) is an emerging condition associated with the Spike protein, originating from both SARS-CoV-2 infection and mRNA-based therapies. This case series explores the significant clinical impact of PSS, characterized By gut dysbiosis, systemic inflammation, and immune activation, leading to multisystem manifestations such as fatigue, brain fog, neuropathies, and reactivation of pre-existing diseases. A simple therapeutic approach was applied to five patients, resulting in notable symptom improvement. METHODS: This case series includes five patients diagnosed with interstitial granulomatous dermatitis, polymyalgia rheumatica, peripheral polyneuropathy, drug-refractory epilepsy, and trigeminal neuralgia. A common pathophysiological mechanism-vasculitis triggered by both SARS-CoV-2 and mRNA-based therapies-was hypothesised. The patients exhibited a satisfactory response to the proposed therapeutic strategy. This is an observational and descriptive study, with data collected retrospectively from medical records at a private clinic in São Paulo, Brazil. CONCLUSION: It is crucial to raise awareness within the medical community About SPIKEOPATHY, particularly in cases of classic pathologies that do not respond to conventional treatments. We believe PSS is currently underestimated. A broad intervention including a focus on restoring the microbiome, in particular Bifidobacterium associated with ivermectin and nattokinase was used as a therapeutic strategy. In other studies, Bifidobacterium has already been shown to significantly reduce harmful bactéria in post-COVID patients. Further studies are needed to confirm these findings and expand our understanding of PSS management.43:T679,Impaired spermatogenesis has been reported in coronavirus disease 2019 (COVID-19) patients. However, the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on male fertility remains unclear. The purpose of this multicenter study was to investigate the possible impact of SARS-CoV-2 infection on male fertility and determine the potential reasons leading to impaired male reproductive functions. In silico approach identified ~60 amino acid sequences containing at least five continuous residues shared by SARS-CoV-2 Spike glycoprotein and spermatogenesis-linked proteins. Four synthetic peptides were tested with sera from independent cohorts of patients with acute and long COVID-19 syndrome (LCS), and naïve vaccinated subjects. Immunogenicity and pathogenicity studies were performed by immunizing mice with two selected peptides and testing the antigenicity of induced antibodies. While none of four peptides were recognized by antibodies from vaccinated people, infected patients exhibited high reactivity to peptide 4, and LCS patients, especially women, showed elevated antibody levels against peptide 2. Women with LCS and chronic fatigue syndrome had higher levels of peptide 2-reacting antibodies than those with idiopathic chronic fatigue syndrome. Noteworthy, peptide 2 antibodies showed, in in vitro experiment, a specific interaction with mouse testicular tissue antigens. These findings raise the possibility that cross-reactive epitopes between SARS-CoV-2 Spike protein and spermatogenesis-related antigens may affect infected patients' fertility, suggesting a potential for autoimmune responses with human consequences.44:T455,Continual evolution of SARS-CoV-2 spike drives the emergence of Omicron variants that show increased spreading and immune evasion. Understanding how the variants orientate themselves towards host immune defence is crucial for controlling future pandemics. Herein, we demonstrate that human cathelicidin LL-37, a crucial component of innate immunity, predominantly binds to the S2 subunit of SARS-CoV-2 spike protein, occupying sites where TMPRSS2 typically binds. This binding impedes TMPRSS2-mediated priming at site S2' and subsequent membrane fusion processes. The mutation N764K within S2 subunit of Omicron variants reduces affinity for LL-37 significantly, thereby diminishing binding capacity and inhibitory effects on membrane fusion. Moreover, the early humoral immune response enhanced by LL-37 is observed in mice against SARS-CoV-2 spike but not Omicron BA.4/5 spike. These findings reveal the mechanism underlying interactions amongst LL-37, TMPRSS2 and SARS-CoV-2 and VOCs, and highlight the distinct mutation for Omicron variants to evade the fusion activity inhibition by host innate immunity.45:T702,The SARS-CoV-2 spike protein is pivotal in the COVID-19 virus's life cycle, facilitating viral attachment to host cells. It is believed that targeting this viral protein could be key to developing effective COVID-19 prophylactics. Using in silico techniques, this study sought to virtually screen for compounds from the literature that strongly bind and disrupt the stability of the HSPA8-spike protein complex. To evaluate the interactions between the individual proteins and the protein complex attained from protein-protein docking using BioLuminate, molecular docking was performed using the Maestro Schrodinger Suite. The screened small molecules met all bioavailability conditions, Lipinski's and Veber's rules, and the required medicinal chemistry properties. Protein-protein docking of the spike protein and HSPA8 identified the optimal pose with a PIPER cluster size of 65, a PIPER pose energy of -748.301 kcal/mol, and a PIPER pose score of -101.189 kcal/mol. Two small molecules, NSC36398 and NSC281245, showed promising docking scores against the spike protein individually and in a complex with HSPA8. NSC36398 had a docking score of -7.934 kcal/mol and a binding free energy of -39.52 kcal/mol with the viral spike protein and a docking score of -8.029 kcal/mol and binding free energy of -38.61 with the viral protein in complex with HSPA8, respectively. Mevastatin had a docking score of -5.099 kcal/mol and a binding free energy of -44.49 kcal/mol with the viral protein and a docking score of -5.285 kcal/mol and binding free energy of -36.65 kcal/mol with the viral protein in complex with HSPA8, respectively. These results, supported by extensive 2D interaction diagrams, suggest that NSC36398 and NSC281245 are potential drug candidates targeting SARS-CoV-2 spike protein.46:T756,Since the beginning of the COVID-19 pandemic, extensive drug repurposing efforts have sought to identify small-molecule antivirals with various mechanisms of action. Here, we aim to review research progress on small-molecule viral entry and fusion inhibitors that directly bind to the SARS-CoV-2 Spike protein. Early in the pandemic, numerous small molecules were identified in drug repurposing screens and reported to be effective in in vitro SARS-CoV-2 viral entry or fusion inhibitors. However, given minimal experimental information regarding the exact location of small-molecule binding sites on Spike, it was unclear what the specific mechanism of action was or where the exact binding sites were on Spike for some inhibitor candidates. The work of countless researchers has yielded great progress, with the identification of many viral entry inhibitors that target elements on the S1 receptor-binding domain (RBD) or N-terminal domain (NTD) and disrupt the S1 receptor-binding function. In this review, we will also focus on highlighting fusion inhibitors that target inhibition of the S2 fusion function, either by disrupting the formation of the postfusion S2 conformation or alternatively by stabilizing structural elements of the prefusion S2 conformation to prevent conformational changes associated with S2 function. We highlight experimentally validated binding sites on the S1/S2 interface and on the S2 subunit. While most substitutions to the Spike protein to date in variants of concern (VOCs) have been localized to the S1 subunit, the S2 subunit sequence is more conserved, with only a few observed substitutions in proximity to S2 binding sites. Several recent small molecules targeting S2 have been shown to have robust activity over recent VOC mutant strains and/or greater broad-spectrum antiviral activity for other more distantly related coronaviruses.47:T456,Immunization via the respiratory route is predicted to increase the effectiveness of a SARS-CoV-2 vaccine. Here, we evaluate the immunogenicity and protective efficacy of one or two doses of a live-attenuated murine pneumonia virus vector expressing SARS-CoV-2 prefusion-stabilized spike protein (MPV/S-2P), delivered intranasally/intratracheally to male rhesus macaques. A single dose of MPV/S-2P is highly immunogenic, and a second dose increases the magnitude and breadth of the mucosal and systemic anti-S antibody responses and increases levels of dimeric anti-S IgA in the airways. MPV/S-2P also induces S-specific CD4+ and CD8+ T-cells in the airways that differentiate into large populations of tissue-resident memory cells within a month after the boost. One dose induces substantial protection against SARS-CoV-2 challenge, and two doses of MPV/S-2P are fully protective against SARS-CoV-2 challenge virus replication in the airways. A prime/boost immunization with a mucosally-administered live-attenuated MPV vector could thus be highly effective in preventing SARS-CoV-2 infection and replication.48:T4ef,Messenger RNA (mRNA) vaccines were pivotal in reducing severe acute respiratory syndrome 2 (SARS-CoV-2) infection burden, yet they have not demonstrated robust durability, especially in older adults. Here, we describe a molecular adjuvant comprising a lipid nanoparticle (LNP)-encapsulated mRNA encoding interleukin-12p70 (IL-12p70). The bioactive adjuvant was engineered with a multiorgan protection (MOP) sequence to restrict transcript expression to the intramuscular injection site. Admixing IL-12-MOP (CTX-1796) with the BNT162b2 SARS-CoV-2 vaccine increased spike protein-specific immune responses in mice. Specifically, the benefits of IL-12-MOP adjuvantation included amplified humoral and cellular immunity and increased immune durability for 1 year after vaccination in mice. An additional benefit included the restoration of immunity in aged mice to amounts comparable to those achieved in young adult animals, alongside amplification with a single immunization. Associated enhanced dendritic cell and germinal center responses were observed. Together, these data demonstrate that an LNP-encapsulated IL-12-MOP mRNA-encoded adjuvant can amplify immunogenicity independent of age, demonstrating translational potential to benefit vulnerable populations.49:T468,The binding of viruses to host-entry factor receptors is an essential step for viral infection. Many studies have shown that macrophages can internalize viruses and degrade them in lysosomes for clearance in vivo. Inspired by these natural behaviors and using SARS-CoV-2 as a testbed, we harvest lysosomes from activated macrophages and anchor the protein-receptor ACE2 as bait, thus constructing a lysosomal "TRAP" (lysoTRAP) that selectively captures, internalizes, and eventually degrades SARS-CoV-2. Through experiments with cells, female mice, female hamsters, and human lung organoids, we demonstrate that lysoTRAP effectively clears SARS-CoV-2. Importantly, unlike therapeutic agents targeting SARS-CoV-2 spike protein, lysoTRAP remains effective against nine pseudotyped variants and the authentic Omicron variant, demonstrating its resistance to SARS-CoV-2 mutations. In addition to the protein-receptor ACE2, we also extend lysoTRAP with the saccharide-receptor sialic acid and verify its excellent antiviral effect against H1N1, highlighting the flexibility of our "TRAP" platform in fighting against various viruses.4a:T7d0,UNLABELLED: Porcine epidemic diarrhea (PED) has caused serious economic losses to the swine livestock industry. Due to the rapid variation in the PEDV) genome, especially the spike (S) protein, the cross-protection ability of antibodies between different vaccine strains is weakened. Hence, the rapid development of safe, broad-spectrum and highly effective attenuated PEDV vaccine still needs further research. Here, we found that the replacement of the S2 subunit had little effect on S protein immunogenicity. Moreover, the chimeric virus (YN-S2DR13), the S protein of the YN strain was replaced by the DR13 S2 subunit, which lost its trypsin tropism and increased its propagation ability (approximately 1 titer) in Vero cells. Then, the pathogenesis of YN-S2DR13 was evaluated in neonatal piglets. Importantly, quantitative real-time PCR, histopathology, and immunohistochemistry confirmed that the virulence of YN-S2DR13 was significantly reduced compared with that of YN. Immunization with YN-S2DR13 induced neutralizing antibodies against both YN and DR13 in weaned piglets. In vitro passaging data also showed that YN-S2DR13 had good genetic stability. Collectively, these results suggest that YN-S2DR13 has significant advantages as a novel vaccine candidate, including a capacity for viral propagation to high titers with no trypsin requirement and the potential to provide protection against both PEDV G1 and G2 strains infections. Our results also suggests that S2 subunit replacement using reverse genetics can be a rapid strategy for the rational design of live attenuated vaccines for PEDV. IMPORTANCE: Emerging highly virulent porcine epidemic diarrhea virus (PEDV) G2 strains has caused substantial economic losses worldwide. Vaccination with a live attenuated vaccine is a promising method to prevent and control PED because it can induce a strong immune response (including T- and B-cell immunity). Previous studies have demonstrated that the S2 subunit of the PEDV spike (S) prote4b:T449,The COVID-19 pandemic prompted rapid research on SARS-CoV-2 pathogenicity. Consequently, new data can be used to advance the molecular understanding of SARS-CoV-2 infection. The present bioinformatics study discusses the "spikeopathy" at the molecular level and focuses on the possible post-transcriptional regulation of the SARS-CoV-2 spike protein S1 subunit in the host cell/tissue. A theoretical protein-RNA recognition code was used to check the compatibility of the SARS-CoV-2 spike protein S1 subunit with mRNAs in the human transcriptome (1-L transcription). The principle for this method is elucidated on the defined RNA binding protein GEMIN5 (gem nuclear organelle-associated protein 5) and RNU2-1 (U2 spliceosomal RNA). Using the method described here, it was shown that 45% of the genes/proteins identified by 1-L transcription of the SARS-CoV-2 spike protein S1 subunit are directly linked to COVID-19, 39% are indirectly linked to COVID-19, and 16% cannot currently be associated with COVID-19. The identified genes/proteins are associated with stroke, diabetes, and cardiac injury.4c:T503,Atrial fibrillation (AF) is a comorbidity of a variety of other chronic, inflammatory diseases for which fibrinaloid microclots are a known accompaniment (and in some cases, a cause, with a mechanistic basis). Clots are, of course, a well-known consequence of atrial fibrillation. We here ask the question whether the fibrinaloid microclots seen in plasma or serum may in fact also be a cause of (or contributor to) the development of AF. We consider known 'risk factors' for AF, and in particular, exogenous stimuli such as infection and air pollution by particulates, both of which are known to cause AF. The external accompaniments of both bacterial (lipopolysaccharide and lipoteichoic acids) and viral (SARS-CoV-2 spike protein) infections are known to stimulate fibrinaloid microclots when added in vitro, and fibrinaloid microclots, as with other amyloid proteins, can be cytotoxic, both by inducing hypoxia/reperfusion and by other means. Strokes and thromboembolisms are also common consequences of AF. Consequently, taking a systems approach, we review the considerable evidence in detail, which leads us to suggest that it is likely that microclots may well have an aetiological role in the development of AF. This has significant mechanistic and therapeutic implications.4d:T6a7,The emergence of Omicron lineages and descendent subvariants continues to present a severe threat to the effectiveness of vaccines and therapeutic antibodies. We have previously suggested that an insufficient mucosal immunoglobulin A (IgA) response induced by the mRNA vaccines is associated with a surge in breakthrough infections. Here, we further show that the intramuscular mRNA and/or inactivated vaccines cannot sufficiently boost the mucosal secretory IgA response in uninfected individuals, particularly against the Omicron variant. We thus engineered and characterized recombinant monomeric, dimeric, and secretory IgA1 antibodies derived from four neutralizing IgG monoclonal antibodies (mAbs 01A05, rmAb23, DXP-604, and XG014) targeting the receptor-binding domain of the spike protein. Compared to their parental IgG antibodies, dimeric and secretory IgA1 antibodies showed a higher neutralizing activity against different variants of concern (VOCs), in part due to an increased avidity. Importantly, the dimeric or secretory IgA1 form of the DXP-604 antibody significantly outperformed its parental IgG antibody, and neutralized the Omicron lineages BA.1, BA.2, and BA.4/5 with a 25- to 75-fold increase in potency. In human angiotensin converting enzyme 2 (ACE2) transgenic mice, a single intranasal dose of the dimeric IgA DXP-604 conferred prophylactic and therapeutic protection against Omicron BA.5. Thus, dimeric or secretory IgA delivered by nasal administration may potentially be exploited for the treatment and prevention of Omicron infection, thereby providing an alternative tool for combating immune evasion by the current circulating subvariants and, potentially, future VOCs.4e:T7d0,Numerous vaccine candidates have emerged in the fight against SARS-CoV-2, yet the challenges posed by viral evolution and the evasion of vaccine-induced immunity persist. The development of broadly protective vaccines is essential in countering the threat posed by variants of concern (VoC) capable of eluding existing vaccine defenses. Among the diverse SARS-CoV-2 vaccine candidates, detailed characterization of those based on the expression of the entire spike protein in mammalian cells have been limited. In our study, we engineered a recombinant prefusion-stabilized trimeric spike protein antigen, IMT-CVAX, encoded by the IMT-C20 gene. This antigen was expressed utilizing a suspension mammalian cell line (CHO-S). The establishment of a stable cell line expressing IMT-CVAX involved the integration of the gene into the CHO genome, followed by the expression, purification, and characterization of the protein. To gauge the vaccine potential of adjuvanted IMT-CVAX, we conducted assessments in small animals. Analyses of blood collected from immunized animals included measurements of anti-spike IgG, SARS-CoV-2 neutralization, and responses from GC-B and Tfh cells. Furthermore, the protective efficacy of IMT-CVAX was evaluated using a Hamster challenge model. Our findings indicate that adjuvanted IMT-CVAX elicits an excellent immune response in both mice and hamsters. Notably, sera from animals immunized with IMT-CVAX effectively neutralize a diverse range of SARS-CoV-2 variants. Moreover, IMT-CVAX immunization conferred complete protection to hamsters against SARS-CoV-2 infection. In hACE2 transgenic mice, IMT-CVAX vaccination induced a robust response from GC-B and Tfh cells. Based on our preclinical model assessments, adjuvanted IMT-CVAX emerges as a highly efficacious vaccine candidate. This protein-subunit-based vaccine exhibits promise for clinical development, offering an affordable solution for both primary and heterologous immunization against SARS-CoV-2 variants.4f:T466,SARS-CoV-2 infection is associated with long-lasting neurological symptoms, although the underlying mechanisms remain unclear. Using optical clearing and imaging, we observed the accumulation of SARS-CoV-2 spike protein in the skull-meninges-brain axis of human COVID-19 patients, persisting long after viral clearance. Further, biomarkers of neurodegeneration were elevated in the cerebrospinal fluid from long COVID patients, and proteomic analysis of human skull, meninges, and brain samples revealed dysregulated inflammatory pathways and neurodegeneration-associated changes. Similar distribution patterns of the spike protein were observed in SARS-CoV-2-infected mice. Injection of spike protein alone was sufficient to induce neuroinflammation, proteome changes in the skull-meninges-brain axis, anxiety-like behavior, and exacerbated outcomes in mouse models of stroke and traumatic brain injury. Vaccination reduced but did not eliminate spike protein accumulation after infection in mice. Our findings suggest persistent spike protein at the brain borders may contribute to lasting neurological sequelae of COVID-19.50:T7db,UNLABELLED: SARS-CoV-2 infects both the upper and lower respiratory tracts, which are characterized by different temperatures (33°C and 37°C, respectively). In addition, fever is a common COVID-19 symptom. SARS-CoV-2 has been shown to replicate more efficiently at low temperatures, but the effect of temperature on different viral proteins remains poorly understood. Here, we investigate how temperature affects the SARS-CoV-2 spike function and evolution. We first observed that increasing temperature from 33°C to 37°C or 39°C increased spike-mediated cell-cell fusion. We then experimentally evolved a recombinant vesicular stomatitis virus expressing the SARS-CoV-2 spike at these different temperatures. We found that spike-mediated cell-cell fusion was maintained during evolution at 39°C but was lost in a high proportion of viruses that evolved at 33°C or 37°C. Consistently, sequencing of the spikes evolved at 33°C or 37°C revealed the accumulation of mutations around the furin cleavage site, a region that determines cell-cell fusion, whereas this did not occur in spikes evolved at 39°C. Finally, using site-directed mutagenesis, we found that disruption of the furin cleavage site had a temperature-dependent effect on spike-induced cell-cell fusion and viral fitness. Our results suggest that variations in body temperature may affect the activity and diversification of the SARS-CoV-2 spike. IMPORTANCE: When it infects humans, SARS-CoV-2 is exposed to different temperatures (e.g., replication site and fever). Temperature has been shown to strongly impact SARS-CoV-2 replication, but how it affects the activity and evolution of the spike protein remains poorly understood. Here, we first show that high temperatures increase the SARS-CoV-2 spike fusogenicity. Then, we demonstrate that the evolution of the spike activity and variants depends on temperature. Finally, we show that the functional effect of specific spike mutations is temperature-dependent. Overall, our results su51:T641,SARS-CoV-2 infection starts from the association of its spike 1 (S1) subunit with sensitive cells. Vesicular endothelial cells and platelets are among the cell types that bind SARS-CoV-2, but the effectors that mediate viral attachment on the cell membrane have not been fully elucidated. Herein, we show that P-selectin (SELP), a biomarker for endothelial dysfunction and platelet activation, can facilitate the attachment of SARS-CoV-2 S1. Since we observe colocalization of SELP with S1 in the lung tissues of COVID-19 patients, we perform molecular biology experiments on human umbilical vein endothelial cells (HUVECs) to confirm the intermolecular interaction between SELP and S1. SELP overexpression increases S1 recruitment to HUVECs and enhances SARS-CoV-2 spike pseudovirion infection. The opposite results are determined after SELP downregulation. As S1 causes endothelial inflammatory responses in a dose-dependent manner, by activating the interleukin (IL)-17 signaling pathway, SELP-induced S1 recruitment may contribute to the development of a "cytokine storm" after viral infection. Furthermore, SELP also promotes the attachment of S1 to the platelet membrane. Employment of PSI-697, a small inhibitor of SELP, markedly decreases S1 adhesion to both HUVECs and platelets. In addition to the role of membrane SELP in facilitating S1 attachment, we also discover that soluble SELP is a prognostic factor for severe COVID-19 through a meta-analysis. In this study, we identify SELP as an adhesive site for the SARS-CoV-2 S1, thus providing a potential drug target for COVID-19 treatment.52:T526,Studies on severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) have highlighted the crucial role of host proteases for viral replication and the immune response. The serine proteases furin and TMPRSS2 and lysosomal cysteine proteases facilitate viral entry by limited proteolytic processing of the spike (S) protein. While neutrophils are recruited to the lungs during COVID-19 pneumonia, little is known about the role of the neutrophil serine proteases (NSPs) cathepsin G (CatG), elastase (NE), and proteinase 3 (PR3) on SARS-CoV-2 entry and replication. Furthermore, the current paradigm is that NSPs may contribute to the pathogenesis of severe COVID-19. Here, we show that these proteases cleaved the S protein at multiple sites and abrogated viral entry and replication in vitro. In mouse models, CatG significantly inhibited viral replication in the lung. Importantly, lung inflammation and pathology were increased in mice deficient in NE and/or CatG. These results reveal that NSPs contribute to innate defenses against SARS-CoV-2 infection via proteolytic inactivation of the S protein and that NE and CatG limit lung inflammation in vivo. We conclude that therapeutic interventions aiming to reduce the activity of NSPs may interfere with viral clearance and inflammation in COVID-19 patients.53:T4e6,The continued emergence of deadly human coronaviruses from animal reservoirs highlights the need for pan-coronavirus interventions for effective pandemic preparedness. Here, using linking B cell receptor to antigen specificity through sequencing (LIBRA-seq), we report a panel of 50 coronavirus antibodies isolated from human B cells. Of these, 54043-5 was shown to bind the S2 subunit of spike proteins from alpha-, beta-, and deltacoronaviruses. A cryoelectron microscopy (cryo-EM) structure of 54043-5 bound to the prefusion S2 subunit of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike defined an epitope at the apex of S2 that is highly conserved among betacoronaviruses. Although non-neutralizing, 54043-5 induced Fc-dependent antiviral responses in vitro, including antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). In murine SARS-CoV-2 challenge studies, protection against disease was observed after introduction of Leu234Ala, Leu235Ala, and Pro329Gly (LALA-PG) substitutions in the Fc region of 54043-5. Together, these data provide new insights into the protective mechanisms of non-neutralizing antibodies and define a broadly conserved epitope within the S2 subunit.54:T466,Predicting the immunogenicity of candidate vaccines in humans remains a challenge. To address this issue, we developed a lymphoid organ-chip (LO chip) model based on a microfluidic chip seeded with human PBMC at high density within a 3D collagen matrix. Perfusion of the SARS-CoV-2 spike protein mimicked a vaccine boost by inducing a massive amplification of spike-specific memory B cells, plasmablast differentiation, and spike-specific antibody secretion. Features of lymphoid tissue, including the formation of activated CD4+ T cell/B cell clusters and the emigration of matured plasmablasts, were recapitulated in the LO chip. Importantly, myeloid cells were competent at capturing and expressing mRNA vectored by lipid nanoparticles, enabling the assessment of responses to mRNA vaccines. Comparison of on-chip responses to Wuhan monovalent and Wuhan/Omicron bivalent mRNA vaccine boosts showed equivalent induction of Omicron neutralizing antibodies, pointing at immune imprinting as reported in vivo. The LO chip thus represents a versatile platform suited to the preclinical evaluation of vaccine-boosting strategies.55:T743,Increased use of antiviral monoclonal antibodies (mAbs) for treatment and prophylaxis necessitates better understanding of their impact on endogenous immunity to vaccines and viruses. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic presented an opportunity to study immunity in individuals who received antiviral mAbs and were subsequently immunized with vaccines encoding the mAb-targeted viral spike antigen. Here, we describe the impact of administration of an antibody combination, casirivimab plus imdevimab (CAS+IMD), on immune responses to subsequent SARS-CoV-2 vaccination in humans, nonhuman primates, and mice. The presence of CAS+IMD at the time of vaccination led to a specific diminishment of vaccine-elicited pseudovirus neutralizing antibody titers without overall dampening of spike protein-directed immune responses, including antibody, B cell, and T cell responses. The impact on pseudovirus neutralizing titers extended to other therapeutic anti-spike protein antibodies when used as either monotherapy or combination therapy. The specific reduction in pseudovirus neutralizing titers was the result of epitope masking, a phenomenon where specific epitopes are bound by high-affinity antibodies and blocked from B cell recognition. Encouragingly, this reduction in pseudovirus neutralizing titers was reversible with additional booster vaccination. Moreover, by assessing the antiviral immune response in SARS-CoV-2-infected individuals treated therapeutically with CAS+IMD, we demonstrated alteration of antiviral humoral immunity in those who had received mAb therapy, but only in those individuals who had yet to start mounting their natural immune response at the time of mAb treatment. Together, these data demonstrate that antiviral mAbs can alter endogenous humoral immunity during vaccination or infection.56:T5b6,The world-wide COVID-19 pandemic has promoted a series of alternative vaccination strategies aiming to elicit neutralizing adaptive immunity in the human host. However, restricted efficacies of these vaccines targeting epitopes on the spike (S) protein that is involved in primary viral entry were observed and putatively assigned to viral glycosylation as an effective escape mechanism. Besides the well-recognized N-glycan shield covering SARS-CoV-2 spike (S) proteins, immunization strategies may be hampered by heavy O-glycosylation and variable O-glycosites fluctuating depending on the organ sites of primary infection and those involved in immunization. A further complication associated with viral glycosylation arises from the development of autoimmune antibodies to self-carbohydrates, including O-linked blood group antigens, as structural parts of viral proteins. This outline already emphasizes the importance of viral glycosylation in general and, in particular, highlights the impact of the site-specific O-glycosylation of virions, since this modification is independent of sequons and varies strongly in dependence on cell-specific repertoires of peptidyl-N-acetylgalactosaminyltransferases with their varying site preferences and of glycan core-specific glycosyltransferases. This review summarizes the current knowledge on the viral O-glycosylation of the SARS-CoV-2 spike protein and its impact on virulence and immune modulation in the host.57:T6e0,The mechanisms of postacute medical conditions and unexplained symptoms after SARS-CoV-2 infection [Long Covid (LC)] are incompletely understood. There is growing evidence that viral persistence, immune dysregulation, and T cell dysfunction may play major roles. We performed whole-body positron emission tomography imaging in a well-characterized cohort of 24 participants at time points ranging from 27 to 910 days after acute SARS-CoV-2 infection using the radiopharmaceutical agent [18F]F-AraG, a selective tracer that allows for anatomical quantitation of activated T lymphocytes. Tracer uptake in the postacute COVID-19 group, which included those with and without continuing symptoms, was higher compared with prepandemic controls in many regions, including the brain stem, spinal cord, bone marrow, nasopharyngeal and hilar lymphoid tissue, cardiopulmonary tissues, and gut wall. T cell activation in the spinal cord and gut wall was associated with the presence of LC symptoms. In addition, tracer uptake in lung tissue was higher in those with persistent pulmonary symptoms specifically. Increased T cell activation in these tissues was also observed in many individuals without LC. Given the high [18F]F-AraG uptake detected in the gut, we obtained colorectal tissue for in situ hybridization of SARS-CoV-2 RNA and immunohistochemical studies in a subset of five participants with LC symptoms. We identified intracellular SARS-CoV-2 single-stranded spike protein-encoding RNA in rectosigmoid lamina propria tissue in all five participants and double-stranded spike protein-encoding RNA in three participants up to 676 days after initial COVID-19, suggesting that tissue viral persistence could be associated with long-term immunologic perturbations.58:T7d2,Patients with long COVID syndrome present with various symptoms affecting multiple organs. Vaccination before or after SARS-CoV-2 infection appears to reduce the incidence of long COVID or at least limit symptom deterioration. However, the impact of vaccination on the severity and extent of multi-organ long COVID symptoms and the relationship between the circulating anti-spike protein antibody levels and the severity and extent of multi-organ symptoms are unclear. This prospective cohort study included 198 patients with previous PCR-verified SARS-CoV-2 infection who met the criteria for long COVID syndrome. Patients were divided into vaccinated (n = 138, 69.7%) or unvaccinated (n = 60, 30.3%) groups. Anti-spike protein antibody levels were determined at initial clinical presentation and compared between the groups. Long COVID symptoms were quantified on the basis of the number of affected organs: Class I (mild) with symptoms in three organs, Class II (moderate) with symptoms in four to five organs, and Class III (severe) with symptoms in six or more organ systems. Associations between time to infection and vaccination with anti-spike protein antibody levels were assessed. The anti-spike protein antibody levels were 1925 ± 938 vs. 481 ± 768 BAU/mL (p < 0.001) in the vaccinated vs. unvaccinated patients. The circulating anti-spike antibody cutoff of 665.5 BAU/mL allowed us to differentiate the vaccinated from the unvaccinated patients. Vaccinated patients had fewer class II and class III multi-organ symptoms (Class II 39.9% vs. 45.0%; Class III 10.1% vs. 23.3%, p-value 0.014). Anti-spike antibody level correlated negatively with multi-organ symptom classes (p = 0.016; 95% CI -1.229 to -0.126). Anti-spike antibody levels in unvaccinated patients declined markedly with time, in contrast to the persistence of high anti-spike antibody levels in the vaccinated patients. Multi-organ symptoms were lower in vaccinated long-COVID patients, especially in those with higher anti-59:T7d4,According to the CDC, both Pfizer and Moderna COVID-19 vaccines contain nucleoside-modified messenger RNA (mRNA) encoding the viral spike glycoprotein of severe acute respiratory syndrome caused by corona virus (SARS-CoV-2), administered via intramuscular injections. Despite their worldwide use, very little is known about how nucleoside modifications in mRNA sequences affect their breakdown, transcription and protein synthesis. It was hoped that resident and circulating immune cells attracted to the injection site make copies of the spike protein while the injected mRNA degrades within a few days. It was also originally estimated that recombinant spike proteins generated by mRNA vaccines would persist in the body for a few weeks. In reality, clinical studies now report that modified SARS-CoV-2 mRNA routinely persist up to a month from injection and can be detected in cardiac and skeletal muscle at sites of inflammation and fibrosis, while the recombinant spike protein may persist a little over half a year in blood. Vaccination with 1-methylΨ (pseudouridine enriched) mRNA can elicit cellular immunity to peptide antigens produced by +1 ribosomal frameshifting in major histocompatibility complex-diverse people. The translation of 1-methylΨ mRNA using liquid chromatography tandem mass spectrometry identified nine peptides derived from the mRNA +1 frame. These products impact on off-target host T cell immunity that include increased production of new B cell antigens with far reaching clinical consequences. As an example, a highly significant increase in heart muscle 18-flourodeoxyglucose uptake was detected in vaccinated patients up to half a year (180 days). This review article focuses on medical biochemistry, proteomics and deutenomics principles that explain the persisting spike phenomenon in circulation with organ-related functional damage even in asymptomatic individuals. Proline and hydroxyproline residues emerge as prominent deuterium (heavy hydrogen) binding site5a:T45e,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and mRNA vaccination induce robust CD4+ T cell responses. Using single-cell transcriptomics, here, we evaluated CD4+ T cells specific for the SARS-CoV-2 spike protein in the blood and draining lymph nodes (dLNs) of individuals 3 months and 6 months after vaccination with the BNT162b2 mRNA vaccine. We analyzed 1,277 spike-specific CD4+ T cells, including 238 defined using Trex, a deep learning-based reverse epitope mapping method to predict antigen specificity. Human dLN spike-specific CD4+ follicular helper T (TFH) cells exhibited heterogeneous phenotypes, including germinal center CD4+ TFH cells and CD4+IL-10+ TFH cells. Analysis of an independent cohort of SARS-CoV-2-infected individuals 3 months and 6 months after infection found spike-specific CD4+ T cell profiles in blood that were distinct from those detected in blood 3 months and 6 months after BNT162b2 vaccination. Our findings provide an atlas of human spike-specific CD4+ T cell transcriptional phenotypes in the dLNs and blood following SARS-CoV-2 vaccination or infection.5b:T7a6,mRNA-based COVID-19 vaccines have played a critical role in reducing severe outcomes of COVID-19. Humoral immune responses against SARS-CoV-2 after vaccination have been extensively studied in blood; however, limited information is available on the presence and duration of SARS-CoV-2 specific antibodies in saliva and other mucosal fluids. Saliva offers a non-invasive sampling method that may also provide a better understanding of mucosal immunity at sites where the virus enters the body. Our objective was to evaluate the salivary immune response after vaccination with the COVID-19 Moderna mRNA-1273 vaccine. Two hundred three staff members of the U.S. Centers for Disease Control and Prevention were enrolled prior to receiving their first dose of the mRNA-1273 vaccine. Participants were asked to self-collect 6 saliva specimens at days 0 (prior to first dose), 14, 28 (prior to second dose), 42, and 56 using a SalivaBio saliva collection device. Saliva specimens were tested for anti-spike protein SARS-CoV-2 specific IgA and IgG enzyme immunoassays. Overall, SARS-CoV-2-specific salivary IgA titers peaked 2 weeks after each vaccine dose, followed by a sharp decrease during the following weeks. In contrast to IgA titers, IgG antibody titers increased substantially 2 weeks after the first vaccine dose, peaked 2 weeks after the second dose and persisted at an elevated level until at least 8 weeks after the first vaccine dose. Additionally, no significant differences in IgA/IgG titers were observed based on age, sex, or race/ethnicity. All participants mounted salivary IgA and IgG immune responses against SARS-CoV-2 after receiving the mRNA-1273 COVID-19 vaccine. Because of the limited follow-up time for this study, more data are needed to assess the antibody levels beyond 2 months after the first dose. Our results confirm the potential utility of saliva in assessing immune responses elicited by immunization and possibly by infection.5c:T7ee,The Editor in Chief and the Publisher are issuing an expression of concern to alert readers to the fact that the Special Issue titled "Omics sciences in the personalization of diagnosis and therapy" and, in particular, the following articles: ·      J. Kaftalli, K. Donato, G. Bonetti, K. Dhuli, A. Macchia, P.E. Maltese, K. Louise Herbst, S. Michelini, P. Chiurazzi, M. Hill, S. Michelini, S. Michelini, G. Marceddu, A. Bernini, M. Bertelli. Aldo-keto reductase 1C2 (AKR1C2) as the second gene associated to non-syndromic primary lipedema: investigating activating mutation or overexpression as causative factors. Eur Rev Med Pharmacol Sci 2023; 27 (6 Suppl): 127-136. DOI: 10.26355/eurrev_202312_34697-PMID: 38112953. ·      M.C. Medori, K. Donato, L. Stuppia, T. Beccari, M. Dundar, R.S. Marks, S. Michelini, E. Borghetti, C. Zuccato, L. Seppilli, H. Elsangak, G. Sozanski, D. Malacarne, M. Bertelli. Achievement of sustainable development goals through the Mediterranean diet. Eur Rev Med Pharmacol Sci 2023; 27 (6 Suppl): 89-99. DOI: 10.26355/eurrev_202312_34693-PMID: 38112950. ·      K. Donato, M.C. Medori, A. Macchia, S. Cecchin, M.R. Ceccarini, T. Beccari, V. Gatta, L. Stuppia, V. Benfatti, L. Dalla Ragione, P. Chiurazzi C. Micheletti, K. Dhuli, G. Madeo, G. Bonetti, G. Marceddu, M. Bertelli. Genetic variants identified in novel candidate genes for anorexia nervosa and analysis of molecular pathways for diagnostic applications. Eur Rev Med Pharmacol Sci 2023; 27 (6 Suppl): 77-88. DOI: 10.26355/eurrev_202312_34692-PMID: 38112957. ·      K. Donato, K. Dhuli, A. Macchia, M.C. Medori, C. Micheletti, G. Bonetti, M.R. Ceccarini, T. Beccari, P. Chiurazzi, S. Cristoni, V. Benfatti, L. Dalla Ragione, M. Bertelli. Metabolomic profiling of amino acid alterations in anorexia nervosa: implications for appetite regulation and therapeutic strategies. Eur Rev Med Pharmacol Sci 2023; 27 (6 Suppl): 64-76. DOI: 10.26355/eurrev_202312_34691-PMID: 38112949. ·      M.R. Ceccarini, M.C. Medori, K5d:T4ca,Up to 25% of individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibit postacute cognitive sequelae. Although millions of cases of coronavirus disease 2019 (COVID-19)-mediated memory dysfunction are accumulating worldwide, the underlying mechanisms and how vaccination lowers risk are unknown. Interleukin-1 (IL-1), a key component of innate immune defense against SARS-CoV-2 infection, is elevated in the hippocampi of individuals with COVID-19. Here we show that intranasal infection of C57BL/6J mice with SARS-CoV-2 Beta variant leads to central nervous system infiltration of Ly6Chi monocytes and microglial activation. Accordingly, SARS-CoV-2, but not H1N1 influenza virus, increases levels of brain IL-1β and induces persistent IL-1R1-mediated loss of hippocampal neurogenesis, which promotes postacute cognitive deficits. Vaccination with a low dose of adenoviral-vectored spike protein prevents hippocampal production of IL-1β during breakthrough SARS-CoV-2 infection, loss of neurogenesis and subsequent memory deficits. Our study identifies IL-1β as one potential mechanism driving SARS-CoV-2-induced cognitive impairment in a new mouse model that is prevented by vaccination.5e:T614,Adenovirus vaccines, particularly the COVID-19 Ad5-nCoV adenovirus vaccine, have emerged as promising tools in the fight against infectious diseases. In this study, we investigated the structure of the T cell response to the Spike protein of the SARS-CoV-2 virus used in the COVID-19 Ad5-nCoV adenoviral vaccine in a phase 3 clinical trial (NCT04540419). In 69 participants, we collected peripheral blood samples at four time points after vaccination or placebo injection. Sequencing of T cell receptor repertoires from Spike-stimulated T cell cultures at day 14 from 17 vaccinated revealed a more diverse CD4+ T cell repertoire compared to CD8+. Nevertheless, CD8+ clonotypes accounted for more than half of the Spike-specific repertoire. Our longitudinal analysis showed a peak T cell response at day 14, followed by a decline until month 6. Remarkably, multiple T cell clonotypes persisted for at least 6 months after vaccination, as demonstrated by ex vivo stimulation. Examination of CDR3 regions revealed homologous sequences in both CD4+ and CD8+ clonotypes, with major CD8+ clonotypes sharing high similarity with annotated sequences specific for the NYNYLYRLF peptide, suggesting potential immunodominance. In conclusion, our study demonstrates the immunogenicity of the Ad5-nCoV adenoviral vaccine and highlights its ability to induce robust and durable T cell responses. These findings provide valuable insight into the efficacy of the vaccine against COVID-19 and provide critical information for ongoing efforts to control infectious diseases.5f:T6a9,The rapid development and authorization of messenger ribonucleic acid (mRNA) vaccines by Pfizer-BioNTech (BNT162b2) and Moderna (mRNA-1273) in 2020 marked a significant milestone in human mRNA product application, overcoming previous obstacles such as mRNA instability and immunogenicity. This paper reviews the strategic modifications incorporated into these vaccines to enhance mRNA stability and translation efficiency, such as the inclusion of nucleoside modifications and optimized mRNA design elements including the 5' cap and poly(A) tail. We highlight emerging concerns regarding the wide systemic biodistribution of these mRNA vaccines leading to prolonged inflammatory responses and other safety concerns. The regulatory framework guiding the biodistribution studies is pivotal in assessing the safety profiles of new mRNA formulations in use today. The stability of mRNA vaccines, their pervasive distribution, and the longevity of the encapsulated mRNA along with unlimited production of the damaging and potentially lethal spike (S) protein call for strategies to mitigate potential adverse effects. Here, we explore the potential of small interfering RNA (siRNA) and ribonuclease targeting chimeras (RIBOTACs) as promising solutions to target, inactivate, and degrade residual and persistent vaccine mRNA, thereby potentially preventing uncontrolled S protein production and reducing toxicity. The targeted nature of siRNA and RIBOTACs allows for precise intervention, offering a path to prevent and mitigate adverse events of mRNA-based therapies. This review calls for further research into siRNA and RIBOTAC applications as antidotes and detoxication products for mRNA vaccine technology.60:T4ff,Despite the success of global vaccination programs in slowing the spread of COVID-19, these efforts have been hindered by the emergence of new SARS-CoV-2 strains capable of evading prior immunity. The mutation and evolution of SARS-CoV-2 have created a demand for persistent efforts in vaccine development. SARS-CoV-2 Spike protein has been the primary target for COVID-19 vaccine development, but it is also the hotspot of mutations directly involved in host susceptibility and virus immune evasion. Our ability to predict emerging mutants and select conserved epitopes is critical for the development of a broadly neutralizing therapy or a universal vaccine. In this article, we review the general paradigm of immune responses to COVID-19 vaccines, highlighting the immunological epitopes of Spike protein that are likely associated with eliciting protective immunity resulting from vaccination in humans. Specifically, we analyze the structural and evolutionary characteristics of the SARS-CoV-2 Spike protein related to immune activation and function via the TLRs, B cells, and T cells. We aim to provide a comprehensive analysis of immune epitopes of Spike protein, thereby contributing to the development of new strategies for broad neutralization or universal vaccination.61:T753,SARS-CoV-2 spike protein (SARS-2-S) induced cell-cell fusion in uninfected cells may occur in long COVID-19 syndrome, as circulating SARS-2-S or extracellular vesicles containing SARS-2-S (S-EVs) were found to be prevalent in post-acute sequelae of COVID-19 (PASC) for up to 12 months after diagnosis. Although isolated recombinant SARS-2-S protein has been shown to increase the SASP in senescent ACE2-expressing cells, the direct linkage of SARS-2-S syncytia with senescence in the absence of virus infection and the degree to which SARS-2-S syncytia affect pathology in the setting of cardiac dysfunction are unknown. Here, we found that the senescent outcome of SARS-2-S induced syncytia exacerbated heart failure progression. We first demonstrated that syncytium formation in cells expressing SARS-2-S delivered by DNA plasmid or LNP-mRNA exhibits a senescence-like phenotype. Extracellular vesicles containing SARS-2-S (S-EVs) also confer a potent ability to form senescent syncytia without de novo synthesis of SARS-2-S. However, it is important to note that currently approved COVID-19 mRNA vaccines do not induce syncytium formation or cellular senescence. Mechanistically, SARS-2-S syncytia provoke the formation of functional MAVS aggregates, which regulate the senescence fate of SARS-2-S syncytia by TNFα. We further demonstrate that senescent SARS-2-S syncytia exhibit shrinked morphology, leading to the activation of WNK1 and impaired cardiac metabolism. In pre-existing heart failure mice, the WNK1 inhibitor WNK463, anti-syncytial drug niclosamide, and senolytic dasatinib protect the heart from exacerbated heart failure triggered by SARS-2-S. Our findings thus suggest a potential mechanism for COVID-19-mediated cardiac pathology and recommend the application of WNK1 inhibitor for therapy especially in individuals with post-acute sequelae of COVID-19.62:T7d0,BACKGROUND: Post-acute COVID-19 syndrome (long COVID) refers to the persistence of COVID-19 symptoms or exceptional symptoms following recovery. Even without conferring fatality, it represents a significant global public health burden. Despite many reports on long COVID, the prevalence and data on associated biological factors remain unclear and limited. This research aimed to determine the prevalence of long COVID during the two distinct epidemic periods in Thailand, due to the Delta and Omicron variants of SARS-CoV-2, and to investigate the biological factors associated with long COVID. In addition, the spike protein amino acid sequences of the Delta and Omicron variants were compared to determine the frequency of mutations and their potential biological implications. METHODS: A retrospective cross-sectional study was established to recruit confirmed COVID-19 participants at Maharat Nakhon Ratchasima Hospital who had recovered for at least three months and were infected between June 2021 and August 2022. The demographic data and long COVID experience were collected via telephone interview. The biological factors were analyzed through binary logistic regression. The datasets of the SARS-CoV-2 spike protein amino acid sequence of the Delta and Omicron variants in Thailand were retrieved from GIDSAID to determine mutation frequencies and to identify possible roles of the mutations based on published data. RESULTS: Data was collected from a total of 247 participants comprising 106 and 141 participants of the Delta and Omicron epidemic periods, respectively. Apart from the COVID-19 severity and health status, the baseline participant data of the two time periods were remarkably similar. The prevalence of long COVID observed in the Omicron period was higher than in the Delta period (74.5% vs. 66.0%). The biological factors associated with long COVID were epidemic variant, age, treatment with symptomatic medicines, and vaccination status. When the spike protein sequence 63:T4fe,OBJECTIVE: Long COVID is a major health concern because many patients develop chronic neuropsychiatric symptoms, but the precise pathogenesis is unknown. Matrix metalloproteinase-9 (MMP-9) can disrupt neuronal connectivity and be elevated in patients with long COVID. METHODS: In this study, MMP-9 was measured in the serum of long COVID patients and healthy controls, as well as in the supernatant fluid of cultured human microglia cell line stimulated by recombinant severe acute respiratory syndrome coronavirus 2 Spike protein, as well as lipopolysaccharide (LPS) and neurotensin (NT) used as positive controls. MMP-9 was measured by commercial enzyme-linked immunosorbent assay. RESULTS: MMP-9 was significantly elevated in the serum of long COVID patients compared to healthy controls. Moreover, there was significant release of MMP-9 from a cultured human microglia cell line stimulated by LPS, NT, or Spike protein. We further show that pretreatment with the flavonoids luteolin and tetramethoxyluteolin (methlut) significantly inhibited the release of MMP-9 stimulated by the Spike protein. CONCLUSION: MMP-9 from Spike protein-stimulated microglia could contribute to the development of long COVID and may serve as a target for treatment including the use of luteolin.64:T636,There is growing evidence that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contaminates the marine environment and is bioaccumulated in filter-feeding shellfish. Previous study shows the Pacific oyster tissues can bioaccumulate the SARS-CoV-2, and the oyster heat shock protein 70 (oHSP70) may play as the primary attachment receptor to bind SARS-CoV-2's recombinant spike protein S1 subunit (rS1). However, detailed information about the interaction between rS1 and oHSP70 is still unknown. In this study, we confirmed that the affinity of recombinant oHSP70 (roHSP70) for rS1 (KD = 20.4 nM) is comparable to the receptor-binding affinity of rACE2 for rS1 (KD = 16.7 nM) by surface plasmon resonance (SPR)-based Biacore and further validated by enzyme-linked immunosorbent assay (ELISA). Three truncated proteins (roHSP70-N/C/M) and five mutated proteins (p.I229del, p.D457del, p.V491_K495del, p.K556I, and p.ΣroHSP70) were constructed according to the molecular docking results. All three truncated proteins have significantly lower affinity for rS1 than the full-length roHSP70, indicating that all three segments of roHSP70 are involved in binding to rS1. Further, the results of SPR and ELISA showed that all five mutant proteins had significantly lower affinity for rS1 than roHSP70, suggesting that amino acids at these sites are involved in binding to rS1. This study provides a preliminary theoretical basis for the bioaccumulation of SARS-CoV-2 in oyster tissues or using roHSP70 as the capture unit to selectively enrich virus particles for detection.65:T4c5,The global coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has devastated public health and the global economy. New variants are continually emerging because of amino acid mutations within the SARS-CoV-2 spike protein. Existing neutralizing antibodies (nAbs) that target the receptor-binding domain (RBD) within the spike protein have been shown to have reduced neutralizing activity against these variants. In particular, the recently expanding omicron subvariants BQ 1.1 and XBB are resistant to nAbs approved for emergency use by the United States Food and Drug Administration. Therefore, it is essential to develop broad nAbs to combat emerging variants. In contrast to the massive accumulation of mutations within the RBD, the S2 subunit remains highly conserved among variants. Therefore, nAbs targeting the S2 region may provide effective cross-protection against novel SARS-CoV-2 variants. Here, we provide a detailed summary of nAbs targeting the S2 subunit: the fusion peptide, stem helix, and heptad repeats 1 and 2. In addition, we provide prospects to solve problems such as the weak neutralizing potency of nAbs targeting the S2 subunit.66:T62c,Life-threatening thrombotic events and neurological symptoms are prevalent in COVID-19 and are persistent in patients with long COVID experiencing post-acute sequelae of SARS-CoV-2 infection1-4. Despite the clinical evidence1,5-7, the underlying mechanisms of coagulopathy in COVID-19 and its consequences in inflammation and neuropathology remain poorly understood and treatment options are insufficient. Fibrinogen, the central structural component of blood clots, is abundantly deposited in the lungs and brains of patients with COVID-19, correlates with disease severity and is a predictive biomarker for post-COVID-19 cognitive deficits1,5,8-10. Here we show that fibrin binds to the SARS-CoV-2 spike protein, forming proinflammatory blood clots that drive systemic thromboinflammation and neuropathology in COVID-19. Fibrin, acting through its inflammatory domain, is required for oxidative stress and macrophage activation in the lungs, whereas it suppresses natural killer cells, after SARS-CoV-2 infection. Fibrin promotes neuroinflammation and neuronal loss after infection, as well as innate immune activation in the brain and lungs independently of active infection. A monoclonal antibody targeting the inflammatory fibrin domain provides protection from microglial activation and neuronal injury, as well as from thromboinflammation in the lung after infection. Thus, fibrin drives inflammation and neuropathology in SARS-CoV-2 infection, and fibrin-targeting immunotherapy may represent a therapeutic intervention for patients with acute COVID-19 and long COVID.67:T46a,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Host cell invasion is mediated by the interaction of the viral spike protein (S) with human angiotensin-converting enzyme 2 (ACE2) through the receptor-binding domain (RBD). In this work, bio-layer interferometry (BLI) was used to screen a series of fifty-two peroxides, including aminoperoxides and bridged 1,2,4 - trioxolanes (ozonides), with the aim of identifying small molecules that interfere with the RBD-ACE2 interaction. We found that two compounds, compound 21 and 29, exhibit the activity to inhibit RBD-ACE2. They are further demonstrated to inhibit SARS-CoV-2 cell entry, as shown in pseudovirus assay and experiment with authentic SARS-CoV-2. A comprehensive in silico analysis was carried out to study the physicochemical and pharmacokinetic properties, revealing that both compounds have good physicochemical properties as well as good bioavailability. Our results highlight the potential of small molecules targeting RBD inhibitors as potential therapeutic drugs for COVID-19.68:T509,The persistence or emergence of long-term symptoms following resolution of primary SARS-CoV-2 infection is referred to as long COVID or post-acute sequelae of COVID-19 (PASC). PASC predominantly affects the cardiovascular, neurological, respiratory, gastrointestinal, reproductive, and immune systems. Among these, the central nervous system (CNS) is significantly impacted, leading to a spectrum of symptoms, including fatigue, headaches, brain fog, cognitive impairment, anosmia, hypogeusia, neuropsychiatric symptoms, and peripheral neuropathy (neuro-PASC). However, the risk factors and pathogenic mechanisms responsible for neuro-PASC remain unclear. This review hypothesis discusses the leading hypotheses regarding the pathophysiological mechanisms involved in long COVID/PASC, focusing on neuro-PASC. We propose vascular dysfunction mediated by activation of astrocytes and pericytes followed by blood-brain barrier (BBB) disruption as underlying pathophysiological mechanisms of neurological manifestations. Additionally, we provide insights into the role of spike protein at the blood-brain interface. Finally, we explore the potential pathogenic mechanisms initiated by the interaction between the spike protein and cellular receptors at the brain endothelial and tissue levels.69:T601,Long COVID is a major public health consequence of COVID-19 and is characterized by multiple neurological and neuropsychatric symptoms. SARS-CoV-2 antigens (e.g., spike S1 subunit) are found in the circulation of Long COVID patients, have been detected in post-mortem brain of COVID patients, and exhibit neuroinflammatory properties. Considering recent observations of chronic neuroinflammation in Long COVID patients, the present study explores the idea that antigens derived from SARS-CoV-2 might produce a long-term priming or sensitization of neuroinflammatory processes, thereby potentiating the magnitude and/or duration of the neuroinflammatory response to future inflammatory insults. Rats were administered S1 or vehicle intra-cisterna magna and 7d later challenged with vehicle or LPS. The neuroinflammatory, physiological, and behavioral responses to LPS were measured at various time points post-LPS. We found that prior S1 treatment potentiated many of these responses to LPS suggesting that S1 produces a protracted priming of these processes. Further, S1 produced a protracted reduction in basal brain corticosteroids. Considering the anti-inflammatory properties of corticosteroids, these findings suggest that S1 might disinhibit innate immune processes in brain by reducing anti-inflammatory drive, thereby priming neuroinflammatory processes. Given that hypocortisolism is observed in Long COVID, we propose that similar S1-induced innate immune priming processes might play role in the pathophysiology of Long COVID.6a:T7d6,OBJECTIVES: To determine the proportion of individuals with detectable antigen in plasma or serum after SARS-CoV-2 infection and the association of antigen detection with postacute sequelae of COVID-19 (PASC) symptoms. METHODS: Plasma and serum samples were collected from adults participating in four independent studies at different time points, ranging from several days up to 14 months post-SARS-CoV-2 infection. The primary outcome measure was to quantify SARS-CoV-2 antigens, including the S1 subunit of spike, full-length spike, and nucleocapsid, in participant samples. The presence of 34 commonly reported PASC symptoms during the postacute period was determined from participant surveys or chart reviews of electronic health records. RESULTS: Of the 1569 samples analysed from 706 individuals infected with SARS-CoV-2, 21% (95% CI, 18-24%) were positive for either S1, spike, or nucleocapsid. Spike was predominantly detected, and the highest proportion of samples was spike positive (20%; 95% CI, 18-22%) between 4 and 7 months postinfection. In total, 578 participants (82%) reported at least one of the 34 PASC symptoms included in our analysis ≥1 month postinfection. Cardiopulmonary, musculoskeletal, and neurologic symptoms had the highest reported prevalence in over half of all participants, and among those participants, 43% (95% CI, 40-45%) on average were antigen-positive. Among the participants who reported no ongoing symptoms (128, 18%), antigen was detected in 28 participants (21%). The presence of antigen was associated with the presence of one or more PASC symptoms, adjusting for sex, age, time postinfection, and cohort (OR, 1.8; 95% CI, 1.4-2.2). DISCUSSION: The findings of this multicohort study indicate that SARS-CoV-2 antigens can be detected in the blood of a substantial proportion of individuals up to 14 months after infection. While approximately one in five asymptomatic individuals was antigen-positive, roughly half of all individuals reporting ongoing c6b:T555,Novel coronavirus disease 2019 (COVID-19), a respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has brought an unprecedented public health crisis and continues to threaten humanity due to the persistent emergence of new variants. Therefore, developing more effective and broad-spectrum therapeutic and prophylactic drugs against infection by SARS-CoV-2 and its variants, as well as future emerging CoVs, is urgently needed. In this study, we screened several US FDA-approved drugs and identified phenothiazine derivatives with the ability to potently inhibit the infection of pseudotyped SARS-CoV-2 and distinct variants of concern (VOCs), including B.1.617.2 (Delta) and currently circulating Omicron sublineages XBB and BQ.1.1, as well as pseudotyped SARS-CoV and MERS-CoV. Mechanistic studies suggested that phenothiazines predominantly inhibited SARS-CoV-2 pseudovirus (PsV) infection at the early stage and potentially bound to the spike (S) protein of SARS-CoV-2, which may prevent the proteolytic cleavage of the S protein, thereby exhibiting inhibitory activity against SARS-CoV-2 infection. In summary, our findings suggest that phenothiazines can serve as a potential broad-spectrum therapeutic drug for the treatment of SARS-CoV-2 infection as well as the infection of future emerging human coronaviruses (HCoVs).6c:T446,The study provides important insights into the immunogenicity and efficacy of a tetravalent protein subunit vaccine candidate against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The vaccine induced both humoral and cellular immune responses in nonhuman primates with controlled SIVagm infection and was able to generate Omicron variant-specific antibodies without specifically vaccinating with Omicron. These findings suggest that the tetravalent composition of the vaccine candidate could provide broad protection against multiple SARS-CoV-2 variants while minimizing the risk of immune escape and the emergence of new variants. Additionally, the use of rhesus macaques with controlled SIVsab infection may better represent vaccine immunogenicity in humans with chronic viral diseases, highlighting the importance of preclinical animal models in vaccine development. Overall, the study provides valuable information for the development and implementation of coronavirus disease 2019 vaccines, particularly for achieving global vaccine equity and addressing emerging variants.6d:T4d6,This paper presents a novel approach for improving the efficacy of COVID-19 vaccines against emergent SARS-CoV-2 variants. We have evaluated the immunogenicity of unadjuvanted wild-type (WU S1-RS09cg) and variant-specific (Delta S1-RS09cg and OM S1-RS09cg) S1 subunit protein vaccines delivered either as a monovalent or a trivalent antigen in BALB/c mice. Our results show that a trivalent approach induced a broader humoral response with more coverage against antigenically distinct variants, especially when compared to monovalent Omicron-specific S1. This trivalent approach was also found to have increased or equivalent ACE2 binding inhibition, and increased S1 IgG endpoint titer at early timepoints, against SARS-CoV-2 spike variants when compared monovalent Wuhan, Delta, or Omicron S1. Our results demonstrate the utility of protein subunit vaccines against COVID-19 and provide insights into the impact of variant-specific COVID-19 vaccine approaches on the immune response in the current SARS-CoV-2 variant landscape. Particularly, our study provides insight into effects of further increasing valency of currently approved SARS-CoV-2 vaccines, a promising approach for improving protection to curtail emerging viral variants.6e:T585,Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a very rare but serious adverse reaction that can occur after Ad26.COV2.S vaccination in humans, leading to thrombosis at unusual anatomic sites. One hypothesis is that accidental intravenous (IV) administration of Ad26.COV2.S or drainage of the vaccine from the muscle into the circulatory system may result in interaction of the vaccine with blood factors associated with platelet activation, leading to VITT. Here, we demonstrate that, similar to intramuscular (IM) administration of Ad26.COV2.S in rabbits, IV dosing was well tolerated, with no significant differences between dosing routes for the assessed hematologic, coagulation time, innate immune, or clinical chemistry parameters and no histopathologic indication of thrombotic events. For both routes, all other non-adverse findings observed were consistent with a normal vaccine response and comparable to those observed for unrelated or other Ad26-based control vaccines. However, Ad26.COV2.S induced significantly higher levels of C-reactive protein on day 1 after IM vaccination compared with an Ad26-based control vaccine encoding a different transgene, suggesting an inflammatory effect of the vaccine-encoded spike protein. Although based on a limited number of animals, these data indicate that an accidental IV injection of Ad26.COV2.S may not represent an increased risk for VITT.6f:T4a0,Alzheimer's disease (AD) is a major cause of dementia inducing memory loss, cognitive decline, and mortality among the aging population. While the amyloid aggregation of peptide Aβ has long been implicated in neurodegeneration in AD, primarily through the production of toxic polymorphic aggregates and reactive oxygen species, viral infection has a less explicit role in the etiology of the brain disease. On the other hand, while the COVID-19 pandemic is known to harm human organs and function, its adverse effects on AD pathobiology and other human conditions remain unclear. Here we first identified the amyloidogenic potential of 1058HGVVFLHVTYV1068, a short fragment of the spike protein of SARS-CoV-2 coronavirus. The peptide fragment was found to be toxic and displayed a high binding propensity for the amyloidogenic segments of Aβ, thereby promoting the aggregation and toxicity of the peptide in vitro and in silico, while retarding the hatching and survival of zebrafish embryos upon exposure. Our study implicated SARS-CoV-2 viral infection as a potential contributor to AD pathogenesis, a little explored area in our quest for understanding and overcoming Long Covid.70:T4b0,Cognitive dysfunction is often reported in patients with post-coronavirus disease 2019 (COVID-19) syndrome, but its underlying mechanisms are not completely understood. Evidence suggests that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike protein or its fragments are released from cells during infection, reaching different tissues, including the CNS, irrespective of the presence of the viral RNA. Here, we demonstrate that brain infusion of Spike protein in mice has a late impact on cognitive function, recapitulating post-COVID-19 syndrome. We also show that neuroinflammation and hippocampal microgliosis mediate Spike-induced memory dysfunction via complement-dependent engulfment of synapses. Genetic or pharmacological blockage of Toll-like receptor 4 (TLR4) signaling protects animals against synapse elimination and memory dysfunction induced by Spike brain infusion. Accordingly, in a cohort of 86 patients who recovered from mild COVID-19, the genotype GG TLR4-2604G>A (rs10759931) is associated with poor cognitive outcome. These results identify TLR4 as a key target to investigate the long-term cognitive dysfunction after COVID-19 infection in humans and rodents.71:T55f,COVID-19, caused by SARS-CoV-2, is a respiratory disease associated with inflammation and endotheliitis. Mechanisms underling inflammatory processes are unclear, but angiotensin converting enzyme 2 (ACE2), the receptor which binds the spike protein of SARS-CoV-2 may be important. Here we investigated whether spike protein binding to ACE2 induces inflammation in endothelial cells and determined the role of ACE2 in this process. Human endothelial cells were exposed to SARS-CoV-2 spike protein, S1 subunit (rS1p) and pro-inflammatory signaling and inflammatory mediators assessed. ACE2 was modulated pharmacologically and by siRNA. Endothelial cells were also exposed to SARS-CoV-2. rSP1 increased production of IL-6, MCP-1, ICAM-1 and PAI-1, and induced NFkB activation via ACE2 in endothelial cells. rS1p increased microparticle formation, a functional marker of endothelial injury. ACE2 interacting proteins involved in inflammation and RNA biology were identified in rS1p-treated cells. Neither ACE2 expression nor ACE2 enzymatic function were affected by rSP1. Endothelial cells exposed to SARS-CoV-2 virus did not exhibit viral replication. We demonstrate that rSP1 induces endothelial inflammation via ACE2 through processes that are independent of ACE2 enzymatic activity and viral replication. We define a novel role for ACE2 in COVID-19- associated endotheliitis.72:T420,The constantly evolving severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOC) fuel the worldwide coronavirus disease (COVID-19) pandemic. The spike protein is essential for the SARS-CoV-2 viral entry and thus has been extensively targeted by therapeutic antibodies. However, mutations along the spike in SARS-CoV-2 VOC and Omicron subvariants have caused more rapid spread and strong antigenic drifts, rendering most of the current antibodies ineffective. Hence, understanding and targeting the molecular mechanism of spike activation is of great interest in curbing the spread and development of new therapeutic approaches. In this review, we summarize the conserved features of spike-mediated viral entry in various SARS-CoV-2 VOC and highlight the converging proteolytic processes involved in priming and activating the spike. We also summarize the roles of innate immune factors in preventing spike-driven membrane fusion and provide outlines for the identification of novel therapeutics against coronavirus infections.73:T4b6,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). About 45% of COVID-19 patients experience several symptoms a few months after the initial infection and develop post-acute sequelae of SARS-CoV-2 (PASC), referred to as "Long-COVID," characterized by persistent physical and mental fatigue. However, the exact pathogenetic mechanisms affecting the brain are still not well-understood. There is increasing evidence of neurovascular inflammation in the brain. However, the precise role of the neuroinflammatory response that contributes to the disease severity of COVID-19 and long COVID pathogenesis is not clearly understood. Here, we review the reports that the SARS-CoV-2 spike protein can cause blood-brain barrier (BBB) dysfunction and damage neurons either directly, or via activation of brain mast cells and microglia and the release of various neuroinflammatory molecules. Moreover, we provide recent evidence that the novel flavanol eriodictyol is particularly suited for development as an effective treatment alone or together with oleuropein and sulforaphane (ViralProtek®), all of which have potent anti-viral and anti-inflammatory actions.74:T67e,The COVID-19 pandemic caused much illness, many deaths, and profound disruption to society. The production of 'safe and effective' vaccines was a key public health target. Sadly, unprecedented high rates of adverse events have overshadowed the benefits. This two-part narrative review presents evidence for the widespread harms of novel product COVID-19 mRNA and adenovectorDNA vaccines and is novel in attempting to provide a thorough overview of harms arising from the new technology in vaccines that relied on human cells producing a foreign antigen that has evidence of pathogenicity. This first paper explores peer-reviewed data counter to the 'safe and effective' narrative attached to these new technologies. Spike protein pathogenicity, termed 'spikeopathy', whether from the SARS-CoV-2 virus or produced by vaccine gene codes, akin to a 'synthetic virus', is increasingly understood in terms of molecular biology and pathophysiology. Pharmacokinetic transfection through body tissues distant from the injection site by lipid-nanoparticles or viral-vector carriers means that 'spikeopathy' can affect many organs. The inflammatory properties of the nanoparticles used to ferry mRNA; N1-methylpseudouridine employed to prolong synthetic mRNA function; the widespread biodistribution of the mRNA and DNA codes and translated spike proteins, and autoimmunity via human production of foreign proteins, contribute to harmful effects. This paper reviews autoimmune, cardiovascular, neurological, potential oncological effects, and autopsy evidence for spikeopathy. With many gene-based therapeutic technologies planned, a re-evaluation is necessary and timely.75:T578,Coronavirus disease COVID-19, which is caused by severe acute respiratory syndrome coronavirus SARS-CoV-2, has become a worldwide pandemic in recent years. In addition to being a respiratory disease, COVID-19 is a 'vascular disease' since it causes a leaky vascular barrier and increases blood clotting by elevating von Willebrand factor (vWF) levels in the blood. In this study, we analyzed in vitro how the SARS-CoV-2 spike protein S1 induces endothelial cell (EC) permeability and its vWF secretion, and the underlying molecular mechanism for it. We showed that the SARS-CoV-2 spike protein S1 receptor-binding domain (RBD) is sufficient to induce endothelial permeability and vWF-secretion through the angiotensin-converting enzyme (ACE)2 in an ADP-ribosylation factor (ARF)6 activation-dependent manner. However, the mutants, including those in South African and South Californian variants of SARS-CoV-2, in the spike protein did not affect its induced EC permeability and vWF secretion. In addition, we have identified a signaling cascade downstream of ACE2 for the SARS-CoV-2 spike protein-induced EC permeability and its vWF secretion by using pharmacological inhibitors. The knowledge gained from this study could be useful in developing novel drugs or repurposing existing drugs for treating infections of SARS-CoV-2, particularly those strains that respond poorly to the existing vaccines.76:T406,A major challenge in understanding SARS-CoV-2 evolution is interpreting the antigenic and functional effects of emerging mutations in the viral spike protein. Here, we describe a deep mutational scanning platform based on non-replicative pseudotyped lentiviruses that directly quantifies how large numbers of spike mutations impact antibody neutralization and pseudovirus infection. We apply this platform to produce libraries of the Omicron BA.1 and Delta spikes. These libraries each contain ∼7,000 distinct amino acid mutations in the context of up to ∼135,000 unique mutation combinations. We use these libraries to map escape mutations from neutralizing antibodies targeting the receptor-binding domain, N-terminal domain, and S2 subunit of spike. Overall, this work establishes a high-throughput and safe approach to measure how ∼105 combinations of mutations affect antibody neutralization and spike-mediated infection. Notably, the platform described here can be extended to the entry proteins of many other viruses.77:T7d4,The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has raised concerns about reduced vaccine effectiveness and the increased risk of infection, and while repeated homologous booster shots are recommended for elderly and immunocompromised individuals, they cannot completely protect against breakthrough infections. In our previous study, we assessed the immunogenicity of an adenovirus-based vaccine expressing SARS-CoV-2 S1 (Ad5.S1) in mice, which induced robust humoral and cellular immune responses (E. Kim, F. J. Weisel, S. C. Balmert, M. S. Khan, et al., Eur J Immunol 51:1774-1784, 2021, https://doi.org/10.1002/eji.202149167). In this follow-up study, we found that the mice had high titers of anti-S1 antibodies 1 year after vaccination, and one booster dose of the nonadjuvanted rS1Beta (recombinant S1 protein of SARS-CoV-2 Beta [B.1.351]) subunit vaccine was effective at stimulating strong long-lived S1-specific immune responses and inducing significantly high neutralizing antibodies against Wuhan, Beta, and Delta strains, with 3.6- to 19.5-fold increases. Importantly, the booster dose also elicited cross-reactive antibodies, resulting in angiotensin-converting enzyme 2 (ACE2) binding inhibition against spikes of SARS-CoV-2, including Omicron variants, persisting for >28 weeks after booster vaccination. Interestingly, the levels of neutralizing antibodies were correlated not only with the level of S1 binding IgG but also with ACE2 inhibition. Our findings suggest that the rS1Beta subunit vaccine candidate as a booster has the potential to offer cross-neutralization against broad variants and has important implications for the vaccine control of newly emerging breakthrough SARS-CoV-2 variants in elderly individuals primed with adenovirus-based vaccines like AZD1222 and Ad26.COV2.S. IMPORTANCE Vaccines have significantly reduced the incidences of severe coronavirus disease 2019 (COVID-19) cases and deaths. However, the emergence of S78:T47d,Critically ill COVID-19 patients display signs of generalized hyperinflammation. Macrophages trigger inflammation to eliminate pathogens and repair tissue, but this process can also lead to hyperinflammation and resulting exaggerated disease. The role of macrophages in dysregulated inflammation during SARS-CoV-2 infection is poorly understood. We inoculated and treated human macrophage cell line THP-1 with SARS-CoV-2 and purified, glycosylated, soluble SARS-CoV-2 spike protein S1 subunit (S1) to clarify the role of macrophages in pro-inflammatory responses. Soluble S1 upregulated TNF-α and CXCL10 mRNAs, and induced secretion of TNF-α from THP-1 macrophages. While THP-1 macrophages did not support productive SARS-CoV-2 replication or viral entry, virus exposure resulted in upregulation of both TNF-α and CXCL10 genes. Our study shows that extracellular soluble S1 protein is a key viral component inducing pro-inflammatory responses in macrophages, independent of virus replication. Thus, virus- or soluble S1-activated macrophages may become sources of pro-inflammatory mediators contributing to hyperinflammation in COVID-19 patients.79:T5fa,The 800 million human infections with SARS-CoV-2 and the likely emergence of new variants and additional coronaviruses necessitate a better understanding of the essential spike glycoprotein and the development of immunogens that foster broader and more durable immunity. The S2 fusion subunit is more conserved in sequence, is essential to function, and would be a desirable immunogen to boost broadly reactive antibodies. It is, however, unstable in structure and in its wild-type form, cannot be expressed alone without irreversible collapse into a six-helix bundle. In addition to the irreversible conformational changes of fusion, biophysical measurements indicate that spike also undergoes a reversible breathing action. However, spike in an open, "breathing" conformation has not yet been visualized at high resolution. Here we describe an S2-only antigen, engineered to remain in its relevant, pre-fusion viral surface conformation in the absence of S1. We also describe a panel of natural human antibodies specific for S2 from vaccinated and convalescent individuals. One of these mAbs, from a convalescent individual, afforded a high-resolution cryo-EM structure of the prefusion S2. The structure reveals a complex captured in an "open" conformation with greater stabilizing intermolecular interactions at the base and a repositioned fusion peptide. Together, this work provides an antigen for advancement of next-generation "booster" immunogens and illuminates the likely breathing adjustments of the coronavirus spike.7a:T4c4,The spike protein of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) can interact with endothelial cells. However, no studies demonstrated the direct effect of the spike protein subunit 1 (S1) in inducing lung vascular damage and the potential mechanisms contributing to lung injury. Here, we found that S1 injection in mice transgenic for human angiotensin converting enzyme 2 (ACE2) induced early loss of lung endothelial thromboresistance at 3 days, as revealed by thrombomodulin loss and von Willebrand factor (vWF) increase. In parallel, vascular and epithelial C3 deposits and enhanced C3a receptor (C3aR) expression were observed. These changes preceded diffuse alveolar damage and lung vascular fibrin(ogen)/platelets aggregates at 7 days, as well as inflammatory cell recruitment and fibrosis. Treatment with C3aR antagonist (C3aRa) inhibited lung C3 accumulation and C3a/C3aR activation, limiting vascular thrombo-inflammation and fibrosis. Our study demonstrates that S1 triggers vascular dysfunction and activates complement system, instrumental to lung thrombo-inflammatory injury. By extension, our data indicate C3aRa as a valuable therapeutic strategy to limit S1-dependent lung pathology.7b:T781,BACKGROUND: Cases of adolescents and young adults developing myocarditis after vaccination with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-targeted mRNA vaccines have been reported globally, but the underlying immunoprofiles of these individuals have not been described in detail. METHODS: From January 2021 through February 2022, we prospectively collected blood from 16 patients who were hospitalized at Massachusetts General for Children or Boston Children's Hospital for myocarditis, presenting with chest pain with elevated cardiac troponin T after SARS-CoV-2 vaccination. We performed extensive antibody profiling, including tests for SARS-CoV-2-specific humoral responses and assessment for autoantibodies or antibodies against the human-relevant virome, SARS-CoV-2-specific T-cell analysis, and cytokine and SARS-CoV-2 antigen profiling. Results were compared with those from 45 healthy, asymptomatic, age-matched vaccinated control subjects. RESULTS: Extensive antibody profiling and T-cell responses in the individuals who developed postvaccine myocarditis were essentially indistinguishable from those of vaccinated control subjects, despite a modest increase in cytokine production. A notable finding was that markedly elevated levels of full-length spike protein (33.9±22.4 pg/mL), unbound by antibodies, were detected in the plasma of individuals with postvaccine myocarditis, whereas no free spike was detected in asymptomatic vaccinated control subjects (unpaired t test; P<0.0001). CONCLUSIONS: Immunoprofiling of vaccinated adolescents and young adults revealed that the mRNA vaccine-induced immune responses did not differ between individuals who developed myocarditis and individuals who did not. However, free spike antigen was detected in the blood of adolescents and young adults who developed post-mRNA vaccine myocarditis, advancing insight into its potential underlying cause.7c:T71a,Exposure to the spike protein or receptor-binding domain (S-RBD) of SARS-CoV-2 significantly influences endothelial cells and induces pulmonary vascular endotheliopathy. In this study, angiotensin-converting enzyme 2 humanized inbred (hACE2 Tg) mice and cultured pulmonary vascular endothelial cells were used to investigate how spike protein/S-RBD impacts pulmonary vascular endothelium. Results show that S-RBD leads to acute-to-prolonged induction of the intracellular free calcium concentration ([Ca2+]i) via acute activation of TRPV4, and prolonged upregulation of mechanosensitive channel Piezo1 and store-operated calcium channel (SOCC) key component Orai1 in cultured human pulmonary arterial endothelial cells (PAECs). In mechanism, S-RBD interacts with ACE2 to induce formation of clusters involving Orai1, Piezo1 and TRPC1, facilitate the channel activation of Piezo1 and SOCC, and lead to elevated apoptosis. These effects are blocked by Kobophenol A, which inhibits the binding between S-RBD and ACE2, or intracellular calcium chelator, BAPTA-AM. Blockade of Piezo1 and SOCC by GsMTx4 effectively protects the S-RBD-induced pulmonary microvascular endothelial damage in hACE2 Tg mice via normalizing the elevated [Ca2+]i. Comparing to prototypic strain, Omicron variants (BA.5.2 and XBB) of S-RBD induces significantly less severe cell apoptosis. Transcriptomic analysis indicates that prototypic S-RBD confers more severe acute impacts than Delta or Lambda S-RBD. In summary, this study provides compelling evidence that S-RBD could induce persistent pulmonary vascular endothelial damage by binding to ACE2 and triggering [Ca2+]i through upregulation of Piezo1 and Orai1. Targeted inhibition of ACE2-Piezo1/SOCC-[Ca2+]i axis proves a powerful strategy to treat S-RBD-induced pulmonary vascular diseases.7d:T5f3,The ongoing global pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused devastating impacts on the public health and the global economy. Rapid viral antigenic evolution has led to the continual generation of new variants. Of special note is the recently expanding Omicron subvariants that are capable of immune evasion from most of the existing neutralizing antibodies (nAbs). This has posed new challenges for the prevention and treatment of COVID-19. Therefore, exploring broad-spectrum antiviral agents to combat the emerging variants is imperative. In sharp contrast to the massive accumulation of mutations within the SARS-CoV-2 receptor-binding domain (RBD), the S2 fusion subunit has remained highly conserved among variants. Hence, S2-based therapeutics may provide effective cross-protection against new SARS-CoV-2 variants. Here, we summarize the most recently developed broad-spectrum fusion inhibitors (e.g., nAbs, peptides, proteins, and small-molecule compounds) and candidate vaccines targeting the conserved elements in SARS-CoV-2 S2 subunit. The main focus includes all the targetable S2 elements, namely, the fusion peptide, stem helix, and heptad repeats 1 and 2 (HR1-HR2) bundle. Moreover, we provide a detailed summary of the characteristics and action-mechanisms for each class of cross-reactive fusion inhibitors, which should guide and promote future design of S2-based inhibitors and vaccines against new coronaviruses.7e:T550,Thromboinflammation is the major cause of morbidity and mortality in COVID-19 patients, and post-mortem examination demonstrates the presence of platelet-rich thrombi and microangiopathy in visceral organs. Moreover, persistent microclots were detected in both acute COVID-19 and long COVID plasma samples. However, the molecular mechanism of SARS-CoV-2-induced thromboinflammation is still unclear. We found that the spleen tyrosine kinase (Syk)-coupled C-type lectin member 2 (CLEC2), which was highly expressed in platelets and alveolar macrophages, interacted with the receptor-binding domain (RBD) of SARS-CoV-2 spike protein (SARS-CoV-2 RBD) directly. Unlike the thread-like NETs, SARS-CoV-2-induced aggregated NET formation in the presence of wild-type (WT), but not CLEC2-deficient platelets. Furthermore, SARS-CoV-2 spike pseudotyped lentivirus was able to induce NET formation via CLEC2, indicating SARS-CoV-2 RBD engaged CLEC2 to activate platelets to enhance NET formation. Administration of CLEC2.Fc inhibited SARS-CoV-2-induced NET formation and thromboinflammation in AAV-ACE2-infected mice. Thus, CLEC2 is a novel pattern recognition receptor for SARS-CoV-2, and CLEC2.Fc and may become a promising therapeutic agent to inhibit SARS-CoV-2-induced thromboinflammation and reduced the risk of post-acute sequelae of COVID-19 (PASC) in the future.7f:T5b5,Cardiopulmonary complications are major drivers of mortality caused by the SARS-CoV-2 virus. Interleukin-18, an inflammasome-induced cytokine, has emerged as a novel mediator of cardiopulmonary pathologies but its regulation via SARS-CoV-2 signaling remains unknown. Based on a screening panel, IL-18 was identified amongst 19 cytokines to stratify mortality and hospitalization burden in patients hospitalized with COVID-19. Supporting clinical data, administration of SARS-CoV-2 Spike 1 (S1) glycoprotein or receptor-binding domain (RBD) proteins into human angiotensin-converting enzyme 2 (hACE2) transgenic mice induced cardiac fibrosis and dysfunction associated with higher NF-κB phosphorylation (pNF-κB) and cardiopulmonary-derived IL-18 and NLRP3 expression. IL-18 inhibition via IL-18BP resulted in decreased cardiac pNF-κB and improved cardiac fibrosis and dysfunction in S1- or RBD-exposed hACE2 mice. Through in vivo and in vitro work, both S1 and RBD proteins induced NLRP3 inflammasome and IL-18 expression by inhibiting mitophagy and increasing mitochondrial reactive oxygenation species. Enhancing mitophagy prevented Spike protein-mediated IL-18 expression. Moreover, IL-18 inhibition reduced Spike protein-mediated pNF-κB and EC permeability. Overall, the link between reduced mitophagy and inflammasome activation represents a novel mechanism during COVID-19 pathogenesis and suggests IL-18 and mitophagy as potential therapeutic targets.80:T557,Swine acute diarrhea syndrome coronavirus (SADS-CoV), a member of the family Coronaviridae and the genus Alphacoronavirus, primarily affects piglets under 7 days old, causing symptoms such as diarrhea, vomiting, and dehydration. It has the potential to infect human primary and passaged cells in vitro, indicating a potential risk of zoonotic transmission. In this study, we successfully generated and purified six monoclonal antibodies (mAbs) specifically targeting the spike protein of SADS-CoV, whose epitope were demonstrated specificity to the S1A or S1B region by immunofluorescence assay and enzyme-linked immunosorbent assay. Three of these mAbs were capable of neutralizing SADS-CoV infection on HeLa-R19 and A549. Furthermore, we observed that SADS-CoV induced the agglutination of erythrocytes from both humans and rats, and the hemagglutination inhibition capacity and antigen-antibody binding capacity of the antibodies were assessed. Our study reveals that mAbs specifically targeting the S1A domain demonstrated notable efficacy in suppressing the hemagglutination phenomenon induced by SADS-CoV. This finding represents the first instance of narrowing down the protein region responsible for SADS-CoV-mediated hemagglutination to the S1A domain, and reveals that the cell attachment domains S1A and S1B are the main targets of neutralizing antibodies.81:T475,COVID-19 is a viral disease caused by SARS-CoV-2. This disease is characterized primarily, but not exclusively, by respiratory tract inflammation. SARS-CoV-2 infection relies on the binding of spike protein to ACE2 on the host cells. The virus uses the protease TMPRSS2 as an entry activator. Human lung macrophages (HLMs) are the most abundant immune cells in the lung and fulfill a variety of specialized functions mediated by the production of cytokines and chemokines. The aim of this project was to investigate the effects of spike protein on HLM activation and the expression of ACE2 and TMPRSS2 in HLMs. Spike protein induced CXCL8, IL-6, TNF-α, and IL-1β release from HLMs; promoted efficient phagocytosis; and induced dysfunction of intracellular Ca2+ concentration by increasing lysosomal Ca2+ content in HLMs. Microscopy experiments revealed that HLM tracking was affected by spike protein activation. Finally, HLMs constitutively expressed mRNAs for ACE2 and TMPRSS2. In conclusion, during SARS-CoV-2 infection, macrophages seem to play a key role in lung injury, resulting in immunological dysfunction and respiratory disease.82:T42b,SARS-CoV-2 is associated with broad tissue tropism, a characteristic often determined by the availability of entry receptors on host cells. Here, we show that TMEM106B, a lysosomal transmembrane protein, can serve as an alternative receptor for SARS-CoV-2 entry into angiotensin-converting enzyme 2 (ACE2)-negative cells. Spike substitution E484D increased TMEM106B binding, thereby enhancing TMEM106B-mediated entry. TMEM106B-specific monoclonal antibodies blocked SARS-CoV-2 infection, demonstrating a role of TMEM106B in viral entry. Using X-ray crystallography, cryogenic electron microscopy (cryo-EM), and hydrogen-deuterium exchange mass spectrometry (HDX-MS), we show that the luminal domain (LD) of TMEM106B engages the receptor-binding motif of SARS-CoV-2 spike. Finally, we show that TMEM106B promotes spike-mediated syncytium formation, suggesting a role of TMEM106B in viral fusion. Together, our findings identify an ACE2-independent SARS-CoV-2 infection mechanism that involves cooperative interactions with the receptors heparan sulfate and TMEM106B.83:T407,Since the onset of the coronavirus disease 2019 (COVID-19), numerous neutralizing antibodies (NAbs) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been developed and authorized for emergency use to control the pandemic. Most COVID-19 therapeutic NAbs prevent the S1 subunit of the SARS-CoV-2 spike (S) protein from binding to the human host receptor. However, the emergence of SARS-CoV-2 immune escape variants, which possess frequent mutations on the S1 subunit, may render current NAbs ineffective. In contrast, the relatively conserved S2 subunit of the S protein can elicit NAbs with broader neutralizing potency against various SARS-CoV-2 variants. In this review, the binding specificity and functional features of SARS-CoV-2 NAbs targeting different domains of the S2 subunit are collectively discussed. The knowledge learned from the investigation of the S2-specific NAbs provides insights and potential strategies for developing antibody cocktail therapy and next-generation coronavirus vaccine.84:T59d,INTRODUCTION: The Coronavirus Disease 2019 (COVID-19) pandemic has caused devastating human and economic costs. Vaccination is an important step in controlling the pandemic. Severe acute respiratory coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19, infects cells by binding a cellular receptor through the receptor-binding domain (RBD) within the S1 subunit of the spike (S) protein. Viral entry and membrane fusion are mediated by the S2 subunit. AREAS COVERED: SARS-CoV-2 S protein, particularly RBD, serves as an important target for vaccines. Here we review the structure and function of SARS-CoV-2 S protein and its RBD, summarize current COVID-19 vaccines targeting the RBD, and outline potential strategies for improving RBD-based vaccines. Overall, this review provides important information that will facilitate rational design and development of safer and more effective COVID-19 vaccines. EXPERT OPINION: The S protein of SARS-CoV-2 harbors numerous mutations, mostly in the RBD, resulting in multiple variant strains. Although many COVID-19 vaccines targeting the RBD of original virus strain (and previous variants) can prevent infection of these strains, their ability against recent dominant variants, particularly Omicron and its offspring, is significantly reduced. Collective efforts are needed to develop effective broad-spectrum vaccines to control current and future variants that have pandemic potential.85:T7d3,The spike protein of SARS-CoV-2 has been found to exhibit pathogenic characteristics and be a possible cause of post-acute sequelae after SARS-CoV-2 infection or COVID-19 vaccination. COVID-19 vaccines utilize a modified, stabilized prefusion spike protein that may share similar toxic effects with its viral counterpart. The aim of this study is to investigate possible mechanisms of harm to biological systems from SARS-CoV-2 spike protein and vaccine-encoded spike protein and to propose possible mitigation strategies. We searched PubMed, Google Scholar, and 'grey literature' to find studies that (1) investigated the effects of the spike protein on biological systems, (2) helped differentiate between viral and vaccine-generated spike proteins, and (3) identified possible spike protein detoxification protocols and compounds that had signals of benefit and acceptable safety profiles. We found abundant evidence that SARS-CoV-2 spike protein may cause damage in the cardiovascular, hematological, neurological, respiratory, gastrointestinal, and immunological systems. Viral and vaccine-encoded spike proteins have been shown to play a direct role in cardiovascular and thrombotic injuries from both SARS-CoV-2 and vaccination. Detection of spike protein for at least 6-15 months after vaccination and infection in those with post-acute sequelae indicates spike protein as a possible primary contributing factor to long COVID. We rationalized that these findings give support to the potential benefit of spike protein detoxification protocols in those with long-term post-infection and/or vaccine-induced complications. We propose a base spike detoxification protocol, composed of oral nattokinase, bromelain, and curcumin. This approach holds immense promise as a base of clinical care, upon which additional therapeutic agents are applied with the goal of aiding in the resolution of post-acute sequelae after SARS-CoV-2 infection and COVID-19 vaccination. Large-scale, prospective, randomi86:T71e,OBJECTIVE: COVID-19 patients experience, in 10-20% of the cases, a prolonged long-COVID syndrome, defined as the persistence of symptoms for at least two months after the infection. The underlying biological mechanisms of this syndrome remain poorly understood. Several hypotheses have been proposed, among which are the potential autoimmunity resulting from molecular mimicry between viral spike protein and human proteins, the reservoir and viral reproduction hypothesis, and the viral integration hypothesis. Although official data state that vaccinal spike protein is harmless and remains at the site of infection, several studies proposed spike protein toxicity and found it in blood circulation several months after the vaccination. To search for the presence of viral and vaccine spike protein in a cohort of long-COVID patients. PATIENTS AND METHODS: In this study, we employed a proteomic-based approach utilizing mass spectrometry to analyze the serum of 81 patients with long-COVID syndrome. Moreover, viral integration in patients' leukocytes was assessed with a preliminary study, without further investigation. RESULTS: We identified the presence of the viral spike protein in one patient after infection clearance and negativity of COVID-19 test and the vaccine spike protein in two patients two months after the vaccination. CONCLUSIONS: This study, in agreement with other published investigations, demonstrates that both natural and vaccine spike protein may still be present in long-COVID patients, thus supporting the existence of a possible mechanism that causes the persistence of spike protein in the human body for much longer than predicted by early studies. According to these results, all patients with long-COVID syndrome should be analyzed for the presence of vaccinal and viral spike protein.87:T72c,OBJECTIVES: Understanding the immune response in very mild and asymptomatic COVID-19 is crucial for developing effective vaccines and immunotherapies, yet remains poorly characterized. This longitudinal study examined the evolution of interferon (IFN)-γ responses to SARS-CoV-2 peptides in 109 asymptomatic or mildly symptomatic Ugandan COVID-19 patients across 365 days and explored their association with antibody generation. METHODS: T-cell responses to spike-containing clusters of differentiation (CD4)-S and CD8 nCoV-A (CD8-A) megapools, and the non-spike CD4-R and CD8 nCoV-B (CD8-B) megapools, were assessed and correlated with demographic and temporal variables. RESULTS: SARS-CoV-2-specific IFN-γ responses were consistently detected in all peptide pools and time points, with the spike-targeted response exhibiting higher potency and durability than the non-spike responses. Throughout the entire 365-day infection timeline, a robust positive correlation was observed between CD4 T-cell responses to the spike-derived peptides and anti-spike immunoglobulin G antibody levels, underscoring their interdependent dynamics in the immune response against SARS-CoV-2; in contrast, CD8 T-cell responses exhibited no such correlation, highlighting their distinctive, autonomous role in defense. No meaningful variations in complete blood count parameters were observed between individuals with COVID-19 infection and those without, indicating clinical insignificance. CONCLUSIONS: This study highlights the dominant role of spike-directed T-cell responses in mild and asymptomatic disease and provides crucial longitudinal data from Sub-Saharan African settings. The findings provide valuable insights into the dynamics of T-cell responses and their potential significance in developing effective strategies for combating COVID-19.88:T561,Lung epithelial cells and fibroblasts poorly express angiotensin-converting enzyme 2, and the study aimed to investigate the role of the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on inflammation and epithelial-mesenchymal transition (EMT) in two lung cell lines and to understand the potential mechanism. Lung epithelial cells (BEAS-2B) and fibroblasts (MRC-5) were treated with the spike protein, then inflammatory and EMT phenotypes were detected by enzyme-linked immunosorbent assay, Transwell, and western blot assays. RNA-sequence and bioinformatic analyses were performed to identify dysregulated genes. The roles of the candidate genes were further investigated. The results showed that treatment with 1,000 ng/mL of spike protein in two lung cell lines caused increased levels of IL-6, TNF-α, CXCL1, and CXCL3, and the occurrence of EMT. RNA-sequence identified 4,238 dysregulated genes in the spike group, and 18 candidate genes were involved in both inflammation- and EMT-related processes. GADD45A had the highest verified fold change (abs), and overexpression of GADD45A promoted the secretion of cytokines and EMT in the two lung cell lines. In conclusion, the spike protein induces inflammation and EMT in lung epithelial cells and fibroblasts by upregulating GADD45A, providing a new target to inhibit inflammation and EMT.89:T5cd,Vaccination has proven effective against SARS-CoV-2 infection but vaccines were originally based on the wild type and emerging variants have led to a decrease in protective efficacy. There is an urgent need for broad-spectrum vaccine protection against emerging variants. A vaccine based on the Delta strain spike protein was created by optimization of vector, codon, and protein structure to produce a subunit immunogen (Delta-6P-S) containing six proline mutations, stable pre-fusion conformation, and with high expression in CHO-S cells. Immunogenicity and protective efficacy were evaluated in mice and golden hamsters using alum adjuvant. The Delta-6P-S recombinant protein induced strong immune responses in C57BL/6J mice and golden hamsters and sera had cross-neutralization activity and neutralized wild type and Beta, Delta, Omicron BA.1, BA.2, and BA.5 variant strains. Golden hamsters were immunized against Delta, Omicron BA.1, and BA.2 variants. Viral RNA detected from throat swabs, lungs and tracheas decreased significantly in vaccine-inoculated animals relative to alum-treated controls and no infectious viruses were detected in lungs and tracheas. Almost no pathological damage to lung tissue was found in vaccinated animals by contrast with those treated only with alum. The Delta-6P-S recombinant protein rapidly eliminated replicating virus in the upper and lower airways of golden hamsters and merits further investigation as a candidate anti-SARS-CoV-2 vaccine.8a:T548,As emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants (Omicron) continue to outpace and negate combinatorial vaccines and monoclonal antibody therapies targeting the spike protein (S) receptor binding domain (RBD), the appetite for developing similar COVID-19 treatments has significantly diminished, with the attention of the scientific community switching to long COVID treatments. However, treatments that reduce the risk of "post-COVID-19 syndrome" and associated sequelae remain in their infancy, particularly as no established criteria for diagnosis currently exist. Thus, alternative therapies that reduce infection and prevent the broad range of symptoms associated with 'post-COVID-19 syndrome' require investigation. This review begins with an overview of the parasitic-diarylamidine connection, followed by the renin-angiotensin system (RAS) and associated angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSSR2) involved in SARS-CoV-2 infection. Subsequently, the ability of diarylamidines to inhibit S-protein binding and various membrane serine proteases associated with SARS-CoV-2 and parasitic infections are discussed. Finally, the roles of diarylamidines (primarily DIZE) in vaccine efficacy, epigenetics, and the potential amelioration of long COVID sequelae are highlighted.8b:T4fe,Human monoclonal antibodies (mAbs) that target the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein have been isolated from convalescent individuals and developed into therapeutics for SARS-CoV-2 infection. However, therapeutic mAbs for SARS-CoV-2 have been rendered obsolete by the emergence of mAb-resistant virus variants. Here we report the generation of a set of six human mAbs that bind the human angiotensin-converting enzyme-2 (hACE2) receptor, rather than the SARS-CoV-2 spike protein. We show that these antibodies block infection by all hACE2 binding sarbecoviruses tested, including SARS-CoV-2 ancestral, Delta and Omicron variants at concentrations of ~7-100 ng ml-1. These antibodies target an hACE2 epitope that binds to the SARS-CoV-2 spike, but they do not inhibit hACE2 enzymatic activity nor do they induce cell-surface depletion of hACE2. They have favourable pharmacology, protect hACE2 knock-in mice against SARS-CoV-2 infection and should present a high genetic barrier to the acquisition of resistance. These antibodies should be useful prophylactic and treatment agents against any current or future SARS-CoV-2 variants and might be useful to treat infection with any hACE2-binding sarbecoviruses that emerge in the future.8c:T4b5,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA generally becomes undetectable in upper airways after a few days or weeks postinfection. Here we used a model of viral infection in macaques to address whether SARS-CoV-2 persists in the body and which mechanisms regulate its persistence. Replication-competent virus was detected in bronchioalveolar lavage (BAL) macrophages beyond 6 months postinfection. Viral propagation in BAL macrophages occurred from cell to cell and was inhibited by interferon-γ (IFN-γ). IFN-γ production was strongest in BAL NKG2r+CD8+ T cells and NKG2Alo natural killer (NK) cells and was further increased in NKG2Alo NK cells after spike protein stimulation. However, IFN-γ production was impaired in NK cells from macaques with persisting virus. Moreover, IFN-γ also enhanced the expression of major histocompatibility complex (MHC)-E on BAL macrophages, possibly inhibiting NK cell-mediated killing. Macaques with less persisting virus mounted adaptive NK cells that escaped the MHC-E-dependent inhibition. Our findings reveal an interplay between NK cells and macrophages that regulated SARS-CoV-2 persistence in macrophages and was mediated by IFN-γ.8d:T7cc,Data show a decrease in the risk of hospitalization and death from COVID-19. To date, global vaccinations for SARS-CoV-2 protections are underway, but additional treatments are urgently needed to prevent and cure infection among naïve and even vaccinated people. Neutralizing monoclonal antibodies are very promising for prophylaxis and therapy of SARS-CoV-2 infections. However, traditional large-scale methods of producing such antibodies are slow, extremely expensive and possess a high risk of contamination with viruses, prions, oncogenic DNA and other pollutants. The present study is aimed at developing an approach of producing monoclonal antibodies (mAbs) against SARS-CoV-2 spike (S) protein in plant systems which offers unique advantages, such as the lack of human and animal pathogens or bacterial toxins, relatively low-cost manufacturing, and ease of production scale-up. We selected a single N-terminal domain functional camelid-derived heavy (H)-chain antibody fragments (VHH, AKA nanobodies) targeted to receptor binding domain of SARS-CoV-2 spike protein and developed methods of their rapid production using transgenic plants and plant cell suspensions. Isolated and purified plant-derived VHH antibodies were compared with mAbs produced in traditional mammalian and bacterial expression systems. It was found that plant generated VHH using the proposed methods of transformation and purification possess the ability to bind to SARS-CoV-2 spike protein comparable to that of monoclonal antibodies derived from bacterial and mammalian cell cultures. The results of the present studies confirm the visibility of producing monoclonal single-chain antibodies with a high ability to bind the targeted COVID-19 spike protein in plant systems within a relatively shorter time span and at a lower cost when compared with traditional methods. Moreover, similar plant biotechnology approaches can be used for producing monoclonal neutralizing antibodies against other types of viruses.8e:T6c4,The crosstalk between viral infections, amyloid formation and neurodegeneration has been discussed with varying intensity since the last century. Several viral proteins are known to be amyloidogenic. Post-acute sequalae (PAS) of viral infections is known for several viruses. SARS-CoV-2 and COVID-19 implicate connections between amyloid formation and severe outcomes in the acute infection, PAS and neurodegenerative diseases. Is the amyloid connection causation or just correlation? In this review we highlight several aspects where amyloids and viruses meet. The evolutionary driving forces that dictate protein amyloid formation propensity are different for viruses compared to prokaryotes and eukaryotes, while posttranslational endoproteolysis appears to be a common mechanism leading up to amyloid formation for both viral and human proteins. Not only do human and viral proteins form amyloid irrespective of each other but there are also several examples of co-operativity between amyloids, viruses and the inter-, and intra-host spread of the respective entity. Abnormal blood clotting in severe and long COVID and as a side effect in some vaccine recipients has been connected to amyloid formation of both the human fibrin and the viral Spike-protein. We conclude that there are many intersects between viruses and amyloids and, consequently, amyloid and virus research need to join forces here. We emphasize the need to accelerate development and implementation in clinical practice of antiviral drugs to preclude PAS and downstream neurological damage. There is also an ample need for retake on suitable antigen targets for the further development of next generation of vaccines against the current and coming pandemics.8f:T568,Postinfectious syndromes have been described since the Spanish influenza pandemic of 1918. A similar syndrome-post-COVID condition (PCC)-is common; it occurs months after COVID-19 infection and involves fatigue, postexertional malaise, dyspnea, memory loss, diffuse pain, and orthostasis. The medical, psychosocial, and economic impact of PCC is immense. In the United States, PCC has caused widespread unemployment and billions in lost wages. Risk factors for development of PCC are female sex and severity of acute COVID-19 infection. Proposed pathophysiologic mechanisms include central nervous system inflammation, viral reservoirs, persistent spike protein, cell receptor dysregulation, and autoimmunity. Because presenting symptoms are often vague, the approach to evaluation should be comprehensive with consideration of other diseases that could masquerade as PCC. Treatments of PCC are little researched, are largely expert based, and are likely to evolve as more evidence emerges. Current therapies, which are symptom targeted, include medications and nonpharmacologic therapies such as optimizing fluid intake, compression garments, progressive activity, meditation, biofeedback, cognitive rehabilitation, and addressing concomitant mood disorders. Many patients will enjoy significant improvements in their quality of life with multimodal treatments and longitudinal care.90:T481,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently emerged pathogenic human coronavirus that belongs to the sarbecovirus lineage of the genus Betacoronavirus. The ancestor strain has evolved into a number of variants of concern, with the Omicron variant of concern now having many distinct sublineages. The ongoing COVID-19 pandemic caused by SARS-CoV-2 has caused serious damage to public health and the global economy, and one strategy to combat COVID-19 has been the development of broadly neutralizing antibodies for prophylactic and therapeutic use. Many are in preclinical and clinical development, and a few have been approved for emergency use. Here we summarize neutralizing antibodies that target four key regions within the SARS-CoV-2 spike (S) protein, namely the N-terminal domain and the receptor-binding domain in the S1 subunit, and the stem helix region and the fusion peptide region in the S2 subunit. Understanding the characteristics of these broadly neutralizing antibodies will accelerate the development of new antibody therapeutics and provide guidance for the rational design of next-generation vaccines.91:T53d,Currently circulating SARS-CoV-2 variants have acquired convergent mutations at hot spots in the receptor-binding domain1 (RBD) of the spike protein. The effects of these mutations on viral infection and transmission and the efficacy of vaccines and therapies remains poorly understood. Here we demonstrate that recently emerged BQ.1.1 and XBB.1.5 variants bind host ACE2 with high affinity and promote membrane fusion more efficiently than earlier Omicron variants. Structures of the BQ.1.1, XBB.1 and BN.1 RBDs bound to the fragment antigen-binding region of the S309 antibody (the parent antibody for sotrovimab) and human ACE2 explain the preservation of antibody binding through conformational selection, altered ACE2 recognition and immune evasion. We show that sotrovimab binds avidly to all Omicron variants, promotes Fc-dependent effector functions and protects mice challenged with BQ.1.1 and hamsters challenged with XBB.1.5. Vaccine-elicited human plasma antibodies cross-react with and trigger effector functions against current Omicron variants, despite a reduced neutralizing activity, suggesting a mechanism of protection against disease, exemplified by S309. Cross-reactive RBD-directed human memory B cells remained dominant even after two exposures to Omicron spikes, underscoring the role of persistent immune imprinting.92:T5f3,Consistent with well-established biochemical properties of coronaviruses, sialylated glycan attachments between SARS-CoV-2 spike protein (SP) and host cells are key to the virus's pathology. SARS-CoV-2 SP attaches to and aggregates red blood cells (RBCs), as shown in many pre-clinical and clinical studies, causing pulmonary and extrapulmonary microthrombi and hypoxia in severe COVID-19 patients. SARS-CoV-2 SP attachments to the heavily sialylated surfaces of platelets (which, like RBCs, have no ACE2) and endothelial cells (having minimal ACE2) compound this vascular damage. Notably, experimentally induced RBC aggregation in vivo causes the same key morbidities as for severe COVID-19, including microvascular occlusion, blood clots, hypoxia and myocarditis. Key risk factors for COVID-19 morbidity, including older age, diabetes and obesity, are all characterized by markedly increased propensity to RBC clumping. For mammalian species, the degree of clinical susceptibility to COVID-19 correlates to RBC aggregability with p = 0.033. Notably, of the five human betacoronaviruses, the two common cold strains express an enzyme that releases glycan attachments, while the deadly SARS, SARS-CoV-2 and MERS do not, although viral loads for COVID-19 and the two common cold infections are similar. These biochemical insights also explain the previously puzzling clinical efficacy of certain generics against COVID-19 and may support the development of future therapeutic strategies for COVID-19 and long COVID patients.93:T4ff,SARS-CoV-2, the causative agent of COVID-19 disease, has resulted in the death of millions worldwide since the beginning of the pandemic in December 2019. While much progress has been made to understand acute manifestations of SARS-CoV-2 infection, less is known about post-acute sequelae of COVID-19 (PASC). We investigated the levels of both Spike protein (Spike) and viral RNA circulating in patients hospitalized with acute COVID-19 and in patients with and without PASC. We found that Spike and viral RNA were more likely to be present in patients with PASC. Among these patients, 30% were positive for both Spike and viral RNA; whereas, none of the individuals without PASC were positive for both. The levels of Spike and/or viral RNA in the PASC+ve patients were found to be increased or remained the same as in the acute phase; whereas, in the PASC-ve group, these viral components decreased or were totally absent. Additionally, this is the first report to show that part of the circulating Spike is linked to extracellular vesicles without any presence of viral RNA in these vesicles. In conclusion, our findings suggest that Spike and/or viral RNA fragments persist in the recovered COVID-19 patients with PASC up to 1 year or longer after acute SARS-CoV-2 infection.94:T6ed,The ongoing COVID-19 pandemic caused by SARS-CoV-2 infection has threatened global health. Since the first case of infection was reported in December 2019, SARS-CoV-2 has rapidly spread worldwide and caused millions of deaths. As vaccination is the best way to protect the host from invading pathogens, several vaccines have been developed to prevent the infection of SARS-CoV-2, saving numerous lives thus far. However, SARS-CoV-2 constantly changes its antigens, resulting in escape from vaccine-induced protection, and the longevity of immunity induced by vaccines remains an issue. Additionally, traditional intramuscular COVID-19 vaccines are insufficient at evoking mucosal-specific immune responses. Because the respiratory tract is the primary route of SARS-CoV-2 entry, the need for mucosal vaccines is strong. Using an adenoviral (Ad) vector platform, we generated Ad5-S.Mod, a recombinant COVID-19 vaccine that encodes modified-spike (S) antigen and the genetic adjuvant human CXCL9. Intranasal delivery of Ad5-S.Mod elicited superior airway humoral and T-cell responses over traditional intramuscular vaccines and protected mice from lethal SARS-CoV-2 infection. cDC1 cells were required for the generation of antigen-specific CD8+ T-cell responses and CD8+ tissue-resident memory T-cell development in intranasal Ad5-S.Mod vaccinated mice. Furthermore, we confirmed the efficacy of the intranasal Ad5-S.Mod vaccine in terms of transcriptional changes and identified lung macrophages as a key supporter of maintenance of lung-resident memory T and B cells. Our study demonstrates Ad5-S.Mod has the potential to confer protective immunity against SARS-CoV-2 and that lung macrophages support the maintenance of vaccine-induced tissue-resident memory lymphocytes.95:T50f,The typical manifestation of coronavirus 2 (CoV-2) infection is a severe acute respiratory syndrome (SARS) accompanied by pneumonia (COVID-19). However, SARS-CoV-2 can also affect the brain, causing chronic neurological symptoms, variously known as long, post, post-acute, or persistent COVID-19 condition, and affecting up to 40% of patients. The symptoms (fatigue, dizziness, headache, sleep disorders, malaise, disturbances of memory and mood) usually are mild and resolve spontaneously. However, some patients develop acute and fatal complications, including stroke or encephalopathy. Damage to the brain vessels mediated by the coronavirus spike protein (S-protein) and overactive immune responses have been identified as leading causes of this condition. However, the molecular mechanism by which the virus affects the brain still needs to be fully delineated. In this review article, we focus on interactions between host molecules and S-protein as the mechanism allowing the transit of SARS-CoV-2 through the blood-brain barrier to reach the brain structures. In addition, we discuss the impact of S-protein mutations and the involvement of other cellular factors conditioning the pathophysiology of SARS-CoV-2 infection. Finally, we review current and future COVID-19 treatment options.96:T597,Despite long-term sequelae of COVID-19 are emerging as a substantial public health concern, the mechanism underlying these processes still unclear. Evidence demonstrates that SARS-CoV-2 Spike protein can reach different brain regions, irrespective of viral brain replication resulting in activation of pattern recognition receptors (PRRs) and neuroinflammation. Considering that microglia dysfunction, which is regulated by a whole array of purinergic receptors, may be a central event in COVID-19 neuropathology, we investigated the impact of SARS-CoV-2 Spike protein on microglial purinergic signaling. Here, we demonstrate that cultured microglial cells (BV2 line) exposed to Spike protein induce ATP secretion and upregulation of P2Y6, P2Y12, NTPDase2 and NTPDase3 transcripts. Also, immunocytochemistry analysis shows that spike protein increases the expression of P2X7, P2Y1, P2Y6, and P2Y12 in BV2 cells. Additional, hippocampal tissue of Spike infused animals (6,5ug/site, i.c.v.) presents increased mRNA levels of P2X7, P2Y1, P2Y6, P2Y12, NTPDase1, and NTPDase2. Immunohistochemistry experiments confirmed high expression of the P2X7 receptor in microglial cells in CA3/DG hippocampal regions after spike infusion. These findings suggest that SARS-CoV-2 Spike protein modulates microglial purinergic signaling and opens new avenues for investigating the potential of purinergic receptors to mitigate COVID-19 consequences.97:T58f,Predictions for a near end of the pandemic by the World Health Organization should be interpreted with caution. Current evidence indicates that the efficacy of a fourth dose of classical mRNA vaccines (BT162b2 or mRNA-1273) is low and short-lived in preventing SARS-CoV-2 infection in its predominant variant (Omicron). However, its efficacy is high against severe symptomatic infection, hospitalization and death. The new vaccines being introduced are bivalent and active against the Omicron variants. Potential new vaccines to be introduced in the coming year include a vaccine based on a recombinant protein that emulates the receptor binding domain of the Spike protein under development by the Spanish company Hipra, as well as vaccines for nasal or oral administration. Available information suggests that vaccines against COVID-19 can be administered in association with influenza vaccination without particular complications. New drugs against COVID-19, both antiviral and anti-inflammatory, are under investigation, but this does not seem to be the case with monoclonal antibodies. The indication to use masks in some circumstances will be maintained next year in view of the accumulation of scientific data on their efficacy. Finally, the long COVID or Post-COVID syndrome may continue to affect a very high proportion of patients who have had the disease, requiring combined diagnostic and therapeutic resources.98:T44b,Syncytia are formed when individual cells fuse. SARS-CoV-2 induces syncytia when the viral spike (S) protein on the surface of an infected cell interacts with receptors on neighboring cells. Syncytia may potentially contribute to pathology by facilitating viral dissemination, cytopathicity, immune evasion, and inflammatory response. SARS-CoV-2 variants of concern possess several mutations within the S protein that enhance receptor interaction, fusogenicity and antibody binding. In this review, we discuss the molecular determinants of S mediated fusion and the antiviral innate immunity components that counteract syncytia formation. Several interferon-stimulated genes, including IFITMs and LY6E act as barriers to S protein-mediated fusion by altering the composition or biophysical properties of the target membrane. We also summarize the effect that the mutations associated with the variants of concern have on S protein fusogenicity. Altogether, this review contextualizes the current understanding of Spike fusogenicity and the role of syncytia during SARS-CoV-2 infection and pathology.99:T653,Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variants have been reported to be resistant to several neutralizing antibodies (NAbs) targeting Receptor Binding Domain (RBD) and N Terminal Domain (NTD) of spike (S) protein and thus inducing immune escape. However, fewer studies were carried out to investigate the neutralizing ability of S2-specific antibodies. In this research, 10 monoclonal antibodies (mAbs) targeting SARS-CoV-2 S2 subunit were generated from Coronavirus Disease 2019 (COVID-19) convalescent patients by phage display technology and molecular cloning technology. The binding activity of these S2-mAbs toward SARS-CoV-2 S, SARS-CoV-2 S2, SARS-CoV-2 RBD, SARS-CoV-2 NTD, severe acute respiratory syndrome coronavirus (SARS-CoV) S, SARS-CoV S2 and Middle East Respiratory Syndrome Coronavirus (MERS-CoV) S proteins were evaluated by enzyme-linked immunosorbent assay (ELISA). Their neutralizing potency toward SARS-CoV-2 wild-type (WT), B.1.1.7, B.1.351, P.1, B.1.617.2, B.1.1.1 and B.1.621 variants were determined by pseudo-virus-based neutralization assay. Results showed that S2E7-mAb had cross-activity to S or S2 proteins of SARS-CoV-2, SARS-CoV and MERS-CoV, while with limited neutralizing activity to pseudo-viruses of SARS-CoV-2 WT and variants. It is undeniable that the binding and neutralizing activities of the S2-targeting mAbs are significantly weaker than the previously reported antibodies targeting RBD and NTD, but our study may provide some evidences for understanding immune protection and identifying targets for vaccine design based on the conserved S2 subunit.9a:T7d0,UNLABELLED: While SARS-CoV-2 continues to adapt for human infection and transmission, genetic variation outside of the spike gene remains largely unexplored. This study investigates a highly variable region at residues 203-205 in the SARS-CoV-2 nucleocapsid protein. Recreating a mutation found in the alpha and omicron variants in an early pandemic (WA-1) background, we find that the R203K+G204R mutation is sufficient to enhance replication, fitness, and pathogenesis of SARS-CoV-2. The R203K+G204R mutant corresponds with increased viral RNA and protein both in vitro and in vivo . Importantly, the R203K+G204R mutation increases nucleocapsid phosphorylation and confers resistance to inhibition of the GSK-3 kinase, providing a molecular basis for increased virus replication. Notably, analogous alanine substitutions at positions 203+204 also increase SARS-CoV-2 replication and augment phosphorylation, suggesting that infection is enhanced through ablation of the ancestral 'RG' motif. Overall, these results demonstrate that variant mutations outside spike are key components in SARS-CoV-2's continued adaptation to human infection. AUTHOR SUMMARY: Since its emergence, SARS-CoV-2 has continued to adapt for human infection resulting in the emergence of variants with unique genetic profiles. Most studies of genetic variation have focused on spike, the target of currently available vaccines, leaving the importance of variation elsewhere understudied. Here, we characterize a highly variable motif at residues 203-205 in nucleocapsid. Recreating the prominent nucleocapsid R203K+G204R mutation in an early pandemic background, we show that this mutation is alone sufficient to enhance SARS-CoV-2 replication and pathogenesis. We also link augmentation of SARS-CoV-2 infection by the R203K+G204R mutation to its modulation of nucleocapsid phosphorylation. Finally, we characterize an analogous alanine double substitution at positions 203-204. This mutant was found to mimic R203K+G204R, su9b:T5cf,Several variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged during the current coronavirus disease 2019 (COVID-19) pandemic. Although antibody cross-reactivity with the spike glycoproteins (S) of diverse coronaviruses, including endemic common cold coronaviruses (HCoVs), has been documented, it remains unclear whether such antibody responses, typically targeting the conserved S2 subunit, contribute to protection when induced by infection or through vaccination. Using a mouse model, we found that prior HCoV-OC43 S-targeted immunity primes neutralizing antibody responses to otherwise subimmunogenic SARS-CoV-2 S exposure and promotes S2-targeting antibody responses. Moreover, vaccination with SARS-CoV-2 S2 elicited antibodies in mice that neutralized diverse animal and human alphacoronaviruses and betacoronaviruses in vitro and provided a degree of protection against SARS-CoV-2 challenge in vivo. Last, in mice with a history of SARS-CoV-2 Wuhan-based S vaccination, further S2 vaccination induced broader neutralizing antibody response than booster Wuhan S vaccination, suggesting that it may prevent repertoire focusing caused by repeated homologous vaccination. These data establish the protective value of an S2-targeting vaccine and support the notion that S2 vaccination may better prepare the immune system to respond to the changing nature of the S1 subunit in SARS-CoV-2 variants of concern, as well as to future coronavirus zoonoses.9c:T65f,This study sought to evaluate the effects of two vaccine doses and the extent of SARS-CoV-2 infection among healthcare workers. We measured immunoglobulin G antibody titers against SARS-CoV-2 nucleocapsid and spike protein among healthcare workers at Gunma University Hospital. In March 2021, prior to BNT-162b2 vaccination, two of 771 participants were seropositive for nucleocapsid and spike protein, whereas 768 were seronegative. The remaining one participant was seropositive for nucleocapsid protein but seronegative for spike protein. A total of 769 participants were seropositive for spike protein after two vaccination doses. The two seropositive participants prior to vaccination showed the highest antibody titers after the second vaccination. They were probably infected with SARS-CoV-2 without clinical symptoms before March 2021. Four weeks after the second vaccination, a younger age was associated with higher antibody titers against SARS-CoV-2 spike protein. Thirty-two weeks after the second vaccination, blood samples were collected from 342 of 769 participants. Antibody titers at 32 weeks after the second vaccination significantly decreased compared with those at 4 weeks after the second vaccination among all age groups. The rate of decrease in antibody titers between 4 and 32 weeks after the second vaccination was greater in the female participants. No sex differences were observed in the antibody titers within each age group. BNT-162b2 vaccination thus induced seroconversion in an age-dependent manner. Serological screening could further establish the likelihood of subclinical SARS-CoV-2 infection.9d:T507,The ongoing coronavirus disease 2019 (COVID-19) pandemic demonstrates the threat posed by novel coronaviruses to human health. Coronaviruses share a highly conserved cell entry mechanism mediated by the spike protein, the sole product of the S gene. The structural dynamics by which the spike protein orchestrates infection illuminate how antibodies neutralize virions and how S mutations contribute to viral fitness. Here, we review the process by which spike engages its proteinaceous receptor, angiotensin converting enzyme 2 (ACE2), and how host proteases prime and subsequently enable efficient membrane fusion between virions and target cells. We highlight mutations common among severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern and discuss implications for cell entry. Ultimately, we provide a model by which sarbecoviruses are activated for fusion competency and offer a framework for understanding the interplay between humoral immunity and the molecular evolution of the SARS-CoV-2 Spike. In particular, we emphasize the relevance of the Canyon Hypothesis (M. G. Rossmann, J Biol Chem 264:14587-14590, 1989) for understanding evolutionary trajectories of viral entry proteins during sustained intraspecies transmission of a novel viral pathogen.9e:T5f4,SARS-CoV-2 infection is associated with a surprising number of morbidities. Uncanny similarities with amyloid-disease associated blood coagulation and fibrinolytic disturbances together with neurologic and cardiac problems led us to investigate the amyloidogenicity of the SARS-CoV-2 spike protein (S-protein). Amyloid fibril assays of peptide library mixtures and theoretical predictions identified seven amyloidogenic sequences within the S-protein. All seven peptides in isolation formed aggregates during incubation at 37 °C. Three 20-amino acid long synthetic spike peptides (sequence 192-211, 601-620, 1166-1185) fulfilled three amyloid fibril criteria: nucleation dependent polymerization kinetics by ThT, Congo red positivity, and ultrastructural fibrillar morphology. Full-length folded S-protein did not form amyloid fibrils, but amyloid-like fibrils with evident branching were formed during 24 h of S-protein coincubation with the protease neutrophil elastase (NE) in vitro. NE efficiently cleaved S-protein, rendering exposure of amyloidogenic segments and accumulation of the amyloidogenic peptide 194-203, part of the most amyloidogenic synthetic spike peptide. NE is overexpressed at inflamed sites of viral infection. Our data propose a molecular mechanism for potential amyloidogenesis of SARS-CoV-2 S-protein in humans facilitated by endoproteolysis. The prospective of S-protein amyloidogenesis in COVID-19 disease associated pathogenesis can be important in understanding the disease and long COVID-19.9f:T567,COVID-19 vaccines have been developed to confer immunity against the SARS-CoV-2 infection. Prior to the pandemic of COVID-19 which started in March 2020, there was a well-established understanding about the structure and pathogenesis of previously known Coronaviruses from the SARS and MERS outbreaks. In addition to this, vaccines for various Coronaviruses were available for veterinary use. This knowledge supported the creation of various vaccine platforms for SARS-CoV-2. Before COVID-19 there are no reports of a vaccine being developed in under a year and no vaccine for preventing coronavirus infection in humans had ever been developed. Approximately nine different technologies are being researched and developed at various levels in order to design an effective COVID-19 vaccine. As the spike protein of SARS-CoV-2 is responsible for generating substantial adaptive immune response, mostly all the vaccine candidates have been targeting the whole spike protein or epitopes of spike protein as a vaccine candidate. In this review, we have compiled the immune response to SARS-CoV-2 infection and followed by the mechanism of action of various vaccine platforms such as mRNA vaccines, Adenoviral vectored vaccine, inactivated virus vaccines and subunit vaccines in the market. In the end we have also summarized the various adjuvants used in the COVID-19 vaccine formulation.a0:T4d3,Endogenous glucocorticoids and their synthetic analogues, such as dexamethasone, stimulate receptor-mediated signal transduction mechanisms on target cells. Some of these mechanisms result in beneficial outcomes whereas others are deleterious in the settings of pathogen infections and immunological disorders. Here, we review recent studies by several groups, including our group, showing that glucocorticoids can directly interact with protein components on SARS-CoV-2, the causative agent of COVID-19. We postulate an antiviral defence mechanism by which endogenous glucocorticoids (e.g., cortisol produced in response to SARS-CoV-2 infection) can bind to multiple sites on SARS-CoV-2 surface protein, Spike, inducing conformational alterations in Spike subunit 1 (S1) that inhibit SARS-CoV-2 interaction with the host SARS-CoV-2 receptor, ACE2. We suggest that glucocorticoids-mediated inhibition of S1 interaction with ACE2 may, consequently, affect SARS-CoV-2 infectivity. Further, glucocorticoids interactions with Spike could protect against a broad spectrum of coronaviruses and their variants that utilize Spike for infection of the host. These notions may be useful for the design of new antivirals for coronavirus diseases.a1:T58f,Increasing evidence suggests incomplete recovery of COVID-19 patients, who continue to suffer from cardiovascular diseases, including cerebral vascular disorders (CVD) and neurological symptoms. Recent findings indicate that some of the damaging effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, especially in the brain, may be induced by the spike protein, leading to the disruption of the initial blood-brain barrier (BBB). SARS-CoV-2-infected cells and animals exhibit age-dependent pathogenesis. In this study, we identified endothelial BACE1 as a critical mediator of BBB disruption and cellular senescence induced by the SARS-CoV-2 spike S1 subunit protein. Increased BACE1 in human brain microvascular endothelial cells (HBMVEC) decreases the levels of tight junction proteins, including ZO-1, occludin, and claudins. Moreover, BACE1 overexpression leads to the accumulation of p16 and p21, typical hallmarks of cellular senescence. Our findings show that the SARS-CoV-2 spike S1 subunit protein upregulated BACE1 expression in HBMVECs, causing endothelial leakage. In addition, the SARS-CoV-2 spike S1 subunit protein induced p16 and p21 expression, indicating BACE1-mediated cellular senescence, confirmed by β-Gal staining in HBMVECs. In conclusion, this study demonstrated that BACE1-mediated endothelial cell damage and senescence may be linked to CVD after COVID-19 infection.a2:T446,SARS-CoV-2 is responsible for the ongoing COVID-19 pandemic. The virus spreads rapidly with a high transmission rate among humans, and hence virus management has been challenging owing to finding specific therapies or vaccinations. Hence, an effective, low-cost vaccine is urgently required. In this study, the immunogenicity of the plant-produced S1 subunit protein of SARS-CoV-2 was examined in order to assess it as a potential candidate for SARS-CoV-2. The SARS-CoV-2 S1-Fc fusion protein was transiently produced in Nicotiana benthamiana. Within four days of infiltration, the SARS-CoV-2 S1-Fc protein was expressed in high quantities, and using protein A affinity column chromatography, plant-produced S1-Fc protein was purified from the crude extracts. The characterization of plant-produced S1-Fc protein was analyzed by SDS-PAGE and Western blotting. Immunogenicity of the purified S1-Fc protein formulated with alum induced both RBD specific antibodies and T cell immune responses in mice. These preliminary results indicated that the plant-produced S1 protein is immunogenic in mice.a3:T5fc,BACKGROUND: Myocarditis, even in a severe and lethal form, may occur after COVID-19 mRNA (BNT162b2) vaccination. However, its pathway, morphomolecular characterization and treatment are still unknown. METHODS: Routine hematochemical screening, ECG, Holter monitoring, 2D echocardiogram cardiac magnetic resonance (CMR) and invasive cardiac studies (cardiac catheterization, selective coronary angiography, left ventriculography and left ventricular endomyocardial biopsy) are reported from three patients (39F-pt1, 78M-pt2, 52M-pt3) with severe compromise of conduction tissue (junctional rhythm and syncope, pt1) or cardiac function compromise (LVEF ≤ 35%, pt2 and pt3) after COVID-19 mRNA (BNT162b2). RESULTS: Hematochemical data and coronary angiography were normal in the patients studied. Histology showed in all three patients extensive myocardial infiltration of degranulated eosinophils and elevation of serum cationic protein directly responsible for cardiomyocyte damage. These findings demonstrate myocarditis hypersensitivity to some component of the vaccine (spike protein?) acting as a hapten to some macromolecules of cardiomyocytes. Steroid administration (prednisone, 1 mg/kg die for 3 days, followed by 0.33 mg/kg for 4 weeks) was followed by complete recovery of cardiac contractility in pt2 and pt3. CONCLUSIONS: Eosinophilic myocarditis is a possible adverse reaction to the mRNA COVID-19 vaccine. Its pathway is mediated by release of cationic protein and responds to short courses of steroid administration.a4:T4b9,With the persistence of the SARS-CoV-2 pandemic and the emergence of novel variants, the development of novel vaccine formulations with enhanced immunogenicity profiles could help reduce disease burden in the future. Intranasally delivered vaccines offer a new modality to prevent SARS-CoV-2 infections through the induction of protective immune responses at the mucosal surface where viral entry occurs. Herein, we evaluated a novel protein subunit vaccine formulation containing a resistin-trimerized prefusion Spike antigen (SmT1v3) and a proteosome-based mucosal adjuvant (BDX301) formulated to enable intranasal immunization. In mice, the formulation induced robust antigen-specific IgG and IgA titers, in the blood and lungs, respectively. In addition, the formulations were highly efficacious in a hamster challenge model, reducing viral load and body weight loss. In both models, the serum antibodies had strong neutralizing activity, preventing the cellular binding of the viral Spike protein based on the ancestral reference strain, the Beta (B.1.351) and Delta (B.1.617.2) variants of concern. As such, this intranasal vaccine formulation warrants further development as a novel SARS-CoV-2 vaccine.a5:T650,The ongoing COVID-19 pandemic is a major public health crisis. Despite the development and deployment of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pandemic persists. The continued spread of the virus is largely driven by the emergence of viral variants, which can evade the current vaccines through mutations in the spike protein. Although these differences in spike are important in terms of transmission and vaccine responses, these variants possess mutations in the other parts of their genome that may also affect pathogenesis. Of particular interest to us are the mutations present in the accessory genes, which have been shown to contribute to pathogenesis in the host through interference with innate immune signaling, among other effects on host machinery. To examine the effects of accessory protein mutations and other nonspike mutations on SARS-CoV-2 pathogenesis, we synthesized both viruses possessing deletions in the accessory genes as well as viruses where the WA-1 spike is replaced by each variant spike gene in a SARS-CoV-2/WA-1 infectious clone. We then characterized the in vitro and in vivo replication of these viruses and compared them to both WA-1 and the full variant viruses. Our work has revealed that the accessory proteins contribute to SARS-CoV-2 pathogenesis and the nonspike mutations in variants can contribute to replication of SARS-CoV-2 and pathogenesis in the host. This work suggests that while spike mutations may enhance receptor binding and entry into cells, mutations in accessory proteins may alter clinical disease presentation.a6:T51a,Long coronavirus disease-19 (COVID-19) is a newly discovered syndrome characterized by multiple organ manifestations that persist for weeks to months, following the recovery from acute disease. Occasionally, neurological and cardiovascular side effects mimicking long COVID-19 have been reported in recipients of COVID-19 vaccines. Hypothetically, the clinical similarity could be due to a shared pathogenic role of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike (S) protein produced by the virus or used for immunization. The S protein can bind to neuropilin (NRP)-1, which normally functions as a coreceptor for the vascular endothelial growth factor (VEGF)-A. By antagonizing the docking of VEGF-A to NRP-1, the S protein could disrupt physiological pathways involved in angiogenesis and nociception. One consequence could be the increase in unbound forms of VEGF-A that could bind to other receptors. SARS-CoV-2-infected individuals may exhibit increased plasma levels of VEGF-A during both acute illness and convalescence, which could be responsible for diffuse microvascular and neurological damage. A few studies suggest that serum VEGF-A may also be a potential biomarker for long COVID-19, whereas evidence for COVID-19 vaccines is lacking and merits further investigation.a7:T738,The surge of COVID-19 infections has been fueled by new SARS-CoV-2 variants, namely Alpha, Beta, Gamma, Delta, and so forth. The molecular mechanism underlying such surge is elusive due to the existence of 28 554 unique mutations, including 4 653 non-degenerate mutations on the spike protein. Understanding the molecular mechanism of SARS-CoV-2 transmission and evolution is a prerequisite to foresee the trend of emerging vaccine-breakthrough variants and the design of mutation-proof vaccines and monoclonal antibodies. We integrate the genotyping of 1 489 884 SARS-CoV-2 genomes, a library of 130 human antibodies, tens of thousands of mutational data, topological data analysis, and deep learning to reveal SARS-CoV-2 evolution mechanism and forecast emerging vaccine-breakthrough variants. We show that prevailing variants can be quantitatively explained by infectivity-strengthening and vaccine-escape (co-)mutations on the spike protein RBD due to natural selection and/or vaccination-induced evolutionary pressure. We illustrate that infectivity strengthening mutations were the main mechanism for viral evolution, while vaccine-escape mutations become a dominating viral evolutionary mechanism among highly vaccinated populations. We demonstrate that Lambda is as infectious as Delta but is more vaccine-resistant. We analyze emerging vaccine-breakthrough comutations in highly vaccinated countries, including the United Kingdom, the United States, Denmark, and so forth. Finally, we identify sets of comutations that have a high likelihood of massive growth: [A411S, L452R, T478K], [L452R, T478K, N501Y], [V401L, L452R, T478K], [K417N, L452R, T478K], [L452R, T478K, E484K, N501Y], and [P384L, K417N, E484K, N501Y]. We predict they can escape existing vaccines. We foresee an urgent need to develop new virus combating strategies.a8:T7d0,In spite of intensive studies of different aspects of a new coronavirus infection, many issues still remain unclear. In a screening analysis of histopathology in l200 lethal cases, authors succeeded in performing a wide spectrum of immune histochemical reactions (CD2, CD 3, CD 4, CD 5, CD 7, CD 8, CD14, CD 20, CD 31, CD 34, CD 56, CD 57, CD 68, CD 163, collagen 1,3, spike protein SARS-CoV-2, caspase-3, MLCM; ACE2 receptor, occludin, and claudin-1 and -3) and electron microscopy. The results of the histological and IHC studies of deceased people with varying degrees of severity of coronavirus infection confirmed the ability of these pathogens to cause cytoproliferative changes, primarily in epithelial and endothelial cells. Lesions of various organs are possible, while the reasons for significant differences in organotropy remain unclear. Severe respiratory failure in COVID-19 in humans is associated with a very peculiar viral pneumonia. In the pathogenesis of COVID-19, the most important role is played by lesions of the microcirculatory bed, the genesis of which requires further study, but direct viral damage is most likely. Endothelial damage can be associated with both thrombosis in vessels of various calibers, leading to characteristic complications, and the development of DIC syndrome with maximal kidney damage. Such lesions can be the basis of clinically diagnosed septic shock, while usually there are no morphological data in favor of classical sepsis caused by bacteria or fungi. A massive infiltration of the lung tissue and other organs, mainly by T lymphocytes, including those with suppressor properties, makes it necessary to conduct a differential diagnosis between the morphological manifestation of the protective cellular immune response and direct viral lesions but does not exclude the hypothesis of an immunopathological component of pathogenesis. In many of the deceased, even in the absence of clear clinical symptoms, a variety of extrapulmonary lesions wa9:T799,COVID-19 emerged in late 2019 in China and quickly spread across the globe, causing over 521 million cases of infection and 6.26 million deaths to date. After 2 years, numerous advances have been made. First of all, the preventive vaccine, which has been implemented in record time, is effective in more than 95% of cases. Additionally, in the diagnostic field, there are numerous molecular and antigenic diagnostic kits that are equipped with high sensitivity and specificity. Real Time-PCR-based assays for the detection of viral RNA are currently considered the gold-standard method for SARS-CoV-2 diagnosis and can be used efficiently on pooled nasopharyngeal, or oropharyngeal samples for widespread screening. Moreover, additional, and more advanced molecular methods such as droplet-digital PCR (ddPCR), clustered regularly interspaced short palindromic repeats (CRISPR) and next-generation sequencing (NGS), are currently under development to detect the SARS-CoV-2 RNA. However, as the number of subjects infected with SARS-CoV-2 continuously increases globally, health care systems are being placed under increased stress. Thus, the clinical laboratory plays an important role, helping to select especially asymptomatic individuals who are actively carrying the live replicating virus, with fast and non-invasive molecular technologies. Recent diagnostic strategies, other than molecular methods, have been adopted to either detect viral antigens, i.e., antigen-based immunoassays, or human anti-SARS-CoV-2 antibodies, i.e., antibody-based immunoassays, in nasal or oropharyngeal swabs, as well as in blood or saliva samples. However, the role of mucosal sIgAs, which are essential in the control of viruses entering the body through mucosal surfaces, remains to be elucidated, and in particular the role of the immune response in counteracting SARS-CoV-2 infection, primarily at the site(s) of virus entry that appears to be promising.aa:T7d0,BACKGROUND: Antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been shown to neutralize the virus in vitro and prevent disease in animal challenge models on reexposure. However, the current understanding of SARS-CoV-2 humoral dynamics and longevity is conflicting. METHODS: The COVID-19 Staff Testing of Antibody Responses Study (Co-Stars) prospectively enrolled 3679 healthcare workers to comprehensively characterize the kinetics of SARS-CoV-2 spike protein (S), receptor-binding domain, and nucleoprotein (N) antibodies in parallel. Participants screening seropositive had serial monthly serological testing for a maximum of 7 months with the Meso Scale Discovery Assay. Survival analysis determined the proportion of seroreversion, while 2 hierarchical gamma models predicted the upper and lower bounds of long-term antibody trajectory. RESULTS: A total of 1163 monthly samples were provided from 349 seropositive participants. At 200 days after symptoms, >95% of participants had detectable S antibodies, compared with 75% with detectable N antibodies. S antibody was predicted to remain detectable in 95% of participants until 465 days (95% confidence interval, 370-575 days) using a "continuous-decay" model and indefinitely using a "decay-to-plateau" model to account for antibody secretion by long-lived plasma cells. S-antibody titers were correlated strongly with surrogate neutralization in vitro (R2 = 0.72). N antibodies, however, decayed rapidly with a half-life of 60 days (95% confidence interval, 52-68 days). CONCLUSIONS: The Co-Stars data presented here provide evidence for long-term persistence of neutralizing S antibodies. This has important implications for the duration of functional immunity after SARS-CoV-2 infection. In contrast, the rapid decay of N antibodies must be considered in future seroprevalence studies and public health decision-making. This is the first study to establish a mathematical framework capable of predicting long-terab:T661,Experimental findings for SARS-CoV-2 related to the glycan biochemistry of coronaviruses indicate that attachments from spike protein to glycoconjugates on the surfaces of red blood cells (RBCs), other blood cells and endothelial cells are key to the infectivity and morbidity of COVID-19. To provide further insight into these glycan attachments and their potential clinical relevance, the classic hemagglutination (HA) assay was applied using spike protein from the Wuhan, Alpha, Delta and Omicron B.1.1.529 lineages of SARS-CoV-2 mixed with human RBCs. The electrostatic potential of the central region of spike protein from these four lineages was studied through molecular modeling simulations. Inhibition of spike protein-induced HA was tested using the macrocyclic lactone ivermectin (IVM), which is indicated to bind strongly to SARS-CoV-2 spike protein glycan sites. The results of these experiments were, first, that spike protein from these four lineages of SARS-CoV-2 induced HA. Omicron induced HA at a significantly lower threshold concentration of spike protein than the three prior lineages and was much more electropositive on its central spike protein region. IVM blocked HA when added to RBCs prior to spike protein and reversed HA when added afterward. These results validate and extend prior findings on the role of glycan bindings of viral spike protein in COVID-19. They furthermore suggest therapeutic options using competitive glycan-binding agents such as IVM and may help elucidate rare serious adverse effects (AEs) associated with COVID-19 mRNA vaccines, which use spike protein as the generated antigen.ac:T5c5,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible coronavirus responsible for the global COVID-19 pandemic. Herein, we provide evidence that SARS-CoV-2 spreads through cell-cell contact in cultures, mediated by the spike glycoprotein. SARS-CoV-2 spike is more efficient in facilitating cell-to-cell transmission than is SARS-CoV spike, which reflects, in part, their differential cell-cell fusion activity. Interestingly, treatment of cocultured cells with endosomal entry inhibitors impairs cell-to-cell transmission, implicating endosomal membrane fusion as an underlying mechanism. Compared with cell-free infection, cell-to-cell transmission of SARS-CoV-2 is refractory to inhibition by neutralizing antibody or convalescent sera of COVID-19 patients. While angiotensin-converting enzyme 2 enhances cell-to-cell transmission, we find that it is not absolutely required. Notably, despite differences in cell-free infectivity, the authentic variants of concern (VOCs) B.1.1.7 (alpha) and B.1.351 (beta) have similar cell-to-cell transmission capability. Moreover, B.1.351 is more resistant to neutralization by vaccinee sera in cell-free infection, whereas B.1.1.7 is more resistant to inhibition by vaccinee sera in cell-to-cell transmission. Overall, our study reveals critical features of SARS-CoV-2 spike-mediated cell-to-cell transmission, with important implications for a better understanding of SARS-CoV-2 spread and pathogenesis.ad:T646,The coronavirus disease 2019 (COVID-19) pandemic is an exceptional public health crisis that demands the timely creation of new therapeutics and viral detection. Owing to their high specificity and reliability, monoclonal antibodies (mAbs) have emerged as powerful tools to treat and detect numerous diseases. Hence, many researchers have begun to urgently develop Ab-based kits for the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Ab drugs for use as COVID-19 therapeutic agents. The detailed structure of the SARS-CoV-2 spike protein is known, and since this protein is key for viral infection, its receptor-binding domain (RBD) has become a major target for therapeutic Ab development. Because SARS-CoV-2 is an RNA virus with a high mutation rate, especially under the selective pressure of aggressively deployed prophylactic vaccines and neutralizing Abs, the use of Ab cocktails is expected to be an important strategy for effective COVID-19 treatment. Moreover, SARS-CoV-2 infection may stimulate an overactive immune response, resulting in a cytokine storm that drives severe disease progression. Abs to combat cytokine storms have also been under intense development as treatments for COVID-19. In addition to their use as drugs, Abs are currently being utilized in SARS-CoV-2 detection tests, including antigen and immunoglobulin tests. Such Ab-based detection tests are crucial surveillance tools that can be used to prevent the spread of COVID-19. Herein, we highlight some key points regarding mAb-based detection tests and treatments for the COVID-19 pandemic.ae:T4ec,Memory B-cell and antibody responses to the SARS-CoV-2 spike protein contribute to long-term immune protection against severe COVID-19, which can also be prevented by antibody-based interventions. Here, wide SARS-CoV-2 immunoprofiling in Wuhan COVID-19 convalescents combining serological, cellular, and monoclonal antibody explorations revealed humoral immunity coordination. Detailed characterization of a hundred SARS-CoV-2 spike memory B-cell monoclonal antibodies uncovered diversity in their repertoire and antiviral functions. The latter were influenced by the targeted spike region with strong Fc-dependent effectors to the S2 subunit and potent neutralizers to the receptor-binding domain. Amongst those, Cv2.1169 and Cv2.3194 antibodies cross-neutralized SARS-CoV-2 variants of concern, including Omicron BA.1 and BA.2. Cv2.1169, isolated from a mucosa-derived IgA memory B cell demonstrated potency boost as IgA dimers and therapeutic efficacy as IgG antibodies in animal models. Structural data provided mechanistic clues to Cv2.1169 potency and breadth. Thus, potent broadly neutralizing IgA antibodies elicited in mucosal tissues can stem SARS-CoV-2 infection, and Cv2.1169 and Cv2.3194 are prime candidates for COVID-19 prevention and treatment.af:T48f,The emerging SARS-CoV-2 variants of concern (VOCs) threaten the effectiveness of current COVID-19 vaccines administered intramuscularly and designed to only target the spike protein. There is a pressing need to develop next-generation vaccine strategies for broader and long-lasting protection. Using adenoviral vectors (Ad) of human and chimpanzee origin, we evaluated Ad-vectored trivalent COVID-19 vaccines expressing spike-1, nucleocapsid, and RdRp antigens in murine models. We show that single-dose intranasal immunization, particularly with chimpanzee Ad-vectored vaccine, is superior to intramuscular immunization in induction of the tripartite protective immunity consisting of local and systemic antibody responses, mucosal tissue-resident memory T cells and mucosal trained innate immunity. We further show that intranasal immunization provides protection against both the ancestral SARS-CoV-2 and two VOC, B.1.1.7 and B.1.351. Our findings indicate that respiratory mucosal delivery of Ad-vectored multivalent vaccine represents an effective next-generation COVID-19 vaccine strategy to induce all-around mucosal immunity against current and future VOC.b0:T737,The review aims to consolidate research findings on the molecular mechanisms and virulence and pathogenicity characteristics of coronavirus disease (COVID-19) causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and their relevance to four typical stages in the development of acute viral infection. These four stages are invasion; primary blockade of antiviral innate immunity; engagement of the virus's protection mechanisms against the factors of adaptive immunity; and acute, long-term complications of COVID-19. The invasion stage entails the recognition of the spike protein (S) of SARS-CoV-2 target cell receptors, namely, the main receptor (angiotensin-converting enzyme 2, ACE2), its coreceptors, and potential alternative receptors. The presence of a diverse repertoire of receptors allows SARS-CoV-2 to infect various types of cells, including those not expressing ACE2. During the second stage, the majority of the polyfunctional structural, non-structural, and extra proteins SARS-CoV-2 synthesizes in infected cells are involved in the primary blockage of antiviral innate immunity. A high degree of redundancy and systemic action characterizing these pathogenic factors allows SARS-CoV-2 to overcome antiviral mechanisms at the initial stages of invasion. The third stage includes passive and active protection of the virus from factors of adaptive immunity, overcoming of the barrier function at the focus of inflammation, and generalization of SARS-CoV-2 in the body. The fourth stage is associated with the deployment of variants of acute and long-term complications of COVID-19. SARS-CoV-2's ability to induce autoimmune and autoinflammatory pathways of tissue invasion and development of both immunosuppressive and hyperergic mechanisms of systemic inflammation is critical at this stage of infection.b1:T7d0,UNLABELLED: The ongoing COVID-19 pandemic is a major public health crisis. Despite the development and deployment of vaccines against SARS-CoV-2, the pandemic persists. The continued spread of the virus is largely driven by the emergence of viral variants, which can evade the current vaccines through mutations in the Spike protein. Although these differences in Spike are important in terms of transmission and vaccine responses, these variants possess mutations in the other parts of their genome which may affect pathogenesis. Of particular interest to us are the mutations present in the accessory genes, which have been shown to contribute to pathogenesis in the host through innate immune signaling, among other effects on host machinery. To examine the effects of accessory protein mutations and other non-spike mutations on SARS-CoV-2 pathogenesis, we synthesized viruses where the WA1 Spike is replaced by each variant spike genes in a SARS-CoV-2/WA-1 infectious clone. We then characterized the in vitro and in vivo replication of these viruses and compared them to the full variant viruses. Our work has revealed that non-spike mutations in variants can contribute to replication of SARS-CoV-2 and pathogenesis in the host and can lead to attenuating phenotypes in circulating variants of concern. This work suggests that while Spike mutations may enhance receptor binding and entry into cells, mutations in accessory proteins may lead to less clinical disease, extended time toward knowing an infection exists in a person and thus increased time for transmission to occur. SIGNIFICANCE: A hallmark of the COVID19 pandemic has been the emergence of SARS-CoV-2 variants that have increased transmission and immune evasion. Each variant has a set of mutations that can be tracked by sequencing but little is known about their affect on pathogenesis. In this work we first identify accessory genes that are responsible for pathogenesis in vivo as well as identify the role of variant spike gb2:T661,Germinal centres (GC) are lymphoid structures in which B cells acquire affinity-enhancing somatic hypermutations (SHM), with surviving clones differentiating into memory B cells (MBCs) and long-lived bone marrow plasma cells1-5 (BMPCs). SARS-CoV-2 mRNA vaccination induces a persistent GC response that lasts for at least six months in humans6-8. The fate of responding GC B cells as well as the functional consequences of such persistence remain unknown. Here, we detected SARS-CoV-2 spike protein-specific MBCs in 42 individuals who had received two doses of the SARS-CoV-2 mRNA vaccine BNT162b2 six month earlier. Spike-specific IgG-secreting BMPCs were detected in 9 out of 11 participants. Using a combined approach of sequencing the B cell receptors of responding blood plasmablasts and MBCs, lymph node GC B cells and plasma cells and BMPCs from eight individuals and expression of the corresponding monoclonal antibodies, we tracked the evolution of 1,540 spike-specific B cell clones. On average, early blood spike-specific plasmablasts exhibited the lowest SHM frequencies. By contrast, SHM frequencies of spike-specific GC B cells increased by 3.5-fold within six months after vaccination. Spike-specific MBCs and BMPCs accumulated high levels of SHM, which corresponded with enhanced anti-spike antibody avidity in blood and enhanced affinity as well as neutralization capacity of BMPC-derived monoclonal antibodies. We report how the notable persistence of the GC reaction induced by SARS-CoV-2 mRNA vaccination in humans culminates in affinity-matured long-term antibody responses that potently neutralize the virus.b3:T7d8,SARS-CoV-2 infection produces neuroinflammation as well as neurological, cognitive (i.e., brain fog), and neuropsychiatric symptoms (e.g., depression, anxiety), which can persist for an extended period (6 months) after resolution of the infection. The neuroimmune mechanism(s) that produces SARS-CoV-2-induced neuroinflammation has not been characterized. Proposed mechanisms include peripheral cytokine signaling to the brain and/or direct viral infection of the CNS. Here, we explore the novel hypothesis that a structural protein (S1) derived from SARS-CoV-2 functions as a pathogen-associated molecular pattern (PAMP) to induce neuroinflammatory processes independent of viral infection. Prior evidence suggests that the S1 subunit of the SARS-CoV-2 spike protein is inflammatory in vitro and signals through the pattern recognition receptor TLR4. Therefore, we examined whether the S1 subunit is sufficient to drive 1) a behavioral sickness response, 2) a neuroinflammatory response, 3) direct activation of microglia in vitro, and 4) activation of transgenic human TLR2 and TLR4 HEK293 cells. Adult male Sprague-Dawley rats were injected intra-cisterna magna (ICM) with vehicle or S1. In-cage behavioral monitoring (8 h post-ICM) demonstrated that S1 reduced several behaviors, including total activity, self-grooming, and wall-rearing. S1 also increased social avoidance in the juvenile social exploration test (24 h post-ICM). S1 increased and/or modulated neuroimmune gene expression (Iba1, Cd11b, MhcIIα, Cd200r1, Gfap, Tlr2, Tlr4, Nlrp3, Il1b, Hmgb1) and protein levels (IFNγ, IL-1β, TNF, CXCL1, IL-2, IL-10), which varied across brain regions (hypothalamus, hippocampus, and frontal cortex) and time (24 h and 7d) post-S1 treatment. Direct exposure of microglia to S1 resulted in increased gene expression (Il1b, Il6, Tnf, Nlrp3) and protein levels (IL-1β, IL-6, TNF, CXCL1, IL-10). S1 also activated TLR2 and TLR4 receptor signaling in HEK293 transgenic cells. Taken together, these findb4:T47b,Additional COVID-19 vaccines that are safe and immunogenic are needed for global vaccine equity. Here, we developed a recombinant type 5 adenovirus vector encoding for the SARS-CoV-2 S1 subunit antigen and nucleocapsid as a fusion protein (Ad5.SARS-CoV-2-S1N). A single subcutaneous immunization with Ad5.SARS-CoV-2-S1N induced a similar humoral response, along with a significantly higher S1-specific cellular response, as a recombinant type 5 adenovirus vector encoding for S1 alone (Ad5.SARS-CoV-2-S1). Immunogenicity was improved by homologous prime-boost vaccination, and further improved through intramuscular heterologous prime-boost vaccination using subunit recombinant S1 protein. Priming with low dose (1 × 1010 v.p.) of Ad5.SARS-CoV-2-S1N and boosting with either wild-type recombinant rS1 or B.1.351 recombinant rS1 induced a robust neutralizing response, which was sustained against Beta and Gamma SARS-CoV-2 variants. This novel Ad5-vectored SARS-CoV-2 vaccine candidate showed promising immunogenicity in mice and supports the further development of COVID-19-based vaccines incorporating the nucleoprotein as a target antigen.b5:T6e0,Coronavirus disease 2019 (COVID-19) is especially severe in aged populations1. Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are highly effective, but vaccine efficacy is partly compromised by the emergence of SARS-CoV-2 variants with enhanced transmissibility2. The emergence of these variants emphasizes the need for further development of anti-SARS-CoV-2 therapies, especially for aged populations. Here we describe the isolation of highly virulent mouse-adapted viruses and use them to test a new therapeutic drug in infected aged animals. Many of the alterations observed in SARS-CoV-2 during mouse adaptation (positions 417, 484, 493, 498 and 501 of the spike protein) also arise in humans in variants of concern2. Their appearance during mouse adaptation indicates that immune pressure is not required for selection. For murine SARS, for which severity is also age dependent, elevated levels of an eicosanoid (prostaglandin D2 (PGD2)) and a phospholipase (phospholipase A2 group 2D (PLA2G2D)) contributed to poor outcomes in aged mice3,4. mRNA expression of PLA2G2D and prostaglandin D2 receptor (PTGDR), and production of PGD2 also increase with ageing and after SARS-CoV-2 infection in dendritic cells derived from human peripheral blood mononuclear cells. Using our mouse-adapted SARS-CoV-2, we show that middle-aged mice lacking expression of PTGDR or PLA2G2D are protected from severe disease. Furthermore, treatment with a PTGDR antagonist, asapiprant, protected aged mice from lethal infection. PTGDR antagonism is one of the first interventions in SARS-CoV-2-infected animals that specifically protects aged animals, suggesting that the PLA2G2D-PGD2/PTGDR pathway is a useful target for therapeutic interventions.b6:T769,Whereas, multiple vaccine types have been developed to curb the spread of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) among humans, there are very few vaccines being developed for animals including pets. To combat the threat of human-to-animal, animal-to-animal, and animal-to-human transmission and the generation of new virus variants, we developed a subunit SARS-CoV-2 vaccine which is based on the recombinant spike protein extracellular domain expressed in insect cells and then formulated with appropriate adjuvants. Sixteen 8-12-week-old outbred female and male kittens (n = 4 per group) were randomly assigned into four treatment groups: spike protein alone; spike plus ESSAI oil-in-water (O/W) 1849102 adjuvant; spike plus aluminum hydroxide adjuvant; and a PBS control. All animals were vaccinated intramuscularly twice, 2 weeks apart, with 5 μg of spike protein in a volume of 0.5 ml. On days 0 and 28, serum samples were collected to evaluate anti-spike IgG, antibody inhibition of spike binding to angiotensin-converting enzyme 2 (ACE-2), neutralizing antibodies against wild-type and delta variant viruses, and hematology studies. At day 28, all groups were challenged with SARS-CoV-2 wild-type virus 106 TCID50 intranasally. On day 31, tissue samples (lung, heart, and nasal turbinates) were collected for viral RNA detection, and virus titration. After two immunizations, both vaccines induced high titers of serum anti-spike IgG that inhibited spike ACE-2 binding and neutralized both wild-type and delta variant virus. Both adjuvanted vaccine formulations protected juvenile cats against virus shedding from the upper respiratory tract and viral replication in the lower respiratory tract and hearts. These promising data warrant ongoing evaluation of the vaccine's ability to protect cats against SARS-CoV-2 infection and in particular to prevent transmission.b7:T7d0,Microvascular thrombosis is associated with multiorgan failure and mortality in coronavirus disease 2019 (COVID-19). Although thrombotic complications may be ascribed to the ability of SARS-CoV-2 to infect and replicate in endothelial cells, it has been poorly investigated whether, in the complexity of viral infection in the human host, specific viral elements alone can induce endothelial damage. Detection of circulating spike protein in the sera of severe COVID-19 patients was evaluated by ELISA. In vitro experiments were performed on human microvascular endothelial cells from the derma and lung exposed to SARS-CoV-2-derived spike protein 1 (S1). The expression of adhesive molecules was studied by immunofluorescence and leukocyte adhesion and platelet aggregation were assessed under flow conditions. Angiotensin converting enzyme 2 (ACE2) and AMPK expression were investigated by Western Blot analysis. In addition, S1-treated endothelial cells were incubated with anti-ACE2 blocking antibody, AMPK agonist, or complement inhibitors. Our results show that significant levels of spike protein were found in the 30.4% of severe COVID-19 patients. In vitro, the activation of endothelial cells with S1 protein, via ACE2, impaired AMPK signalling, leading to robust leukocyte recruitment due to increased adhesive molecule expression and thrombomodulin loss. This S1-induced pro-inflammatory phenotype led to exuberant C3 and C5b-9 deposition on endothelial cells, along with C3a and C5a generation that further amplified S1-induced complement activation. Functional blockade of ACE2 or complement inhibition halted S1-induced platelet aggregates by limiting von Willebrand factor and P-selectin exocytosis and expression on endothelial cells. Overall, we demonstrate that SARS-CoV-2-derived S1 is sufficient in itself to propagate inflammatory and thrombogenic processes in the microvasculature, amplified by the complement system, recapitulating the thromboembolic complications of COVID-19b8:T507,Frequent outbreaks of coronaviruses underscore the need for antivirals and vaccines that can counter a broad range of coronavirus types. We isolated a human antibody named 76E1 from a COVID-19 convalescent patient, and report that it has broad-range neutralizing activity against multiple α- and β-coronaviruses, including the SARS-CoV-2 variants. 76E1 also binds its epitope in peptides from γ- and δ-coronaviruses. 76E1 cross-protects against SARS-CoV-2 and HCoV-OC43 infection in both prophylactic and therapeutic murine animal models. Structural and functional studies revealed that 76E1 targets a unique epitope within the spike protein that comprises the highly conserved S2' site and the fusion peptide. The epitope that 76E1 binds is partially buried in the structure of the SARS-CoV-2 spike trimer in the prefusion state, but is exposed when the spike protein binds to ACE2. This observation suggests that 76E1 binds to the epitope at an intermediate state of the spike trimer during the transition from the prefusion to the postfusion state, thereby blocking membrane fusion and viral entry. We hope that the identification of this crucial epitope, which can be recognized by 76E1, will guide epitope-based design of next-generation pan-coronavirus vaccines and antivirals.b9:T4d6,Placental pathology can identify characteristic features of specific infectious pathogens. The histopathology of acute SARS-CoV-2 placental infection and exposure without infection has been well described. However, whether the characteristic placental pathology persists after the acute phase of the infection is less clear. We retrospectively identified 67 COVID-19-recovered pregnant patients who had placental pathology available. After reviewing the gross and histopathology, we categorized the findings and studied the placentas for evidence of chronic infection by immunohistochemistry for the spike protein of the virus. We found these placentas showed significantly increased prevalence of maternal and a trend towards significance of fetal vascular malperfusion when compared to a control group of placentas examined for the sole indication of maternal group B streptococcal colonization. None of the COVID-19-recovered placentas showed expression of the viral spike protein; therefore, we found no evidence of persistent infection of the placenta in women with a history of COVID-19 during their pregnancy. We conclude that recovery from a SARS-CoV-2 infection during pregnancy puts the pregnancy at risk for specific pathology.ba:T692,The world continues to be in the midst of a distressing pandemic of coronavirus disease 2019 (COVID-19) infection caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a novel virus with multiple antigenic systems. The virus enters via nasopharynx, oral and infects cells by the expression of the spike protein, and enters the lungs using the angiotensin-converting enzyme-2 receptor. The spectrum of specific immune responses to SARS-CoV-2 virus infection is increasingly challenging as frequent mutations have been reported and their antigen specificity varies accordingly. The development of monoclonal antibodies (mAbs) will have a more significant advantage in suppressing SARS-CoV-2 virus infectivity. Recently, mAbs have been developed to target included specific neutralizing antibodies against SARS-CoV-2 infection. The use of the therapeutic index of mAbs that can elicit neutralization by binding to the viral spike protein and suppress the cytokine network is a classic therapeutic approach for a potential cure. The development of mAbs against B-cell function as well as inhibition of the cytokine network has also been a focus in recent research. Recent studies have demonstrated the efficacy of mAbs as antibody cocktail preparations against SARS-CoV-2 infection. Target specific therapeutic accomplishment with mAbs, a milestone in the modern therapeutic age, can be used to achieve a specific therapeutic strategy to suppress SARS-CoV-2 virus infection. This review focuses on the molecular aspects of the cytokine network and antibody formation to better understand the development of mAbs against SARS- CoV-2 infection along with recent patents.bb:T7d2,Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), rapidly evolved into a pandemic -the likes of which has not been experienced in 100 years. While novel vaccines show great efficacy, and therapeutics continue to be developed, the persistence of disease, with the concomitant threat of emergent variants, continues to impose massive health and socioeconomic issues worldwide. Studies show that in susceptible individuals, SARS-CoV-2 infection can rapidly progress toward lung injury and acute respiratory distress syndrome (ARDS), with evidence for an underlying dysregulated innate immune response or cytokine release syndrome (CRS). The mechanisms responsible for this CRS remain poorly understood, yet hyper-inflammatory features were also evident with predecessor viruses within the β-coronaviridae family, namely SARS-CoV-1 and the Middle East Respiratory Syndrome (MERS)-CoV. It is further known that the spike protein (S) of SARS-CoV-2 (as first reported for other β-coronaviruses) possesses a so-called galectin-fold within the N-terminal domain of the S1 subunit (S1-NTD). This fold (or pocket) shows structural homology nearly identical to that of human galectin-3 (Gal-3). In this respect, we have recently shown that Gal-3, when associated with epithelial cells or anchored to a solid phase matrix, facilitates the activation of innate immune cells, including basophils, DC, and monocytes. A synthesis of these findings prompted us to test whether segments of the SARS-CoV-2 spike protein might also activate innate immune cells in a manner similar to that observed in our Gal-3 studies. Indeed, by immobilizing S components onto microtiter wells, we show that only the S1 subunit (with the NTD) activates human monocytes to produce a near identical pattern of cytokines as those reported in COVID-19-related CRS. In contrast, both the S1-CTD/RBD, which binds ACE2, and the S2 subunit (stalk), failed to mediate the same effecbc:T74e,Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 has spread worldwide, leading the World Health Organization (WHO) to declare a pandemic, on 11 March 2020. Variants of concern have appeared at regular intervals-Alpha, Beta, Gamma, Delta, and now Omicron. Omicron variant, first identified in Botswana in November 2021, is rapidly becoming the dominant circulating variant. In this review, we provide an overview regarding the molecular profile of the Omicron variant, epidemiology, transmissibility, the impact on vaccines, as well as vaccine escape, and finally, we report the pharmacological agents able to block the endocellular entry of SARS-CoV-2 or to inhibit its viral replication. The Omicron has more than 50 mutations, of which the spike protein has 26-35 amino acids different from the original SARS-CoV-2 virus or the Delta, some of which are associated with humoral immune escape potential and greater transmissibility. Omicron has a significant growth advantage over Delta, leading to rapid spread with higher incidence levels. The disease so far has been mild compared to the Delta. The two vaccination doses offer little or no protection against Omicron infection while the booster doses provide significant protection against mild illness and likely offer even greater levels of protection against serious illness. Recently, new oral antiviral agents such as molnupiravir and paxlovid have been approved and represent important therapeutic alternatives to antiviral remdesivir. In addition, monoclonal antibodies such as casirivimab/imdevimab bind different epitopes of the spike protein receptor; is this class of drugs effective against the Omicron variant? However, more research is needed to define whether Omicron is indeed more infectious and whether the vaccines, monoclonal antibodies, and antivirals currently available are effective.bd:T7d0,SARS-CoV-2 infects cells via its spike protein binding to its surface receptor on target cells and results in acute symptoms involving especially the lungs known as COVID-19. However, increasing evidence indicates that many patients develop a chronic condition characterized by fatigue and neuropsychiatric symptoms, termed long-COVID. Most of the vaccines produced so far for COVID-19 direct mammalian cells via either mRNA or an adenovirus vector to express the spike protein, or administer recombinant spike protein, which is recognized by the immune system leading to the production of neutralizing antibodies. Recent publications provide new findings that may help decipher the pathogenesis of long-COVID. One paper reported perivascular inflammation in brains of deceased patients with COVID-19, while others showed that the spike protein could damage the endothelium in an animal model, that it could disrupt an in vitro model of the blood-brain barrier (BBB), and that it can cross the BBB resulting in perivascular inflammation. Moreover, the spike protein appears to share antigenic epitopes with human molecular chaperons resulting in autoimmunity and can activate toll-like receptors (TLRs), leading to release of inflammatory cytokines. Moreover, some antibodies produced against the spike protein may not be neutralizing, but may change its conformation rendering it more likely to bind to its receptor. As a result, one wonders whether the spike protein entering the brain or being expressed by brain cells could activate microglia, alone or together with inflammatory cytokines, since protective antibodies could not cross the BBB, leading to neuro-inflammation and contributing to long-COVID. Hence, there is urgent need to better understand the neurotoxic effects of the spike protein and to consider possible interventions to mitigate spike protein-related detrimental effects to the brain, possibly via use of small natural molecules, especially the flavonoids luteolin and quercebe:T70e,Understanding antibody responses after natural severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can guide the coronavirus disease 2019 (COVID-19) vaccine schedule, especially in resource-limited settings. This study aimed to assess the dynamics of SARS-CoV-2 antibodies, including anti-spike protein 1 (S1) immunoglobulin (Ig)G, anti-receptor-binding domain (RBD) total Ig, anti-S1 IgA, and neutralizing antibody against wild-type SARS-CoV-2 over time in a cohort of patients who were previously infected with the wild-type SARS-CoV-2. Between March and May 2020, 531 individuals with virologically confirmed cases of wild-type SARS-CoV-2 infection were enrolled in our immunological study. Blood samples were collected at 3-, 6-, 9-, and 12-months post symptom onset or detection of SARS-CoV-2 by RT-PCR (in asymptomatic individuals). The neutralizing titers against SARS-CoV-2 were detected in 95.2%, 86.7%, 85.0%, and 85.4% of recovered COVID-19 patients at 3, 6, 9, and 12 months after symptom onset, respectively. The seropositivity rate of anti-S1 IgG, anti-RBD total Ig, anti-S1 IgA, and neutralizing titers remained at 68.6%, 89.6%, 77.1%, and 85.4%, respectively, at 12 months after symptom onset. We observed a high level of correlation between neutralizing and SARS-CoV-2 spike protein-specific antibody titers. The half-life of neutralizing titers was estimated at 100.7 days (95% confidence interval = 44.5-327.4 days, R2 = 0.106). These results support that the decline in serum antibody levels over time in both participants with severe disease and mild disease were depended on the symptom severity, and the individuals with high IgG antibody titers experienced a significantly longer persistence of SARS-CoV-2-specific antibody responses than those with lower titers.bf:T7d0,Young age, female sex, absence of comorbidities, and prior infection or vaccination are known epidemiological barriers for contracting the new infection and/or increased disease severity. Demographic trends from the recent coronavirus disease 2019 waves, which are believed to be driven by newer severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, indicate that the aforementioned epidemiological barriers are being breached and a larger number of younger and healthy individuals are developing severe disease. The new SARS-CoV-2 variants have key mutations that can induce significant changes in the virus-host interactions. Recent studies report that, some of these mutations, singly or in a group, enhance key mechanisms, such as binding of the receptor-binding domain (RBD) of the viral spike protein with the angiotensin-converting enzyme 2 (ACE2) receptor in the host-cells, increase the glycosylation of spike protein at the antigenic sites, and enhance the proteolytic cleavage of the spike protein, thus leading to improved host-cell entry and the replication of the virus. The putative changes in the virus-host interactions imparted by the mutations in the RBD sequence can potentially be the reason behind the breach of the observed epidemiological barriers. Susceptibility for contracting SARS-CoV-2 infection and the disease outcomes are known to be influenced by host-cell expressions of ACE2 and other proteases. The new variants can act more efficiently, and even with the lesser availability of the viral entry-receptor and the associated proteases, can have more efficient host-cell entry and greater replication resulting in high viral loads and prolonged viral shedding, widespread tissue-injury, and severe inflammation leading to increased transmissibility and lethality. Furthermore, the accumulating evidence shows that multiple new variants have reduced neutralization by both, natural and vaccine-acquired antibodies, indicating that repeated and vaccinec0:T5c0,The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the deadly coronavirus disease 2019 (Covid-19) and is a concerning hazard to public health. This virus infects cells by establishing a contact between its spike protein (S-protein) and host human angiotensin-converting enzyme 2 (hACE2) receptor, subsequently initiating viral fusion. The inhibition of the interaction between the S-protein and hACE2 has immediately drawn attention amongst the scientific community, and the S-protein was considered the prime target to design vaccines and to develop affinity ligands for diagnostics and therapy. Several S-protein binders have been reported at a fast pace, ranging from antibodies isolated from immunised patients to de novo designed ligands, with some binders already yielding promising in vivo results in protecting against SARS-CoV-2. Natural, engineered and designed affinity ligands targeting the S-protein are herein summarised, focusing on molecular recognition aspects, whilst identifying preferred hot spots for ligand binding. This review serves as inspiration for the improvement of already existing ligands or for the design of new affinity ligands towards SARS-CoV-2 proteins. Lessons learnt from the Covid-19 pandemic are also important to consolidate tools and processes in protein engineering to enable the fast discovery, production and delivery of diagnostic, prophylactic, and therapeutic solutions in future pandemics.c1:T7ec,Effective mRNA SARS-CoV-2 vaccines are available but need to be stored in freezers, limiting their use to countries that have appropriate storage capacity. ChulaCov19 is a prefusion non-stabilized SARS-CoV-2 spike-protein-encoding, nucleoside-modified mRNA, lipid nanoparticle encapsulated vaccine that we report to be stable when stored at 2-8 °C for up to 3 months. Here we report safety and immunogenicity data from a phase I open-label, dose escalation, first-in-human trial of the ChulaCov19 vaccine (NCT04566276). Seventy-two eligible volunteers, 36 of whom were aged 18-55 (adults) and 36 aged 56-75 (elderly), were enroled. Two doses of vaccine were administered 21 d apart at 10, 25 or 50 μg per dose (12 per group). The primary outcome was safety and the secondary outcome was immunogenicity. All three dosages of ChulaCov19 were well tolerated and elicited robust dose-dependent and age-dependent B- and T-cell responses. Transient mild/moderate injection site pain, fever, chills, fatigue and headache were more common after the second dose. Four weeks after the second dose, in the adult cohort, MicroVNT-50 geometric mean titre against wild-type SARS-CoV-2 was 848 (95% CI, 483-1,489), 736 (459-1,183) and 1,140 (854-1,522) IU ml-1 at 10, 25 and 50 μg doses, respectively, versus 285 (196-413) IU ml-1 for human convalescent sera. All dose levels elicited 100% seroconversion, with geometric mean titre ratios 4-8-fold higher than for human convalescent sera (P < 0.01), and high IFNγ spot-forming cells per million peripheral blood mononuclear cells. The 50 μg dose induced better cross-neutralization against Alpha, Beta, Gamma and Delta variants than lower doses. ChulaCov19 at 50 μg is well tolerated and elicited higher neutralizing antibodies than human convalescent sera, with strong T-cell responses. These antibodies cross-neutralized four variants of concern. ChulaCov19 has proceeded to phase 2 clinical trials. We conclude that the mRNA vaccine expressing a prefusion non-stc2:T7bc,The ongoing SARS-CoV-2 pandemic has shocked the world due to its persistence, COVID-19-related morbidity and mortality, and the high mutability of the virus. One of the major concerns is the emergence of new viral variants that may increase viral transmission and disease severity. In addition to mutations of spike protein, mutations of viral proteins that affect virulence, such as ORF3a, also must be considered. The purpose of this article is to review the current literature on ORF3a, to summarize the molecular actions of SARS-CoV-2 ORF3a, and its role in viral pathogenesis and COVID-19. ORF3a is a polymorphic, multifunctional viral protein that is specific to SARS-CoV/SARS-CoV-2. It was acquired from β-CoV lineage and likely originated from bats through viral evolution. SARS-CoV-2 ORF3a is a viroporin that interferes with ion channel activities in host plasma and endomembranes. It is likely a virion-associated protein that exerts its effect on the viral life cycle during viral entry through endocytosis, endomembrane-associated viral transcription and replication, and viral release through exocytosis. ORF3a induces cellular innate and pro-inflammatory immune responses that can trigger a cytokine storm, especially under hypoxic conditions, by activating NLRP3 inflammasomes, HMGB1, and HIF-1α to promote the production of pro-inflammatory cytokines and chemokines. ORF3a induces cell death through apoptosis, necrosis, and pyroptosis, which leads to tissue damage that affects the severity of COVID-19. ORF3a continues to evolve along with spike and other viral proteins to adapt in the human cellular environment. How the emerging ORF3a mutations alter the function of SARS-CoV-2 ORF3a and its role in viral pathogenesis and COVID-19 is largely unknown. This review provides an in-depth analysis of ORF3a protein's structure, origin, evolution, and mutant variants, and how these characteristics affect its functional role in viral pathogenesis and COVID-19.c3:T6d4,Vascular endothelial cells (ECs) form a critical interface between blood and tissues that maintains whole-body homeostasis. In COVID-19, disruption of the EC barrier results in edema, vascular inflammation, and coagulation, hallmarks of this severe disease. However, the mechanisms by which ECs are dysregulated in COVID-19 are unclear. Here, we show that the spike protein of SARS-CoV-2 alone activates the EC inflammatory phenotype in a manner dependent on integrin ⍺5β1 signaling. Incubation of human umbilical vein ECs with whole spike protein, its receptor-binding domain, or the integrin-binding tripeptide RGD induced the nuclear translocation of NF-κB and subsequent expression of leukocyte adhesion molecules (VCAM1 and ICAM1), coagulation factors (TF and FVIII), proinflammatory cytokines (TNFα, IL-1β, and IL-6), and ACE2, as well as the adhesion of peripheral blood leukocytes and hyperpermeability of the EC monolayer. In addition, inhibitors of integrin ⍺5β1 activation prevented these effects. Furthermore, these vascular effects occur in vivo, as revealed by the intravenous administration of spike, which increased expression of ICAM1, VCAM1, CD45, TNFα, IL-1β, and IL-6 in the lung, liver, kidney, and eye, and the intravitreal injection of spike, which disrupted the barrier function of retinal capillaries. We suggest that the spike protein, through its RGD motif in the receptor-binding domain, binds to integrin ⍺5β1 in ECs to activate the NF-κB target gene expression programs responsible for vascular leakage and leukocyte adhesion. These findings uncover a new direct action of SARS-CoV-2 on EC dysfunction and introduce integrin ⍺5β1 as a promising target for treating vascular inflammation in COVID-19.c4:T6de,Omicron (B.1.1.529), the most heavily mutated SARS-CoV-2 variant so far, is highly resistant to neutralizing antibodies, raising concerns about the effectiveness of antibody therapies and vaccines1,2. Here we examined whether sera from individuals who received two or three doses of inactivated SARS-CoV-2 vaccine could neutralize authentic Omicron. The seroconversion rates of neutralizing antibodies were 3.3% (2 out of 60) and 95% (57 out of 60) for individuals who had received 2 and 3 doses of vaccine, respectively. For recipients of three vaccine doses, the geometric mean neutralization antibody titre for Omicron was 16.5-fold lower than for the ancestral virus (254). We isolated 323 human monoclonal antibodies derived from memory B cells in triple vaccinees, half of which recognized the receptor-binding domain, and showed that a subset (24 out of 163) potently neutralized all SARS-CoV-2 variants of concern, including Omicron. Therapeutic treatments with representative broadly neutralizing monoclonal antibodies were highly protective against infection of mice with SARS-CoV-2 Beta (B.1.351) and Omicron. Atomic structures of the Omicron spike protein in complex with three classes of antibodies that were active against all five variants of concern defined the binding and neutralizing determinants and revealed a key antibody escape site, G446S, that confers greater resistance to a class of antibodies that bind on the right shoulder of the receptor-binding domain by altering local conformation at the binding interface. Our results rationalize the use of three-dose immunization regimens and suggest that the fundamental epitopes revealed by these broadly ultrapotent antibodies are rational targets for a universal sarbecovirus vaccine.c5:T6c2,INTRODUCTION: Since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), substantial effort has been made to gain knowledge about the immunity elicited by infection or vaccination. METHODS: We studied the kinetics of antibodies and virus neutralisation induced by vaccination with BNT162b2 in a Swiss cohort of SARS-CoV-2 naïve (n = 40) and convalescent (n = 9) persons. Blood sera were analysed in a live virus neutralisation assay and specific IgG and IgA levels were measured by enzyme-linked immunoassay and analysed by descriptive statistics. RESULTS: Virus neutralisation was detected in all individuals 2-4 weeks after the second vaccine. Both neutralisation and antibodies remained positive for >4 months. Neutralisation and antibodies showed positive correlation, but immunoglobulin G (IgG) and immunoglobulin A (IgA) seroconversion took place 2-4 weeks faster than neutralisation. Spike-protein specific IgG levels rose significantly faster and were more stable over time than virus neutralisation titres or IgA responses. For naïve but not convalescent persons, a clear boosting effect was observed. Convalescent individuals showed faster, more robust and longer-lasting immune responses after vaccination compared to noninfected persons. No threshold could be determined for spike protein-specific IgG or IgA that would confer protection in the neutralisation assay, implicating the need for a better correlate of protection then antibody titres alone. CONCLUSIONS: This study clearly shows the complex translation of antibody data and virus neutralisation, while supporting the evidence of a single dose being sufficient for effective antibody response in convalescent individuals.c6:T497,Vaccination against SARS-CoV-2 just started in most of the countries. However, the development of specific vaccines against SARS-CoV-2 is not the only approach to control the virus and monoclonal antibodies (mAbs) start to merit special attention as a therapeutic option to treat COVID-19 disease. Here, the main conformations and interactions between the receptor-binding domain (RBD) of spike glycoprotein of SARS-CoV-2 (S protein) with two mAbs (CR3022 and S309) and the ACE2 cell receptor are studied as the main representatives of three different epitopes on the RBD of S protein. The combined approach of 1 μs accelerated molecular dynamics (aMD) and ab-initio hybrid molecular dynamics is used to identify the most predominant interactions under physiological conditions. Results allow to determine the main receptor-binding mapping, hydrogen bonding network and salt bridges in the most populated antigen-antibody interface conformations. The deep knowledge on the protein-protein interactions involving mAbs and ACE2 receptor with the spike glycoprotein of SARS-CoV-2 increases background knowledge to speed up the development of new vaccines and therapeutic drugs.c7:T586,Coronaviruses (CoVs) have the largest genome among RNA viruses and store large amounts of information without genome integration as they replicate in the cell cytoplasm. The replication of the virus is a continuous process, whereas the transcription of the subgenomic mRNAs is a discontinuous one, involving a template switch, which resembles a high frequency recombination mechanism that may favor virus genome variability. The origin of the three deadly human CoVs SARS-CoV, MERS-CoV and SARS-CoV-2 are zoonotic events. SARS-CoV-2 has incorporated in its spike protein a furine proteolytic site that facilitates the activation of the virus in any tissue, making this CoV strain highly polytropic and pathogenic. Using MERS-CoV as a model, a propagation-deficient RNA replicon was generated by removing E protein gene (essential for viral morphogenesis and involved in virulence), and accessory genes 3, 4a, 4b and 5 (responsible for antagonism of the innate immune response) to attenuate the virus: MERS-CoV-Δ[3,4a,4b,5,E]. This RNA replicon is strongly attenuated and elicits sterilizing protection after a single immunization in transgenic mice with the receptor for MERS-CoV, making it a promising vaccine candidate for this virus and an interesting platform for vector-based vaccine development. A strategy could be developed for the design of RNA replicon vaccines for other human pathogenic coronaviruses.c8:T468,While SARS-CoV-2 continues to adapt for human infection and transmission, genetic variation outside of the spike gene remains largely unexplored. This study investigates a highly variable region at residues 203-205 in the SARS-CoV-2 nucleocapsid protein. Recreating a mutation found in the alpha and omicron variants in an early pandemic (WA-1) background, we find that the R203K+G204R mutation is sufficient to enhance replication, fitness, and pathogenesis of SARS-CoV-2. The R203K+G204R mutant corresponds with increased viral RNA and protein both in vitro and in vivo. Importantly, the R203K+G204R mutation increases nucleocapsid phosphorylation and confers resistance to inhibition of the GSK-3 kinase, providing a molecular basis for increased virus replication. Notably, analogous alanine substitutions at positions 203+204 also increase SARS-CoV-2 replication and augment phosphorylation, suggesting that infection is enhanced through ablation of the ancestral 'RG' motif. Overall, these results demonstrate that variant mutations outside spike are key components in SARS-CoV-2's continued adaptation to human infection.c9:T71b,The purpose of this study was to identify factors associated with the increase in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S1) protein and neutralizing antibody titer following SARS-CoV-2 vaccination. This observational study was conducted among healthcare workers working for a private hospital group in Fukushima Prefecture, Japan. Two blood samples were obtained from each participant. The first sample was obtained before the first dose of BNT162b2 (Pfizer-BioNTech) vaccine, and a second sample was obtained approximately 6 weeks later. Immunoglobulin G (IgG) antibody against the SARS-CoV-2 spike (S1) protein, immunoglobulin M (IgM) antibody against SARS-CoV-2 N-protein, and neutralizing activity were measured using the chemiluminescent immunoassay with iFlash 3000. A total of 231 healthcare workers who agreed to participate, and were negative for anti-SARS-CoV-2 IgM antibodies at enrollment, were included in the analysis. All participants had elevated IgG antibodies and neutralizing activity above the cutoff values. A total of 174 (75.3%) and 208 (90.0%) participants experienced adverse reactions after the first and second vaccine doses, respectively. Younger age, female sex, not taking immunosuppressive or antipyretic analgesic medication regularly, a lack of local adverse reactions after the first dose, and the presence of adverse reactions (fever, muscle, and joint pain) after the second dose were associated with higher IgG antibody titers and neutralizing activity. Intake of analgesic antipyretic for adverse reactions to vaccines was not significantly associated with antibody and neutralizing activity titer production. Immune responses after vaccination may differ among individuals, and continued countermeasures to prevent SARS-CoV-2 infection are vital.ca:T410,The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged as a public health crisis and led to tremendous economic devastation. The spike protein (S) of SARS-CoV-2 hijacks the angiotensin converting enzyme 2 (ACE2) as a receptor for virus entry, representing the initial step of viral infection. S is one of the major targets for development of the antiviral drugs, antibodies, and vaccines. ACE2 is a peptidase that plays a physiologically important role in the renin-angiotensin system. Concurrently, it also forms dimer of heterodimer with the neutral amino acid transporter B0AT1 to regulate intestinal amino acid metabolism. The symptoms of COVID-19 are closely correlated with the physiological functions of ACE2. In this review, we summarize the functional and structural studies on ACE2, B0AT1, and their complex with S of SARS-CoV-2, providing insights into the various symptoms caused by viral infection and the development of therapeutic strategies.cb:T495,Coronavirus outbreak was declared a pandemic by World Health Organization (WHO) in March 2020. The pandemic has led to a devastating loss of life. It has shown us how infectious diseases can cause human existence at stake, and community health is important. The spike protein is the most immunogenic component of the virus. Most vaccine development strategies have focused on the receptor-binding domain (RBD) in the spike protein because it is the most specific target site that recognizes and interacts with human lung cells. Neutralizing antibodies are generated by the humoral immune system and reduce the viral load by binding to spike protein components. Neutralizing antibodies are the proteins secreted by plasma cells and serve as an important part of the defense mechanism. In the recent Covid-19 infection, neutralizing antibodies can be utilized for both diagnostic such as immune surveillance and therapeutic tools such as plasma therapy. So far, many monoclonal antibodies are in the clinical trial phase, and few of them are already in use. In this review, we have discussed details about neutralizing antibodies and their role in combating Covid-19 disease.cc:T6ee,The SARS-CoV-2 Omicron BA.1 variant emerged in 20211 and has multiple mutations in its spike protein2. Here we show that the spike protein of Omicron has a higher affinity for ACE2 compared with Delta, and a marked change in its antigenicity increases Omicron's evasion of therapeutic monoclonal and vaccine-elicited polyclonal neutralizing antibodies after two doses. mRNA vaccination as a third vaccine dose rescues and broadens neutralization. Importantly, the antiviral drugs remdesivir and molnupiravir retain efficacy against Omicron BA.1. Replication was similar for Omicron and Delta virus isolates in human nasal epithelial cultures. However, in lung cells and gut cells, Omicron demonstrated lower replication. Omicron spike protein was less efficiently cleaved compared with Delta. The differences in replication were mapped to the entry efficiency of the virus on the basis of spike-pseudotyped virus assays. The defect in entry of Omicron pseudotyped virus to specific cell types effectively correlated with higher cellular RNA expression of TMPRSS2, and deletion of TMPRSS2 affected Delta entry to a greater extent than Omicron. Furthermore, drug inhibitors targeting specific entry pathways3 demonstrated that the Omicron spike inefficiently uses the cellular protease TMPRSS2, which promotes cell entry through plasma membrane fusion, with greater dependency on cell entry through the endocytic pathway. Consistent with suboptimal S1/S2 cleavage and inability to use TMPRSS2, syncytium formation by the Omicron spike was substantially impaired compared with the Delta spike. The less efficient spike cleavage of Omicron at S1/S2 is associated with a shift in cellular tropism away from TMPRSS2-expressing cells, with implications for altered pathogenesis.cd:T610,MOTIVATION: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused more than 14 million cases and more than half million deaths. Given the absence of implemented therapies, new analysis, diagnosis and therapeutics are of great importance. RESULTS: Analysis of SARS-CoV-2 genomes from the current outbreak reveals the presence of short persistent DNA/RNA sequences that are absent from the human genome and transcriptome (PmRAWs). For the PmRAWs with length 12, only four exist at the same location in all SARS-CoV-2. At the gene level, we found one PmRAW of size 13 at the Spike glycoprotein coding sequence. This protein is fundamental for binding in human ACE2 and further use as an entry receptor to invade target cells. Applying protein structural prediction, we localized this PmRAW at the surface of the Spike protein, providing a potential targeted vector for diagnostics and therapeutics. In addition, we show a new pattern of relative absent words (RAWs), characterized by the progressive increase of GC content (Guanine and Cytosine) according to the decrease of RAWs length, contrarily to the virus and host genome distributions. New analysis shows the same property during the Ebola virus outbreak. At a computational level, we improved the alignment-free method to identify pathogen-specific signatures in balance with GC measures and removed previous size limitations. AVAILABILITY AND IMPLEMENTATION: https://github.com/cobilab/eagle. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.ce:T40a,The worldwide CoVid-19 pandemic has led to an unprecedented push across the whole of the scientific community to develop a potent antiviral drug and vaccine as soon as possible. Existing academic, governmental and industrial institutions and companies have engaged in large-scale screening of existing drugs, in vitro, in vivo and in silico. Here, we are using in silico modelling of possible SARS-CoV-2 drug targets, as deposited on the Protein Databank (PDB), and ascertain their dynamics, flexibility and rigidity. For example, for the SARS-CoV-2 spike protein-using its complete homo-trimer configuration with 2905 residues-our method identifies a large-scale opening and closing of the S1 subunit through movement of the S[Formula: see text] domain. We compute the full structural information of this process, allowing for docking studies with possible drug structures. In a dedicated database, we present similarly detailed results for the further, nearly 300, thus far resolved SARS-CoV-2-related protein structures in the PDB.cf:T4a4,The COVID-19 pandemic has revealed the pronounced vulnerability of the elderly and chronically ill to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced morbidity and mortality. Cellular senescence contributes to inflammation, multiple chronic diseases, and age-related dysfunction, but effects on responses to viral infection are unclear. Here, we demonstrate that senescent cells (SnCs) become hyper-inflammatory in response to pathogen-associated molecular patterns (PAMPs), including SARS-CoV-2 spike protein-1, increasing expression of viral entry proteins and reducing antiviral gene expression in non-SnCs through a paracrine mechanism. Old mice acutely infected with pathogens that included a SARS-CoV-2-related mouse β-coronavirus experienced increased senescence and inflammation, with nearly 100% mortality. Targeting SnCs by using senolytic drugs before or after pathogen exposure significantly reduced mortality, cellular senescence, and inflammatory markers and increased antiviral antibodies. Thus, reducing the SnC burden in diseased or aged individuals should enhance resilience and reduce mortality after viral infection, including that of SARS-CoV-2.d0:T7d0,Rationale: In life-threatening coronavirus disease (COVID-19), corticosteroids reduce mortality, suggesting that immune responses have a causal role in death. Whether this deleterious inflammation is primarily a direct reaction to the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or an independent immunopathologic process is unknown.Objectives: To determine SARS-CoV-2 organotropism and organ-specific inflammatory responses and the relationships among viral presence, inflammation, and organ injury.Methods: Tissue was acquired from 11 detailed postmortem examinations. SARS-CoV-2 organotropism was mapped by using multiplex PCR and sequencing, with cellular resolution achieved by in situ viral S (spike) protein detection. Histologic evidence of inflammation was quantified from 37 anatomic sites, and the pulmonary immune response was characterized by using multiplex immunofluorescence.Measurements and Main Results: Multiple aberrant immune responses in fatal COVID-19 were found, principally involving the lung and reticuloendothelial system, and these were not clearly topologically associated with the virus. Inflammation and organ dysfunction did not map to the tissue and cellular distribution of SARS-CoV-2 RNA and protein between or within tissues. An arteritis was identified in the lung, which was further characterized as a monocyte/myeloid-rich vasculitis, and occurred together with an influx of macrophage/monocyte-lineage cells into the pulmonary parenchyma. In addition, stereotyped abnormal reticuloendothelial responses, including excessive reactive plasmacytosis and iron-laden macrophages, were present and dissociated from viral presence in lymphoid tissues.Conclusions: Tissue-specific immunopathology occurs in COVID-19, implicating a significant component of the immune-mediated, virus-independent immunopathologic process as a primary mechanism in severe disease. Our data highlight novel immunopathologic mechanisms and validate ongoing andd1:T49a,The renin-angiotensin system (RAS) plays a pivotal role in a wide series of physiological processes, among which inflammation and blood pressure regulation. One of its key components, the angiotensin-converting enzyme 2, has been identified as the entry point of the SARS-CoV-2 virus into the host cells, and therefore a lot of research has been devoted to study RAS dysregulation in COVID-19. Here we discuss the alterations of the regulatory RAS axes due to SARS-CoV-2 infection on the basis of a series of recent clinical investigations and experimental analyzes quantifying, e.g., the levels and activity of RAS components. We performed a comprehensive meta-analysis of these data in view of disentangling the links between the impaired RAS functioning and the pathophysiological characteristics of COVID-19. We also review the effects of several RAS-targeting drugs and how they could potentially help restore the normal RAS functionality and minimize the COVID-19 severity. Finally, we discuss the conflicting evidence found in the literature and the open questions on RAS dysregulation in SARS-CoV-2 infection whose resolution would improve our understanding of COVID-19.d2:T615,Viruses are the simplest of pathogens, but possess sophisticated molecular mechanisms to manipulate host behavior, frequently utilizing molecular mimicry. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been shown to bind to the host receptor neuropilin-1 in order to gain entry into the cell. To do this, the virus utilizes its spike protein polybasic cleavage site (PCS), which mimics the CendR motif of neuropilin-1's endogenous ligands. In addition to facilitating cell entry, binding to neuropilin-1 has analgesic effects. We discuss the potential impact of neuropilin-1 binding by SARS-CoV-2 in ameliorating sickness behavior of the host, and identify a convergent evolutionary strategy of PCS cleavage and subsequent neuropilin binding in other human viruses. In addition, we discuss the evolutionary leap of the ancestor of SARS-COV-2, which involved acquisition of the PCS thus faciliting binding to the neuropilin-1 receptor. Acquisition of the PCS by the ancestor of SARS-CoV-2 appears to have led to pleiotropic beneficial effects including enhancement of cell entry via binding to ACE2, facilitation of cell entry via binding to neuropilin-1, promotion of analgesia, and potentially the formation of decoy epitopes via enhanced shedding of the S1 subunit. Lastly, other potential neuromanipulation strategies employed by SARS-CoV-2 are discussed, including interferon suppression and the resulting reduction in sickness behavior, enhanced transmission through neurally mediated cough induction, and reduction in sense of smell.d3:T7d2,Increased mortality in COVID-19 cases is often associated with microvascular complications. We have recently shown that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein promotes an inflammatory cytokine interleukin 6 (IL-6)/IL-6R-induced trans signaling response and alarmin secretion. Virus-infected or spike-transfected human epithelial cells exhibited an increase in senescence, with a release of senescence-associated secretory phenotype (SASP)-related inflammatory molecules. Introduction of the bromodomain-containing protein 4 (BRD4) inhibitor AZD5153 to senescent epithelial cells reversed this effect and reduced SASP-related inflammatory molecule release in TMNK-1 or EAhy926 (representative human endothelial cell lines), when cells were exposed to cell culture medium (CM) derived from A549 cells expressing SARS-CoV-2 spike protein. Cells also exhibited a senescence phenotype with enhanced p16, p21, and senescence-associated β-galactosidase (SA-β-Gal) expression and triggered SASP pathways. Inhibition of IL-6 trans signaling by tocilizumab and inhibition of inflammatory receptor signaling by the Bruton's tyrosine kinase (BTK) inhibitor zanubrutinib, prior to exposure of CM to endothelial cells, inhibited p21 and p16 induction. We also observed an increase in reactive oxygen species (ROS) in A549 spike-transfected and endothelial cells exposed to spike-transfected CM. ROS generation in endothelial cell lines was reduced after treatment with tocilizumab and zanubrutinib. Cellular senescence was associated with an increased level of the endothelial adhesion molecules vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1), which have in vitro leukocyte attachment potential. Inhibition of senescence or SASP function prevented VCAM-1/ICAM-1 expression and leukocyte attachment. Taken together, we identified that human endothelial cells exposed to cell culture supernatant derived from SARS-CoV-2 spike protein expd4:T6d6,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected 78 million individuals and is responsible for over 1.7 million deaths to date. Infection is associated with the development of variable levels of antibodies with neutralizing activity, which can protect against infection in animal models1,2. Antibody levels decrease with time, but, to our knowledge, the nature and quality of the memory B cells that would be required to produce antibodies upon reinfection has not been examined. Here we report on the humoral memory response in a cohort of 87 individuals assessed at 1.3 and 6.2 months after infection with SARS-CoV-2. We find that titres of IgM and IgG antibodies against the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 decrease significantly over this time period, with IgA being less affected. Concurrently, neutralizing activity in plasma decreases by fivefold in pseudotype virus assays. By contrast, the number of RBD-specific memory B cells remains unchanged at 6.2 months after infection. Memory B cells display clonal turnover after 6.2 months, and the antibodies that they express have greater somatic hypermutation, resistance to RBD mutations and increased potency, indicative of continued evolution of the humoral response. Immunofluorescence and PCR analyses of intestinal biopsies obtained from asymptomatic individuals at 4 months after the onset of coronavirus disease 2019 (COVID-19) revealed the persistence of SARS-CoV-2 nucleic acids and immunoreactivity in the small bowel of 7 out of 14 individuals. We conclude that the memory B cell response to SARS-CoV-2 evolves between 1.3 and 6.2 months after infection in a manner that is consistent with antigen persistence.d5:T56d,Activation of endothelial cells following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is thought to be the primary driver for the increasingly recognized thrombotic complications in coronavirus disease 2019 patients, potentially due to the SARS-CoV-2 Spike protein binding to the human angiotensin-converting enzyme 2 (hACE2). Vaccination therapies use the same Spike sequence or protein to boost host immune response as a protective mechanism against SARS-CoV-2 infection. As a result, cases of thrombotic events are reported following vaccination. Although vaccines are generally considered safe, due to genetic heterogeneity, age, or the presence of comorbidities in the population worldwide, the prediction of severe adverse outcome in patients remains a challenge. To elucidate Spike proteins underlying patient-specific-vascular thrombosis, the human microcirculation environment is recapitulated using a novel microfluidic platform coated with human endothelial cells and exposed to patient specific whole blood. Here, the blood coagulation effect is tested after exposure to Spike protein in nanoparticles and Spike variant D614G in viral vectors and the results are corroborated using live SARS-CoV-2. Of note, two potential strategies are also examined to reduce blood clot formation, by using nanoliposome-hACE2 and anti-Interleukin (IL) 6 antibodies.d6:T7d3,The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for virus infection through the engagement of the human ACE2 protein1 and is a major antibody target. Here we show that chronic infection with SARS-CoV-2 leads to viral evolution and reduced sensitivity to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma, by generating whole-genome ultra-deep sequences for 23 time points that span 101 days and using in vitro techniques to characterize the mutations revealed by sequencing. There was little change in the overall structure of the viral population after two courses of remdesivir during the first 57 days. However, after convalescent plasma therapy, we observed large, dynamic shifts in the viral population, with the emergence of a dominant viral strain that contained a substitution (D796H) in the S2 subunit and a deletion (ΔH69/ΔV70) in the S1 N-terminal domain of the spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype were reduced in frequency, before returning during a final, unsuccessful course of convalescent plasma treatment. In vitro, the spike double mutant bearing both ΔH69/ΔV70 and D796H conferred modestly decreased sensitivity to convalescent plasma, while maintaining infectivity levels that were similar to the wild-type virus.The spike substitution mutant D796H appeared to be the main contributor to the decreased susceptibility to neutralizing antibodies, but this mutation resulted in an infectivity defect. The spike deletion mutant ΔH69/ΔV70 had a twofold higher level of infectivity than wild-type SARS-CoV-2, possibly compensating for the reduced infectivity of the D796H mutation. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy, which is associated with the emergence of viral variants that show evidence of reduced susceptibility to neutralizing antibodies in immunosuppressed individuals.d7:T7d0,Importance: Despite the availability of a vaccine against the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), humans will have to live with this virus and the after-effects of the coronavirus disease 2019 (COVID-19) infection for a long time. Cholesterol plays an important role in the infection and prognosis of SARS-CoV-2, and the study of its mechanism is of great significance not only for the treatment of COVID-19 but also for research on generic antiviral drugs. Observations: Cholesterol promotes the development of atherosclerosis by activating NLR family pyrin domain containing 3 (NLRP3), and the resulting inflammatory environment indirectly contributes to COVID-19 infection and subsequent deterioration. In in vitro studies, membrane cholesterol increased the number of viral entry sites on the host cell membrane and the number of angiotensin-converting enzyme 2 (ACE2) receptors in the membrane fusion site. Previous studies have shown that the fusion protein of the virus interacts with cholesterol, and the spike protein of SARS-CoV-2 also requires cholesterol to enter the host cells. Cholesterol in blood interacts with the spike protein to promote the entry of spike cells, wherein the scavenger receptor class B type 1 (SR-B1) plays an important role. Because of the cardiovascular protective effects of lipid-lowering therapy and the additional anti-inflammatory effects of lipid-lowering drugs, it is currently recommended to continue lipid-lowering therapy for patients with COVID-19, but the safety of extremely low LDL-C is questionable. Conclusions and Relevance: Cholesterol can indirectly increase the susceptibility of patients to SARS-CoV-2 and increase the risk of death from COVID-19, which are mediated by NLRP3 and atherosclerotic plaques, respectively. Cholesterol present in the host cell membrane, virus, and blood may also directly participate in the virus cell entry process, but the specific mechanism still needs further study. Patients with Cd8:T5df,COVID-19 is a disease with unique characteristics that include lung thrombosis1, frequent diarrhoea2, abnormal activation of the inflammatory response3 and rapid deterioration of lung function consistent with alveolar oedema4. The pathological substrate for these findings remains unknown. Here we show that the lungs of patients with COVID-19 contain infected pneumocytes with abnormal morphology and frequent multinucleation. The generation of these syncytia results from activation of the SARS-CoV-2 spike protein at the cell plasma membrane level. On the basis of these observations, we performed two high-content microscopy-based screenings with more than 3,000 approved drugs to search for inhibitors of spike-driven syncytia. We converged on the identification of 83 drugs that inhibited spike-mediated cell fusion, several of which belonged to defined pharmacological classes. We focused our attention on effective drugs that also protected against virus replication and associated cytopathicity. One of the most effective molecules was the antihelminthic drug niclosamide, which markedly blunted calcium oscillations and membrane conductance in spike-expressing cells by suppressing the activity of TMEM16F (also known as anoctamin 6), a calcium-activated ion channel and scramblase that is responsible for exposure of phosphatidylserine on the cell surface. These findings suggest a potential mechanism for COVID-19 disease pathogenesis and support the repurposing of niclosamide for therapy.d9:T42f,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of the current coronavirus disease 2019 (COVID-19) pandemic, has evolved to adapt to human host and transmission over the past 12 months. One prominent adaptive mutation is the asparagine-to-glycine substitution at amino acid position 614 in the viral spike protein (D614G), which has become dominant in the currently circulating virus strains. Since spike protein determines host ranges, tissue tropism, and pathogenesis through binding to the cellular receptor of angiotensin converting enzyme 2 (ACE2), the D614G mutation is hypothesized to enhance viral fitness in human host, leading to increased transmission during the global pandemic. Here we summarize the recent progress on the role of the D614G mutation in viral replication, pathogenesis, transmission, and vaccine and therapeutic antibody development. These findings underscore the importance in closely monitoring viral evolution and defining their functions to ensure countermeasure efficacy against newly emerging variants.da:T57c,Recent emergence of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transpired into pandemic coronavirus disease 2019 (COVID-19). SARS-CoV-2 has been rapidly transmitted across the globe within a short period of time, with more than 106 million cases and 2.3 million deaths. The continuous rise in worldwide cases of COVID-19, transmission dynamics of SARS-CoV-2 including re-infections and enormous case-fatality rates emphasizes the urgent need of potential preventive and therapeutic measures. The development of effective therapeutic and preventive measures relies on understanding the molecular and cellular mechanism of replication exhibited by SARS-CoV-2. The structure of SARS-CoV-2 is ranging from 90-120 nm that comprises surface viral proteins including spike, envelope, membrane which are attached in host lipid bilayer containing the helical nucleocapsid comprising viral RNA. Spike (S) glycoprotein initiates the attachment of SARS-CoV-2 with a widely expressed cellular receptor angiotensin-converting enzyme 2 (ACE2), and subsequent S glycoprotein priming via serine protease TMPRSS2. Prominently, comprehensive analysis of structural insights into the crucial SARS-CoV-2 proteins may lead us to design effective therapeutics molecules. The present article, emphasizes the molecular and structural perspective of SARS-CoV-2 including mechanistic insights in its replication.db:T5a2,The COVID-19 pandemic necessitated the rapid production of vaccines aimed at the production of neutralizing antibodies against the COVID-19 spike protein required for the corona virus binding to target cells. The best well-known vaccines have utilized either mRNA or an adenovirus vector to direct human cells to produce the spike protein against which the body produces mostly neutralizing antibodies. However, recent reports have raised some skepticism as to the biologic actions of the spike protein and the types of antibodies produced. One paper reported that certain antibodies in the blood of infected patients appear to change the shape of the spike protein so as to make it more likely to bind to cells, while other papers showed that the spike protein by itself (without being part of the corona virus) can damage endothelial cells and disrupt the blood-brain barrier. These findings may be even more relevant to the pathogenesis of long-COVID syndrome that may affect as many as 50% of those infected with SARS-CoV-2. In COVID-19, a response to oxidative stress is required by increasing anti-oxidant enzymes. In this regard, it is known that polyphenols are natural anti-oxidants with multiple health effects. Hence, there are even more reasons to intervene with the use of anti-oxidant compounds, such as luteolin, in addition to available vaccines and anti-inflammatory drugs to prevent the harmful actions of the spike protein.dc:T4a9,Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) initiates the infection process by binding to the viral cellular receptor angiotensin-converting enzyme 2 through the receptor-binding domain (RBD) in the S1 subunit of the viral spike (S) protein. This event is followed by virus-cell membrane fusion mediated by the S2 subunit, which allows virus entry into the host cell. Therefore, the SARS-CoV-2 S protein is a key therapeutic target, and prevention and treatment of coronavirus disease 2019 (COVID-19) have focused on the development of neutralizing monoclonal antibodies (nAbs) that target this protein. In this review, we summarize the nAbs targeting SARS-CoV-2 proteins that have been developed to date, with a focus on the N-terminal domain and RBD of the S protein. We also describe the roles that binding affinity, neutralizing activity, and protection provided by these nAbs play in the prevention and treatment of COVID-19 and discuss the potential to improve nAb efficiency against multiple SARS-CoV-2 variants. This review provides important information for the development of effective nAbs with broad-spectrum activity against current and future SARS-CoV-2 strains.dd:T43a,The Spike (S) protein of the SARS-CoV-2 virus is critical for its ability to attach and fuse into the host cells, leading to infection, and transmission. In this review, we have initially performed a meta-analysis of keywords associated with the S protein to frame the outline of important research findings and directions related to it. Based on this outline, we have reviewed the structure, uniqueness, and origin of the S protein of SARS-CoV-2. Furthermore, the interactions of the Spike protein with host and its implications in COVID-19 pathogenesis, as well as drug and vaccine development, are discussed. We have also summarized the recent advances in detection methods using S protein-based RT-PCR, ELISA, point-of-care lateral flow immunoassay, and graphene-based field-effect transistor (FET) biosensors. Finally, we have also discussed the emerging Spike mutants and the efficacy of the Spike-based vaccines against those strains. Overall, we have covered most of the recent advances on the SARS-CoV-2 Spike protein and its possible implications in countering this virus.de:T6a3,It is hypothesized that several comorbidities increase the severity of COVID-19 symptoms. Cardiovascular disease including hypertension was shown to play a critical role in the severity of COVID-19 infection by affecting the survival of patients with COVID-19. Hypertension and the renin-angiotensin-aldosterone system are involved in increasing vascular inflammation and endothelial dysfunction (ED), and both processes are instrumental in COVID-19. Angiotensin-converting enzyme 2 is an essential component of the renin-angiotensin-aldosterone system and the target receptor that mediates SARS-CoV-2 entry to the cell. This led to speculations that major renin-angiotensin-aldosterone system inhibitors, such as angiotensin receptor blockers and angiotensin-converting enzyme inhibitors might affect the course of the disease, since their administration enhances angiotensin-converting enzyme (ACE)2 expression. An increase in ACE2 activity could reduce angiotensin II concentration in the lungs and mitigate virus-driven lung injury. This could also be associated with a reduction in blood coagulation, which plays a critical role in the pathogenesis of SARS-CoV-2; of note, COVID-19 is now regarded as a disorder of blood clotting. Therefore, there is an urgent need to better understand the effect of targeting ACE2 as a potential treatment for SARS-CoV-2 driven injury, and in alleviating COVID-19 symptoms by reversing SARS-CoV-2-induced excessive coagulation and fatalities. Ongoing therapeutic strategies that include recombinant human ACE2 and anti-spike monoclonal antibodies are essential for future clinical practice in order to better understand the effect of targeting ED in COVID-19.df:T77a,In the absence of effective antiviral chemotherapy and still in the context of emerging vaccines for severe acute respiratory syndrome-CoV-2 infections, passive immunotherapy remains a key treatment and possible prevention strategy. What might initially be conceived as a simplified donor-recipient process, the intricacies of donor plasma, IV immunoglobulins, and monoclonal antibody modality applications are becoming more apparent. Key targets of such treatment have largely focused on virus neutralization and the specific viral components of the attachment Spike protein and its constituents (e.g., receptor binding domain, N-terminal domain). The cumulative laboratory and clinical experience suggests that beneficial protective and treatment outcomes are possible. Both a dose- and a time-dependency emerge. Lesser understood are the concepts of bioavailability and distribution. Apart from direct antigen binding from protective immunoglobulins, antibody effector functions have potential roles in outcome. In attempting to mimic the natural but variable response to infection or vaccination, a strong functional polyclonal approach attracts the potential benefits of attacking antigen diversity, high antibody avidity, antibody persistence, and protection against escape viral mutation. The availability and ease of administration for any passive immunotherapy product must be considered in the current climate of need. There is never a perfect product, but yet there is considerable room for improving patient outcomes. Given the variability of human genetics, immunity, and disease, and given the nuances of the virus and its potential for change, passive immunotherapy can be developed that will be effective for some but not all patients. An understanding of such patient variability and limitations is just as important as the understanding of the direct interactions between immunotherapy and virus.e0:T67c,PURPOSE: COVID-19 pandemic has emerged as a result of infection by the deadly pathogenic severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), causing enormous threats to humans. Coronaviruses are distinguished by a clove-like spike (S) protein, which plays a key role in viral pathogenesis, evolutions, and transmission. The objectives of this study are to investigate the distinctive structural features of SARS-CoV-2 S protein, its essential role in pathogenesis, and its use in the development of potential therapies and vaccines. METHODOLOGY: A literature review was conducted to summarize, analyze, and interpret the available scientific data related to SARS-CoV-2 S protein in terms of characteristics, vaccines development and potential therapies. RESULTS: The data indicate that S protein subunits and their variable conformational states significantly affect the virus pathogenesis, infectivity, and evolutionary mutation. A considerable number of potential natural and synthetic therapies were proposed based on S protein. Additionally, neutralizing antibodies were recently approved for emergency use. Furthermore, several vaccines utilizing the S protein were developed. CONCLUSION: A better understanding of S protein features, structure and mutations facilitate the recognition of the importance of SARS-CoV-2 S protein in viral infection, as well as the development of therapies and vaccines. The efficacy and safety of these therapeutic compounds and vaccines are still controversial. However, they may potentially reduce or prevent SARS-CoV-2 infection, leading to a significant reduction of the global health burden of this pandemic.e1:T52b,The COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has quickly spread around the globe. At present, there is no precise and effective treatment for the patients with COVID-19, so rapid development of drugs is urgently needed in order to contain the highly infectious disease. The virus spike protein (S protein) can recognize the angiotensin-converting enzyme 2 (ACE2) receptor on the host cell membrane and undergo a series of conformational changes, protease cleavage and membrane fusion to complete the virus entry, so S protein is an important target for vaccine and drug development. Here we provide a brief overview of molecular mechanisms of virus entry, as well as some potential antiviral agents that act on S/ACE2 protein-protein interaction. Specifically, we focused on experimentally validated and/or computational prediction identified inhibitors that target SARS-CoV-2 S protein, ACE2 and enzymes associated with viral infection. This review offers valuable information for the discovery and development of potential antiviral agents in combating SARS-CoV-2. In addition, with the deepening understanding of the mechanism of SARS-CoV-2 infection, more targeted prevention and treatment drugs will be explored with the aid of the advanced technology in the future.e2:T49a,SARS-CoV-2 causes the respiratory syndrome COVID-19 and is responsible for the current pandemic. The S protein of SARS-CoV-2-mediating virus binding to target cells and subsequent viral uptake is extensively glycosylated. Here we focus on how glycosylation of both SARS-CoV-2 and target cells crucially impacts SARS-CoV-2 infection at different levels: (1) virus binding and entry to host cells, with glycosaminoglycans of host cells acting as a necessary co-factor for SARS-CoV-2 infection by interacting with the receptor-binding domain of the SARS-CoV-2 spike glycoprotein, (2) innate and adaptive immune response where glycosylation plays both a protective role and contributes to immune evasion by masking of viral polypeptide epitopes and may add to the cytokine cascade via non-fucosylated IgG, and (3) therapy and vaccination where a monoclonal antibody-neutralizing SARS-CoV-2 was shown to interact also with a distinct glycan epitope on the SARS-CoV-2 spike protein. These evidences highlight the importance of ensuring that glycans are considered when tackling this disease, particularly in the development of vaccines, therapeutic strategies and serological testing.e3:T7d2,Acute severe respiratory syndrome coronavirus-2 (SARS-CoV-2) infection causes coronavirus disease-2019 (COVID-19) which is associated with inflammation, thrombosis edema, hemorrhage, intra-alveolar fibrin deposition, and vascular and pulmonary damage. In COVID-19, the coronavirus activates macrophages by inducing the generation of pro-inflammatory cytokines [interleukin (IL)-1, IL-6, IL-18 and TNF] that can damage endothelial cells, activate platelets and neutrophils to produce thromboxane A2 (TxA2), and mediate thrombus generation. In severe cases, all these phenomena can lead to patient death. The binding of SARS-CoV-2 to the Toll Like Receptor (TLR) results in the release of pro-IL-1β that is cleaved by caspase-1, followed by the production of active mature IL-1β which is the most important cytokine in causing fever and inflammation. Its activation in COVID-19 can cause a "cytokine storm" with serious biological and clinical consequences. Blockade of IL-1 with inhibitory and anti-inflammatory cytokines represents a new therapeutic strategy also for COVID-19. Recently, very rare allergic reactions to vaccines have been reported, with phenomena of pulmonary thrombosis. These side effects have raised substantial concern in the population. Highly allergic subjects should therefore be vaccinated under strict medical supervision. COVID-19 has accelerated vaccine therapy but also the use of drugs and monoclonal antibodies (mABs) which have been used in COVID-19 therapy. They are primarily adopted to treat high-risk mild-to-moderate non-hospitalized patients, and it has been noted that the administration of two mABs gave better results. mABs, other than polyclonal plasma antibodies from infected subjects with SARS-CoV-2, are produced in the laboratory and are intended to fight SARS-CoV-2. They bind specifically to the antigenic determinant of the spike protein, inhibiting the pathogenicity of the virus. The most suitable individuals for mAB therapy are people at particule4:T7d1,COVID-19, a new human respiratory disease that has killed nearly 3 million people in a year since the start of the pandemic, is a global public health challenge. Its infectious agent, SARS-CoV-2, differs from other coronaviruses in a number of structural features that make this virus more pathogenic and transmissible. In this review, we discuss some important characteristics of the main SARS-CoV-2 surface antigen, the spike (S) protein, such as (i) ability of the receptor-binding domain (RBD) to switch between the "standing-up" position (open pre-fusion conformation) for receptor binding and the "lying-down" position (closed pre-fusion conformation) for immune system evasion; (ii) advantage of a high binding affinity of the RBD open conformation to the human angiotensin-converting enzyme 2 (ACE2) receptor for efficient cell entry; and (iii) S protein preliminary activation by the intracellular furin-like proteases for facilitation of the virus spreading across different cell types. We describe interactions between the S protein and cellular receptors, co-receptors, and antagonists, as well as a hypothetical mechanism of the homotrimeric spike structure destabilization that triggers the fusion of the viral envelope with the cell membrane at physiological pH and mediates the viral nucleocapsid entry into the cytoplasm. The transition of the S protein pre-fusion conformation to the post-fusion one on the surface of virions after their treatment with some reagents, such as β-propiolactone, is essential, especially in relation to the vaccine production. We also compare the COVID-19 pathogenesis with that of severe outbreaks of "avian" influenza caused by the A/H5 and A/H7 highly pathogenic viruses and discuss the structural similarities between the SARS-CoV-2 S protein and hemagglutinins of those highly pathogenic strains. Finally, we touch on the prospective and currently used COVID-19 antiviral and anti-pathogenetic therapeutics, as well as recently approved conventione5:T58b,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible coronavirus responsible for the global COVID-19 pandemic. Herein we provide evidence that SARS-CoV-2 spreads through cell-cell contact in cultures, mediated by the spike glycoprotein. SARS-CoV-2 spike is more efficient in facilitating cell-to-cell transmission than SARS-CoV spike, which reflects, in part, their differential cell-cell fusion activity. Interestingly, treatment of cocultured cells with endosomal entry inhibitors impairs cell-to-cell transmission, implicating endosomal membrane fusion as an underlying mechanism. Compared with cell-free infection, cell-to-cell transmission of SARS-CoV-2 is refractory to inhibition by neutralizing antibody or convalescent sera of COVID-19 patients. While ACE2 enhances cell-to-cell transmission, we find that it is not absolutely required. Notably, despite differences in cell-free infectivity, the variants of concern (VOC) B.1.1.7 and B.1.351 have similar cell-to-cell transmission capability. Moreover, B.1.351 is more resistant to neutralization by vaccinee sera in cell-free infection, whereas B.1.1.7 is more resistant to inhibition by vaccine sera in cell-to-cell transmission. Overall, our study reveals critical features of SARS-CoV-2 spike-mediated cell-to-cell transmission, with important implications for a better understanding of SARS-CoV-2 spread and pathogenesis.e6:T545,Coronaviruses have caused three major epidemics since 2003, including the ongoing SARS-CoV-2 pandemic. In each case, the emergence of coronavirus in our species has been associated with zoonotic transmissions from animal reservoirs1,2, underscoring how prone such pathogens are to spill over and adapt to new species. Among the four recognized genera of the family Coronaviridae, human infections reported so far have been limited to alphacoronaviruses and betacoronaviruses3-5. Here we identify porcine deltacoronavirus strains in plasma samples of three Haitian children with acute undifferentiated febrile illness. Genomic and evolutionary analyses reveal that human infections were the result of at least two independent zoonoses of distinct viral lineages that acquired the same mutational signature in the genes encoding Nsp15 and the spike glycoprotein. In particular, structural analysis predicts that one of the changes in the spike S1 subunit, which contains the receptor-binding domain, may affect the flexibility of the protein and its binding to the host cell receptor. Our findings highlight the potential for evolutionary change and adaptation leading to human infections by coronaviruses outside of the previously recognized human-associated coronavirus groups, particularly in settings where there may be close human-animal contact.e7:T671,BACKGROUND: Coronaviruses (CoVs) are single-stranded, polyadenylated, enveloped RNA of positive polarity with a unique potential to alter host tropism. This has been exceptionally demonstrated by the emergence of deadly virus outbreaks of the past: Severe Acute Respiratory Syndrome (SARS-CoV) in 2003 and Middle East Respiratory Syndrome (MERS-CoV) in 2012. SUMMARY: The 2019 outbreak by the new cross-species transmission of SARS-CoV-2 has put the world on alert. CoV infection is triggered by receptor recognition, membrane fusion, and successive viral entry mediated by the surface Spike (S) glycoprotein. S protein is one of the major antigenic determinants and the target for neutralizing antibodies. It is a valuable target in antiviral therapies because of its central role in cell-cell fusion, viral antigen spread, and host immune responses leading to immunopathogenesis. The receptor-binding domain of S protein has received greater attention as it initiates host attachment and contains major antigenic determinants. However, investigating the therapeutic potential of fusion peptide as a part of the fusion core complex assembled by the heptad repeats 1 and 2 (HR1 and HR2) is also warranted. Along with receptor attachment and entry, fusion mechanisms should also be explored for designing inhibitors as a therapeutic intervention. KEY MESSAGE: In this article, we review the S protein function and its role in mediating membrane fusion, spread, tropism, and its associated pathogenesis with notable therapeutic strategies focusing on results obtained from studies on a murine β-Coronavirus (m-CoV) and its associated disease process.e8:T41e,Rotavirus (RV) is an important pathogen causing acute gastroenteritis in young humans and animals. Attachment to the host receptor is a crucial step for the virus infection. The recent advances in illustrating the interactions between RV and glycans promoted our understanding of the host range and epidemiology of RVs. VP8*, the distal region of the RV outer capsid spike protein VP4, played a critical role in the glycan recognition. Group A RVs were classified into different P genotypes based on the VP4 sequences and recognized glycans in a P genotype-dependent manner. Glycans including sialic acid, gangliosides, histo-blood group antigens (HBGAs), and mucin cores have been reported to interact with RV VP8*s. The glycan binding specificities of VP8*s of different RV genotypes have been studied. Here, we mainly discussed the structural basis for the interactions between RV VP8*s and glycans, which provided molecular insights into the receptor recognition and host tropism, offering new clues to the design of RV vaccine and anti-viral agents.e9:T64e,SARS-CoV-2 symptoms are non-specific and can range from asymptomatic presentation to severe pneumonia. Asymptomatic subjects carrying SARS-CoV-2 often remain undiagnosed and it is still debated whether they develop immunoglobulins (Ig) and how long they persist. The aim of this study was to investigate the development and persistence of antibodies against SARS-CoV-2 in asymptomatic subjects infected by the virus. This follow-up study was performed on the 31 asymptomatic subjects who presented a positive nasal swab or serology against SARS-CoV-2 (Ig against Spike-RBD) in the first part of the UNICORN study (March 2020) aimed at attesting previous or current contacts with the virus in the personnel of the University of Milan. Eight weeks after the first Ig measure, these subjects were invited to donate a second blood sample for testing serum antibodies (IgM, IgG and total antibodies) and to fill-in a structured questionnaire. About 80% of asymptomatic subjects did not present circulating immunoglobulins against SARS-CoV-2 after 8 weeks from a positive nasal swab against the virus. Moreover, in more than 40% of these subjects, no Ig against SARS-CoV-2 were detected at any time. Finally, about two third of subjects with immunoglobulins at baseline did not present IgG against SARS-CoV-2 after 8 weeks. The majority of subjects who developed an asymptomatic SARS-CoV-2 infection do not present antibodies against the RBD-spike protein after 8 weeks of follow-up. These data should be taken into account for the interpretation of the serological evidences on SARS-CoV-2 that are emerging nowadays.ea:T42d,The recent outbreak of the betacoronavirus SARS-CoV-2 has become a significant concern to public health care worldwide. As of August 19, 2020, more than 22,140,472 people are infected, and over 781,135 people have died due to this deadly virus. In the USA alone, over 5,482,602 people are currently infected, and more than 171,823 people have died. SARS-CoV-2 has shown a higher infectivity rate and a more extended incubation period as compared to previous coronaviruses. SARS-CoV-2 binds much more strongly than SARS-CoV to the same host receptor, angiotensin-converting enzyme 2 (ACE2). Previously, several methods to develop a vaccine against SARS-CoV or MERS-CoV have been tried with limited success. Since SARS-CoV-2 uses the spike (S) protein for entry to the host cell, it is one of the most preferred targets for making vaccines or therapeutics against SARS-CoV-2. In this review, we have summarised the characteristics of the S protein, as well as the different approaches being used for the development of vaccines and/or therapeutics based on the S protein.eb:T6f0,The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), represents an unprecedented challenge to global public health. At the time of this review, COVID-19 has been diagnosed in over 40 million cases and associated with 1.1 million deaths worldwide. Current management strategies for COVID-19 are largely supportive, and while there are more than 2000 interventional clinical trials registered with the U.S. National Library of Medicine (clinicaltrials.gov), results that can clarify benefits and risks of candidate therapies are only gradually becoming available. We herein describe recent advances in understanding SARS-CoV-2 pathobiology and potential therapeutic targets that are involved in viral entry into host cells, viral spread in the body, and the subsequent COVID-19 progression. We highlight two major lines of therapeutic strategies for COVID-19 treatment: 1) repurposing the existing drugs for use in COVID-19 patients, such as antiviral medications (e.g., remdesivir) and immunomodulators (e.g., dexamethasone) which were previously approved for other disease conditions, and 2) novel biological products that are designed to target specific molecules that are involved in SARS-CoV-2 viral entry, including neutralizing antibodies against the spike protein of SARS-CoV-2, such as REGN-COV2 (an antibody cocktail), as well as recombinant human soluble ACE2 protein to counteract SARS-CoV-2 binding to the transmembrane ACE2 receptor in target cells. Finally, we discuss potential drug resistance mechanisms and provide thoughts regarding clinical trial design to address the diversity in COVID-19 clinical manifestation. Of note, preventive vaccines, cell and gene therapies are not within the scope of the current review.ec:T573,As the number of people infected with the newly identified 2019 novel coronavirus (SARS-CoV2) is continuously increasing every day, development of potential therapeutic platforms is vital. Based on the comparatively high similarity of receptor-binding domain (RBD) in SARS-CoV2 and SARS-CoV, it seems crucial to assay the cross-reactivity of anti-SARS-CoV monoclonal antibodies (mAbs) with SARS-CoV2 spike (S)-protein. Indeed, developing mAbs targeting SARS-CoV2 S-protein RBD could show novel applications for rapid and sensitive development of potential epitope-specific vaccines (ESV). Herein, we present an overview on the discovery of new CoV followed by some explanation on the SARS-CoV2 S-protein RBD site. Furthermore, we surveyed the novel therapeutic mAbs for targeting S-protein RBD such as S230, 80R, F26G18, F26G19, CR3014, CR3022, M396, and S230.15. Afterwards, the mechanism of interaction of RBD and different mAbs were explained and it was suggested that one of the SARS-CoV-specific human mAbs, namely CR3022, could show the highest binding affinity with SARS-CoV2 S-protein RBD. Finally, some ongoing challenges and future prospects for rapid and sensitive advancement of therapeutic mAbs targeting S-protein RBD were discussed. In conclusion, it may be proposed that this review may pave the way for recognition of RBD and different mAbs to develop potential therapeutic ESV.ed:T763,The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has shown once again that coronavirus (CoV) in animals are potential sources for epidemics in humans. Porcine deltacoronavirus (PDCoV) is an emerging enteropathogen of swine with a worldwide distribution. Here, we implemented and described an approach to analyze the epidemiology of PDCoV following its emergence in the pig population. We performed an integrated analysis of full genome sequence data from 21 newly sequenced viruses, along with comprehensive epidemiological surveillance data collected globally over the last 15 years. We found four distinct phylogenetic lineages of PDCoV, which differ in their geographic circulation patterns. Interestingly, we identified more frequent intra- and interlineage recombination and higher virus genetic diversity in the Chinese lineages compared with the USA lineage where pigs are raised in different farming systems and ecological environments. Most recombination breakpoints are located in the ORF1ab gene rather than in genes encoding structural proteins. We also identified five amino acids under positive selection in the spike protein suggesting a role for adaptive evolution. According to structural mapping, three positively selected sites are located in the N-terminal domain of the S1 subunit, which is the most likely involved in binding to a carbohydrate receptor, whereas the other two are located in or near the fusion peptide of the S2 subunit and thus might affect membrane fusion. Finally, our phylogeographic investigations highlighted notable South-North transmission as well as frequent long-distance dispersal events in China that could implicate human-mediated transmission. Our findings provide new insights into the evolution and dispersal of PDCoV that contribute to our understanding of the critical factors involved in CoVs emergence.ee:T715,The recent outbreak of coronavirus disease (COVID-19) caused by SARS-CoV-2 infection in Wuhan, China has posed a serious threat to global public health. To develop specific anti-coronavirus therapeutics and prophylactics, the molecular mechanism that underlies viral infection must first be defined. Therefore, we herein established a SARS-CoV-2 spike (S) protein-mediated cell-cell fusion assay and found that SARS-CoV-2 showed a superior plasma membrane fusion capacity compared to that of SARS-CoV. We solved the X-ray crystal structure of six-helical bundle (6-HB) core of the HR1 and HR2 domains in the SARS-CoV-2 S protein S2 subunit, revealing that several mutated amino acid residues in the HR1 domain may be associated with enhanced interactions with the HR2 domain. We previously developed a pan-coronavirus fusion inhibitor, EK1, which targeted the HR1 domain and could inhibit infection by divergent human coronaviruses tested, including SARS-CoV and MERS-CoV. Here we generated a series of lipopeptides derived from EK1 and found that EK1C4 was the most potent fusion inhibitor against SARS-CoV-2 S protein-mediated membrane fusion and pseudovirus infection with IC50s of 1.3 and 15.8 nM, about 241- and 149-fold more potent than the original EK1 peptide, respectively. EK1C4 was also highly effective against membrane fusion and infection of other human coronavirus pseudoviruses tested, including SARS-CoV and MERS-CoV, as well as SARSr-CoVs, and potently inhibited the replication of 5 live human coronaviruses examined, including SARS-CoV-2. Intranasal application of EK1C4 before or after challenge with HCoV-OC43 protected mice from infection, suggesting that EK1C4 could be used for prevention and treatment of infection by the currently circulating SARS-CoV-2 and other emerging SARSr-CoVs.ef:T5eb,The continual Middle East respiratory syndrome (MERS) threat highlights the importance of developing effective antiviral therapeutics to prevent and treat MERS coronavirus (MERS-CoV) infection. A surface spike (S) protein guides MERS-CoV entry into host cells by binding to cellular receptor dipeptidyl peptidase-4 (DPP4), followed by fusion between virus and host cell membranes. MERS-CoV S protein represents a key target for developing therapeutics to block viral entry and inhibit membrane fusion. Areas covered: This review illustrates MERS-CoV S protein's structure and function, particularly S1 receptor-binding domain (RBD) and S2 heptad repeat 1 (HR1) as therapeutic targets, and summarizes current advancement on developing anti-MERS-CoV therapeutics, focusing on neutralizing monoclonal antibodies (mAbs) and antiviral peptides. Expert opinion: No anti-MERS-CoV therapeutic is approved for human use. Several S-targeting neutralizing mAbs and peptides have demonstrated efficacy against MERS-CoV infection, providing feasibility for development. Generally, human neutralizing mAbs targeting RBD are more potent than those targeting other regions of S protein. However, emergence of escape mutant viruses and mAb's limitations make it necessary for combining neutralizing mAbs recognizing different neutralizing epitopes and engineering them with improved efficacy and reduced cost. Optimization of the peptide sequences is expected to produce next-generation anti-MERS-CoV peptides with improved potency.f0:T5ba,Interaction with cellular glycans is a critical initial step in the pathogenesis of many infectious agents. Technological advances in glycobiology have expanded the repertoire of studies delineating host glycan-pathogen interactions. For rotavirus, the VP8* domain of the outer capsid spike protein VP4 is known to interact with cellular glycans. Sialic acid was considered the key cellular attachment factor for rotaviruses for decades. Although this is true for many rotavirus strains causing infections in animals, glycan array screens show that many human rotavirus strains bind nonsialylated glycoconjugates, called histo-blood group antigens, in a strain-specific manner. The expression of histo-blood group antigens is determined genetically and is regulated developmentally. Variations in glycan binding between different rotavirus strains are biologically relevant and provide new insights into multiple aspects of virus pathogenesis such as interspecies transmission, host range restriction, and tissue tropism. The genetics of glycan expression may affect susceptibility to different rotavirus strains and vaccine viruses, and impact the efficacy of rotavirus vaccination in different populations. A multidisciplinary approach to understanding rotavirus-host glycan interactions provides molecular insights into the interaction between microbial pathogens and glycans, and opens up new avenues to translate findings from the bench to the human population.f1:T63f,Feline infectious peritonitis (FIP) belongs to the few animal virus diseases in which, in the course of a generally harmless persistent infection, a virus acquires a small number of mutations that fundamentally change its pathogenicity, invariably resulting in a fatal outcome. The causative agent of this deadly disease, feline infectious peritonitis virus (FIPV), arises from feline enteric coronavirus (FECV). The review summarizes our current knowledge of the genome and proteome of feline coronaviruses (FCoVs), focusing on the viral surface (spike) protein S and the five accessory proteins. We also review the current classification of FCoVs into distinct serotypes and biotypes, cellular receptors of FCoVs and their presumed role in viral virulence, and discuss other aspects of FIPV-induced pathogenesis. Our current knowledge of genetic differences between FECVs and FIPVs has been mainly based on comparative sequence analyses that revealed "discriminatory" mutations that are present in FIPVs but not in FECVs. Most of these mutations result in amino acid substitutions in the S protein and these may have a critical role in the switch from FECV to FIPV. In most cases, the precise roles of these mutations in the molecular pathogenesis of FIP have not been tested experimentally in the natural host, mainly due to the lack of suitable experimental tools including genetically engineered virus mutants. We discuss the recent progress in the development of FCoV reverse genetics systems suitable to generate recombinant field viruses containing appropriate mutations for in vivo studies.18:["$","section",null,{"id":"timeline","children":[["$","h2",null,{"className":"text-2xl font-semibold text-foreground","children":"Key studies timeline"}],["$","div",null,{"className":"mt-4","children":["$","$L22",null,{"papers":[{"id":"pmid-41677601","title":"Cellular and Molecular Mechanisms of SARS-CoV-2 Spike Protein-Induced Endothelial Dysfunction.","authors":["Muir Kelsey C","Harris Dwight D","Kanuparthy Meghamsh","Hu Jiayu","Nho Ju-Woo","Stone Christopher","Banerjee Debolina","Sellke Frank W"],"doi":"10.3390/cells15030234","pmid":"41677601","pmcid":"PMC12896700","publicationDate":"2026-01-26","journal":"Cells","abstract":"$23","categories":["mechanisms","therapeutics"],"tags":[],"studyType":"review","spikeSource":["infection"],"keyFindings":["Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is initiated by the viral spike proteins, which are key structural components that mediate host cell binding and entry and alter downstream signaling through multiple interactions with endothelial surface receptors.","Endothelial dysfunction is a central consequence of COVID-19, contributing to vascular inflammation, barrier disruption, thrombosis, and multi-organ injury affecting the pulmonary, cardiovascular, cerebral, and renal systems.","Emerging evidence demonstrates that spike protein-mediated effects, independent of productive viral infection, disrupt endothelial homeostasis through angiotensin-converting enzyme 2 (ACE2) dysregulation, integrin engagement, altered calcium signaling, junctional protein remodeling, oxidative stress, and pro-inflammatory and pro-apoptotic pathways."],"persistenceDuration":null,"mechanisms":["inflammation","endothelial damage","ACE2 binding"],"therapeuticTargets":null,"symptoms":["cardiovascular"],"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12896700/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/41677601/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-42150851","title":"Spike 1 protein of SARS-CoV-2 induces endothelial inflammation and vascular dysfunction through interferon ISG15-dependent mechanisms.","authors":["Rios Francisco J","Montezano Augusto C","Camargo Livia L","Lopes Rheure A","García-Redondo Ana B","Aranday-Cortes Elihu","Briones Ana M","McLauchlan John"],"doi":"10.1093/cvr/cvag111","pmid":"42150851","pmcid":null,"publicationDate":"2026-01-18","journal":"Cardiovascular research","abstract":"$24","categories":["mechanisms"],"tags":[],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["AIMS: Interferon (IFN) alpha (IFNα) and lambda3 (IFNλ3) constitute first line responses of immunity against SARS-CoV-2 infection by increasing interferon-stimulated genes (ISGs).","Prolonged IFN production may exacerbate inflammation, contributing to endotheliitis and vascular dysfunction in COVID-19.","We investigated whether spike protein S1 (SP1) of SARS-CoV-2 via IFN influences inflammation in human vascular and lymphatic endothelial cells (EC) and whether these processes contribute to vascular dysfunction in the context of hypertension."],"persistenceDuration":null,"mechanisms":["inflammation","endothelial damage"],"therapeuticTargets":null,"symptoms":["cardiovascular"],"pdfUrl":null,"pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/42150851/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"doi-10.1186-s43094-026-00939-2","title":"The persistence of COVID-19 vaccine artifacts in bodily fluids and tissues: a systematic review","authors":["Various"],"doi":"10.1186/s43094-026-00939-2","publicationDate":"2026-01-15","journal":"BMC Infectious Diseases","abstract":"Systematic review synthesizing evidence on vaccine-derived spike protein and mRNA persistence across bodily fluids and tissues, including blood (up to ~709 days), breast milk, lymph nodes, and autopsy findings.","summary":"Definitive 2026 synthesis: spike detected in blood for months to years; tissue persistence in lymph nodes, heart, brain-meningeal borders. Tables 2 & 3 catalog fluids and autopsy tissues.","categories":["persistence","mechanisms"],"tags":["systematic-review","vaccine","mRNA"],"studyType":"review","spikeSource":["vaccine-derived"],"keyFindings":["Blood spike persistence reported up to ~709 days in some cohorts","Vaccine mRNA and spike detected in multiple tissues via autopsy/biopsy","Detection rates vary by assay sensitivity and cohort selection"],"persistenceDuration":"Up to ~709 days (blood); tissue up to ~4 years (limited autopsy)","mechanisms":["tissue reservoirs","immune sequestration"],"pubmedUrl":"https://link.springer.com/article/10.1186/s43094-026-00939-2","reviewed":true,"lastUpdated":"2026-07-06"},{"id":"pmid-42285033","title":"Spike protein and fibrin(ogen) interactions.","authors":["Hammarstrom Per","Nystrom Sofie"],"doi":"10.1182/bloodadvances.2026020807","pmid":"42285033","pmcid":null,"publicationDate":"2026-01-12","journal":"Blood advances","abstract":"","categories":["mechanisms"],"tags":["fibrin"],"studyType":"clinical","spikeSource":["unspecified"],"keyFindings":[],"persistenceDuration":null,"mechanisms":["fibrin/clotting"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":null,"pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/42285033/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-41790576","title":"Long COVID neuropathy: The role of mast cells.","authors":["Morcos Zachary L","Theoharides Theoharis C"],"doi":"10.1093/jnen/nlag016","pmid":"41790576","pmcid":null,"publicationDate":"2026-01-01","journal":"Journal of neuropathology and experimental neurology","abstract":"$25","categories":["persistence","mechanisms","therapeutics","symptoms"],"tags":["long-covid","pasc","neuroinflammation"],"studyType":"review","spikeSource":["infection"],"keyFindings":["Postacute sequelae of SARS-CoV-2 infection (PASC), or Long COVID, is estimated to affect over 60 million individuals globally, with almost half of COVID-19 survivors experiencing persistent symptoms such as neuropathic pain, fatigue, and autonomic dysfunction.","Despite its prevalence, the pathophysiology of PASC remains poorly understood.","This narrative review highlights activation of mast cells (MCs), the unique tissue immune cells as a central contributor to neuropathic manifestations in PASC."],"persistenceDuration":null,"mechanisms":["inflammation","neuroinflammation"],"therapeuticTargets":null,"symptoms":["fatigue","neuropathy"],"pdfUrl":null,"pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/41790576/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-41028062","title":"SARS-CoV-2 spike protein-induced inflammation underlies proarrhythmia in COVID-19.","authors":["Mezache Louisa","Soltisz Andrew","Tili Esmerina","Nuovo Gerard J","Veeraraghavan Rengasayee"],"doi":"10.1038/s41598-025-12807-9","pmid":"41028062","pmcid":"PMC12484841","publicationDate":"2025-01-30","journal":"Scientific reports","abstract":"$26","categories":["persistence","mechanisms","symptoms"],"tags":["long-covid"],"studyType":"mouse-model","spikeSource":["infection"],"keyFindings":["Coronavirus disease 2019 (COVID-19) patients have a 1.7-fold higher arrhythmia risk with rates of cardiac complications ranging from 2% non-ICU patients to 59% in non-survivors.","Atrial fibrillation (AF), the most common arrhythmia, is a frequent complication of acute and long COVID-19.","The high expression of ACE2 in the heart suggested that infectious virus may underlie cardiac complications."],"persistenceDuration":null,"mechanisms":["inflammation","ACE2 binding"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12484841/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/41028062/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-40447603","title":"Ultrapotent SARS coronavirus-neutralizing single-domain antibodies that clamp the spike at its base.","authors":["De Cae Sieglinde","Van Molle Inge","van Schie Loes","Shoemaker Sophie R","Deckers Julie","Debeuf Nincy","Lameire Sahine","Nerinckx Wim"],"doi":"10.1038/s41467-025-60250-1","pmid":"40447603","pmcid":"PMC12125293","publicationDate":"2025-01-30","journal":"Nature communications","abstract":"$27","categories":["mechanisms","therapeutics"],"tags":[],"studyType":"mouse-model","spikeSource":["infection"],"keyFindings":["Therapeutic monoclonal antibodies can prevent severe disease in SARS-CoV-2 exposed individuals.","However, currently circulating virus variants have evolved to gain significant resistance to nearly all neutralizing human immune system-derived therapeutic monoclonal antibodies that had previously been emergency-authorized for use in the clinic.","Here, we describe the discovery of a panel of single-domain antibodies (VHHs) directed against the spike protein S2 subunit that broadly neutralize SARS-CoV-1 and -2 with unusually high potency."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":["Monoclonal antibodies","Antivirals"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12125293/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/40447603/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-41318533","title":"Development of ACE2-tropic-betacoronavirus therapeutics for future pandemic preparedness.","authors":["Utz Ashley","Armbrust Matt","Nguyen Thuy-Tien T","Morris Mary Kate","Matthews Chris O","Kompella Pallavi","Cao Zheng","Ha Ji Won"],"doi":"10.1038/s41467-025-66805-6","pmid":"41318533","pmcid":"PMC12775405","publicationDate":"2025-01-29","journal":"Nature communications","abstract":"$28","categories":["mechanisms","therapeutics"],"tags":[],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["A major challenge during viral pandemics is the ability to develop therapeutics whose efficacy can withstand viral genetic evolution.","During the COVID-19 pandemic, five SARS-CoV-2 monoclonal antibody (mAb) therapeutics were rendered ineffective within a period of 2 years, leading to the U.S.","FDA revoking their emergency use authorization."],"persistenceDuration":"Up to 2 years","mechanisms":["ACE2 binding"],"therapeuticTargets":["Monoclonal antibodies"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12775405/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/41318533/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-40705599","title":"Structure of a SARS-CoV-2 spike S2 subunit in a pre-fusion, open conformation.","authors":["Olmedillas Eduardo","Rajamanickam Roshan R","Avalos Ruben Diaz","Ana-Sosa-Batiz Fernanda","Zyla Dawid","Zandonatti Michelle A","Harkins Stephanie S","Shresta Sujan"],"doi":"10.1016/j.celrep.2025.116052","pmid":"40705599","pmcid":null,"publicationDate":"2025-01-26","journal":"Cell reports","abstract":"$29","categories":["mechanisms"],"tags":["vaccine"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["The continued emergence of SARS-CoV-2 variants necessitates the development of immunogens that promote broad and durable immunity.","The SARS-CoV-2 S2 fusion subunit drives viral entry and has sequence conservation among coronavirus spike proteins.","Therefore, S2 could represent an immunogen to boost broadly reactive antibodies."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":null,"pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/40705599/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-40431631","title":"SARS-CoV-2 Spike Protein and Long COVID-Part 2: Understanding the Impact of Spike Protein and Cellular Receptor Interactions on the Pathophysiology of Long COVID Syndrome.","authors":["de Melo Bruno Pereira","da Silva Jhéssica Adriane Mello","Rodrigues Mariana Alves","Palmeira Julys da Fonseca","Amato Angélica Amorim","Argañaraz Gustavo Adolfo","Argañaraz Enrique Roberto"],"doi":"10.3390/v17050619","pmid":"40431631","pmcid":"PMC12115913","publicationDate":"2025-01-25","journal":"Viruses","abstract":"$2a","categories":["mechanisms","symptoms"],"tags":["long-covid","pasc","vaccine"],"studyType":"review","spikeSource":["both"],"keyFindings":["SARS-CoV-2 infection has had a significant impact on global health through both acute illness, referred to as coronavirus disease 2019 (COVID-19), and chronic conditions (long COVID or post-acute sequelae of COVID-19, PASC).","Despite substantial advancements in preventing severe COVID-19 cases through vaccination, the rise in the prevalence of long COVID syndrome and a notable degree of genomic mutation, primarily in the S protein, underscores the necessity for a deeper understanding of the underlying pathophysiological mechanisms related to the S protein of SARS-CoV-2.","In this review, the latest part of this series, we investigate the potential pathophysiological molecular mechanisms triggered by the interaction between the spike protein and cellular receptors."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12115913/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/40431631/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-40431629","title":"SARS-CoV-2 Spike Protein and Long COVID-Part 1: Impact of Spike Protein in Pathophysiological Mechanisms of Long COVID Syndrome.","authors":["de Melo Bruno Pereira","da Silva Jhéssica Adriane Mello","Rodrigues Mariana Alves","Palmeira Julys da Fonseca","Saldanha-Araujo Felipe","Argañaraz Gustavo Adolfo","Argañaraz Enrique Roberto"],"doi":"10.3390/v17050617","pmid":"40431629","pmcid":"PMC12115690","publicationDate":"2025-01-25","journal":"Viruses","abstract":"SARS-CoV-2 infection has resulted in more than 700 million cases and nearly 7 million deaths worldwide. Although vaccination efforts have effectively reduced mortality and transmission rates, a significant proportion of recovered patients-up to 40%-develop long COVID syndrome (LC) or post-acute sequelae of COVID-19 infection (PASC). LC is characterized by the persistence or emergence of new symptoms following initial SARS-CoV-2 infection, affecting the cardiovascular, neurological, respiratory, gastrointestinal, reproductive, and immune systems. Despite the broad range of clinical symptoms that have been described, the risk factors and pathogenic mechanisms behind LC remain unclear. This review, the first of a two-part series, is distinguished by the discussion of the role of the SARS-CoV-2 spike protein in the primary mechanisms underlying the pathophysiology of LC.","categories":["persistence","mechanisms","symptoms"],"tags":["long-covid","pasc","vaccine","neuroinflammation"],"studyType":"review","spikeSource":["both"],"keyFindings":["SARS-CoV-2 infection has resulted in more than 700 million cases and nearly 7 million deaths worldwide.","Although vaccination efforts have effectively reduced mortality and transmission rates, a significant proportion of recovered patients-up to 40%-develop long COVID syndrome (LC) or post-acute sequelae of COVID-19 infection (PASC).","LC is characterized by the persistence or emergence of new symptoms following initial SARS-CoV-2 infection, affecting the cardiovascular, neurological, respiratory, gastrointestinal, reproductive, and immune systems."],"persistenceDuration":null,"mechanisms":["neuroinflammation"],"therapeuticTargets":null,"symptoms":["cardiovascular"],"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12115690/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/40431629/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-41164857","title":"Combined Adaptive Immune Mechanisms Mediate Cardiac Injury After COVID-19 Vaccination.","authors":["Fanti Silvia","Dyer Carlene","Ingimarsdóttir Inga Jóna","Harding Daniel","Wang Guosu","D'Amati Antonio","Shahaj Eriomina","Sigurbergsdóttir Adalbjorg Ýr"],"doi":"10.1161/CIRCULATIONAHA.125.074644","pmid":"41164857","pmcid":"PMC12643570","publicationDate":"2025-01-25","journal":"Circulation","abstract":"$2b","categories":["persistence","mechanisms","symptoms"],"tags":["vaccine","mRNA","myocarditis"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["BACKGROUND: The COVID-19 pandemic, caused by SARS-CoV-2, has led to the first approval of mRNA vaccines in humans.","By producing the full-length SARS-CoV-2 Spike protein, they induce protective antiviral immunity.","Acute myopericarditis (AMP) development after vaccination has repeatedly been reported; however, the pathogenesis of this complication remains elusive."],"persistenceDuration":null,"mechanisms":["inflammation","autoimmunity"],"therapeuticTargets":["Antivirals"],"symptoms":["myocarditis"],"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12643570/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/41164857/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-41257850","title":"Spike conformational and glycan heterogeneity associated with furin cleavage causes incomplete neutralization of SARS-CoV-2.","authors":["Kumar Sahil","Delipan Rathina","Sharma Chanchal","Jadoun Jyoti","Kanjo Kawkab","Singh Randhir","Rajmani Raju","Deshpande Suprit"],"doi":"10.1038/s41467-025-65099-y","pmid":"41257850","pmcid":"PMC12630640","publicationDate":"2025-01-19","journal":"Nature communications","abstract":"$2c","categories":["persistence","mechanisms","therapeutics"],"tags":[],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["SARS-CoV-2 Spike - the sole neutralization target, is highly resilient to the immune pressure driving genetic evolution.","While potency and breadth of neutralization are widely studied, the incomplete neutralization - the mechanism of resistance without needing genetic change - remains unexplored.","Several monoclonal antibodies, although potent, showed incomplete neutralization of genetically homogeneous pseudovirus suggesting the existence of distinct spike conformations."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":["Monoclonal antibodies"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12630640/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/41257850/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-41008646","title":"Mitochondrial Reactive Oxygen Species: A Unifying Mechanism in Long COVID and Spike Protein-Associated Injury: A Narrative Review.","authors":["Lee Eunseuk","Ozigbo Adaobi Amelia","Varon Joseph","Halma Mathew","Laezzo Madison","Ang Song Peng","Iglesias Jose"],"doi":"10.3390/biom15091339","pmid":"41008646","pmcid":"PMC12467101","publicationDate":"2025-01-18","journal":"Biomolecules","abstract":"$2d","categories":["persistence","mechanisms","therapeutics","symptoms"],"tags":["long-covid","vaccine"],"studyType":"review","spikeSource":["both"],"keyFindings":["Post-acute sequelae of SARS-CoV-2 infection (long COVID) present with persistent fatigue, cognitive impairment, and autonomic and multisystem dysfunctions that often go unnoticed by standard diagnostic tests.","Increasing evidence suggests that mitochondrial dysfunction and oxidative stress are central drivers of these post-viral sequelae.","Viral infections, particularly SARS-CoV-2, disrupt mitochondrial bioenergetics by altering membrane integrity, increasing mitochondrial reactive oxygen species (mtROS), and impairing mitophagy, leading to sustained immune activation and metabolic imbalance."],"persistenceDuration":null,"mechanisms":["inflammation"],"therapeuticTargets":null,"symptoms":["fatigue","cognitive dysfunction"],"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12467101/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/41008646/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-40573981","title":"VITT Pathophysiology: An Update.","authors":["Petito Eleonora","Gresele Paolo"],"doi":"10.3390/vaccines13060650","pmid":"40573981","pmcid":"PMC12197362","publicationDate":"2025-01-17","journal":"Vaccines","abstract":"$2e","categories":["mechanisms","therapeutics"],"tags":["vaccine","mRNA"],"studyType":"review","spikeSource":["both"],"keyFindings":["Vaccine-induced thrombotic thrombocytopenia (VITT) is a rare thrombotic disorder first identified in 2021 as a catastrophic syndrome associated with anti-SARS-CoV-2 adenoviral vector (AdV)-vaccine administration.","It is characterized by the presence of oligo- or monoclonal anti-PF4 antibodies able to induce in vitro platelet activation in the presence of PF4.","In addition to this immune-based pathomechanism, random splicing events of the Adv-vector DNA encoding for SARS-CoV-2 spike protein resulting in the secretion of soluble spike variants have been postulated as a possible pathophysiological mechanism."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":["Monoclonal antibodies"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12197362/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/40573981/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-41295749","title":"SARS-CoV-2 Spike Protein Amyloid Fibrils Impair Fibrin Formation and Fibrinolysis.","authors":["Westman Henrik","Hammarström Per","Nyström Sofie"],"doi":"10.1021/acs.biochem.5c00550","pmid":"41295749","pmcid":"PMC12713721","publicationDate":"2025-01-16","journal":"Biochemistry","abstract":"$2f","categories":["persistence","mechanisms","symptoms"],"tags":["long-covid","fibrin"],"studyType":"preclinical","spikeSource":["infection"],"keyFindings":["Long COVID, or postacute sequelae of COVID-19 from SARS-CoV-2 infection, is a persistent debilitating disease affecting multiple systems and organs.","Long COVID pathophysiology is a complex and not fully established process.","One prevailing theory is that the formation of fibrin amyloid microclots (fibrinaloids), due to SARS-CoV-2 infection, can induce persistent inflammation and capillary blockage."],"persistenceDuration":null,"mechanisms":["inflammation","fibrin/clotting"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12713721/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/41295749/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-40869200","title":"Do Long COVID and COVID Vaccine Side Effects Share Pathophysiological Picture and Biochemical Pathways?","authors":["Lesgards Jean-François","Cerdan Dominique","Perronne Christian"],"doi":"10.3390/ijms26167879","pmid":"40869200","pmcid":"PMC12386580","publicationDate":"2025-01-15","journal":"International journal of molecular sciences","abstract":"$30","categories":["persistence","mechanisms","therapeutics","symptoms"],"tags":["long-covid","vaccine","mRNA","neuroinflammation"],"studyType":"review","spikeSource":["both"],"keyFindings":["COVID affects around 400 million individuals today with a strong economic impact on the global economy.","The list of long COVID symptoms is extremely broad because it is derived from neurological, cardiovascular, respiratory, immune, and renal dysfunctions and damages.","We review here these pathophysiological manifestations and the predictors of this multi-organ pathology like the persistence of the virus, altered endothelial function, unrepaired tissue damage, immune dysregulation, and gut dysbiosis."],"persistenceDuration":null,"mechanisms":["inflammation","endothelial damage","neuroinflammation","complement activation","ACE2 binding"],"therapeuticTargets":null,"symptoms":["cardiovascular"],"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12386580/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/40869200/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-40136024","title":"Neutralization and spike stability of JN.1-derived LB.1, KP.2.3, KP.3, and KP.3.1.1 subvariants.","authors":["Li Pei","Faraone Julia N","Hsu Cheng Chih","Chamblee Michelle","Liu Yajie","Zheng Yi-Min","Xu Yan","Carlin Claire"],"doi":"10.1128/mbio.00464-25","pmid":"40136024","pmcid":"PMC12077133","publicationDate":"2025-01-14","journal":"mBio","abstract":"$31","categories":["persistence","mechanisms"],"tags":["vaccine","mRNA"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["During the summer of 2024, coronavirus disease 2019 (COVID-19) cases surged globally, driven by variants derived from JN.1 subvariants of severe acute respiratory syndrome coronavirus 2 that feature new mutations, particularly in the N-terminal domain (NTD) of the spike protein.","In this study, we report on the neutralizing antibody (nAb) escape, infectivity, fusion, and spike stability of these subvariants-LB.1, KP.2.3, KP.3, and KP.3.1.1.","Our findings demonstrate that all of these subvariants are highly evasive of nAbs elicited by the bivalent mRNA vaccine, the XBB.1.5 monovalent mumps virus-based vaccine, or from infections during the BA.2.86/JN.1 wave."],"persistenceDuration":null,"mechanisms":["ACE2 binding"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077133/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/40136024/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-40004616","title":"Serum Spike Protein Persistence Post COVID Is Not Associated with ME/CFS.","authors":["Fehrer Annick","Sotzny Franziska","Kim Laura","Kedor Claudia","Freitag Helma","Heindrich Cornelia","Grabowski Patricia","Babel Nina"],"doi":"10.3390/jcm14041086","pmid":"40004616","pmcid":"PMC11856657","publicationDate":"2025-01-08","journal":"Journal of clinical medicine","abstract":"$32","categories":["persistence","therapeutics","symptoms"],"tags":["vaccine"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["Background/Objectives: According to the World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC), an estimated 3-6% of people suffer from post-COVID condition or syndrome (PCS).","A subset meets the diagnostic criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).","Studies have reported that SARS-CoV-2 proteins or RNA can persist after acute infection in serum or tissues, but their role in PCS is unclear."],"persistenceDuration":"Up to 31 months","mechanisms":null,"therapeuticTargets":null,"symptoms":["fatigue"],"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11856657/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/40004616/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-41278654","title":"Human coronavirus HKU1 neutralization by glycan receptor mimicry.","authors":["Feng Ziqi","Kose Nurgun","Moreira Fernando R","Kimpel Anne L M","Copps Jeffrey","Suryadevara Naveenchandra","Jackson Daniel J","Gern James E"],"doi":"10.1101/2025.11.05.686863","pmid":"41278654","pmcid":"PMC12637458","publicationDate":"2025-01-07","journal":"bioRxiv : the preprint server for biology","abstract":"$33","categories":["mechanisms","therapeutics"],"tags":[],"studyType":"preprint","spikeSource":["unspecified"],"keyFindings":["Entry of seasonal human coronavirus HKU1 (HCoV-HKU1) into host cells is facilitated by sequential binding to sialoglycans and transmembrane serine protease 2 (TMPRSS2) receptors.","However, the neutralizing capacity of antibodies disrupting these receptor interactions have not been examined.","Here, we describe the isolation and characterization of a human monoclonal antibody (mAb) HKU1-2 that recognizes the HCoV-HKU1 spike protein and exhibits dose-dependent neutralization of the virus."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":["Monoclonal antibodies"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12637458/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/41278654/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-41012643","title":"Biomarker-Based Risk Assessment Strategy for Long COVID: Leveraging Spike Protein and Proinflammatory Mediators to Inform Broader Postinfection Sequelae.","authors":["Yang Ying-Fei","Ling Min-Pei","Chen Szu-Chieh","Lin Yi-Jun","You Shu-Han","Lu Tien-Hsuan","Chen Chi-Yun","Wang Wei-Min"],"doi":"10.3390/v17091215","pmid":"41012643","pmcid":"PMC12474022","publicationDate":"2025-01-05","journal":"Viruses","abstract":"$34","categories":["persistence","symptoms"],"tags":["long-covid"],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["Long COVID, characterized by persistent symptoms following acute SARS-CoV-2 infection, has emerged as a significant public health challenge with wide-ranging clinical and socioeconomic implications.","Developing an effective risk assessment strategy is essential for the early identification and management of individuals susceptible to prolonged symptoms.","This study uses a quantitative approach to characterize the dose-response relationships between spike protein concentrations and effects, including Long COVID symptom numbers and the release of proinflammatory mediators."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12474022/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/41012643/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-41289395","title":"Tattoo ink induces inflammation in the draining lymph node and alters the immune response to vaccination.","authors":["Capucetti Arianna","Falivene Juliana","Pizzichetti Chiara","Latino Irene","Mazzucchelli Luca","Schacht Vivien","Hauri Urs","Raimondi Andrea"],"doi":"10.1073/pnas.2510392122","pmid":"41289395","pmcid":"PMC12685120","publicationDate":"2025-01-02","journal":"Proceedings of the National Academy of Sciences of the United States of America","abstract":"$35","categories":["mechanisms"],"tags":["vaccine","mRNA"],"studyType":"mouse-model","spikeSource":["both"],"keyFindings":["Despite safety concerns regarding the toxicity of tattoo ink, no studies have reported the consequences of tattooing on the immune response.","In this work, we have characterized the transport and accumulation of different tattoo inks in the lymphatic system using a murine model.","Upon quick lymphatic drainage, we observed that macrophages mainly capture the ink in the lymph node (LN)."],"persistenceDuration":null,"mechanisms":["inflammation"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12685120/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/41289395/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-40184822","title":"Expression of SARS-CoV-2 spike protein in cerebral Arteries: Implications for hemorrhagic stroke Post-mRNA vaccination.","authors":["Ota Nakao","Itani Masahiko","Aoki Tomohiro","Sakurai Aki","Fujisawa Takashi","Okada Yasuaki","Noda Kosumo","Arakawa Yoshiki"],"doi":"10.1016/j.jocn.2025.111223","pmid":"40184822","pmcid":null,"publicationDate":"2025-01-01","journal":"Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia","abstract":"$36","categories":["persistence","symptoms"],"tags":["vaccine","mRNA"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["BACKGROUND: The rapid deployment of mRNA vaccines for SARS-CoV-2, such as BNT162b2 (BioNTech-Pfizer) and mRNA-1273 (Moderna), provided a critical tool in combating the COVID-19 pandemic.","While their short-term safety and efficacy were demonstrated in clinical trials, rare adverse events, including hemorrhagic strokes, have been reported after widespread use.","However, the long-term biodistribution and effects of mRNA vaccines remain underexplored."],"persistenceDuration":"Up to 17 months","mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":null,"pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/40184822/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-40163530","title":"Enhanced RNA replication and pathogenesis in recent SARS-CoV-2 variants harboring the L260F mutation in NSP6.","authors":["Taha Taha Y","Ezzatpour Shahrzad","Hayashi Jennifer M","Ye Chengjin","Zapatero-Belinchón Francisco J","Rosecrans Julia A","Kimmerly Gabriella R","Chen Irene P"],"doi":"10.1371/journal.ppat.1013020","pmid":"40163530","pmcid":"PMC11981139","publicationDate":"2025-01-01","journal":"PLoS pathogens","abstract":"$37","categories":["mechanisms","therapeutics"],"tags":[],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["The COVID-19 pandemic has been driven by SARS-CoV-2 variants with enhanced transmission and immune escape.","Apart from extensive evolution in the Spike protein, non-Spike mutations are accumulating across the entire viral genome and their functional impact is not well understood.","To address the contribution of these mutations, we reconstructed genomes of recent Omicron variants with disabled Spike expression (replicons) to systematically compare their RNA replication capabilities independently from Spike."],"persistenceDuration":null,"mechanisms":["complement activation"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11981139/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/40163530/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-40534870","title":"Soluble SARS-CoV-2 Spike glycoprotein: considering some potential pathogenic effects.","authors":["Azzarone Bruno","Landolina Nadine","Mariotti Francesca Romana","Moretta Lorenzo","Maggi Enrico"],"doi":"10.3389/fimmu.2025.1616106","pmid":"40534870","pmcid":"PMC12174082","publicationDate":"2025-01-01","journal":"Frontiers in immunology","abstract":"$38","categories":["persistence","mechanisms","symptoms"],"tags":["pasc","vaccine","s1-subunit"],"studyType":"review","spikeSource":["both"],"keyFindings":["The soluble S1 subunit of Spike protein (SP) from the SARS-CoV-2 of different variants of concern (VOCs) may directly bind and activate human NK cells in vitro through the engagement of the toll-like receptor (TLR) 2 and TLR4.","This mechanism revealed a novel pathogenic role played by NK cells not only in the different phases of disease but also in the post-acute sequelae of COVID-19 (PASC) and some post-vaccination side effects.","In addition to its binding to angiotensin-converting enzyme 2 (ACE2), which mediates virus attachment and cell entry, soluble SP triggers several active receptors/molecules expressed by many cells, inducing, in turn, type I/III interferon decrease, altered autophagy and apoptosis, the release of inflammatory cytokines and chemokines, complement activation and endothelial damage, which favour clotting events."],"persistenceDuration":null,"mechanisms":["endothelial damage","complement activation","ACE2 binding"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12174082/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/40534870/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-40562255","title":"Insights into the pathogenic mechanisms associated with the SARS-CoV-2 spike protein.","authors":["Argyrou Mia","Pitsillou Eleni","Hung Andrew","El-Osta Assam","Karagiannis Tom C"],"doi":"10.1016/j.jsb.2025.108229","pmid":"40562255","pmcid":null,"publicationDate":"2025-01-01","journal":"Journal of structural biology","abstract":"$39","categories":["persistence","mechanisms","therapeutics","symptoms"],"tags":["s1-subunit","neuroinflammation"],"studyType":"review","spikeSource":["infection"],"keyFindings":["Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogenic agent responsible for the coronavirus disease 2019 (COVID-19) pandemic, uses the trimeric spike protein to gain entry into the host cell.","Structural studies have revealed that the spike protein is comprised of the S1 and S2 subunits.","The S1 subunit of the spike protein contains the receptor-binding domain (RBD), which binds to the human angiotensin-converting enzyme 2 (ACE2) receptor."],"persistenceDuration":null,"mechanisms":["neuroinflammation","ACE2 binding"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":null,"pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/40562255/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-40849821","title":"Pathogen virulence genes: Advances, challenges and future directions in infectious disease research (Review).","authors":["Chen Yun","Wu Xiaolong","Xu Chengcheng","Huang Jianxiang","Zhang Lingyu","Qiu Peng","Zheng Danling","Chen Wang"],"doi":"10.3892/ijmm.2025.5614","pmid":"40849821","pmcid":"PMC12404894","publicationDate":"2025-01-01","journal":"International journal of molecular medicine","abstract":"$3a","categories":["persistence","mechanisms"],"tags":["vaccine"],"studyType":"review","spikeSource":["both"],"keyFindings":["Pathogens, including bacteria, viruses and fungi, employ virulence genes to invade their hosts, circumvent immunity and induce diseases.","The present review examines the categorization and regulatory mechanisms of virulence genes and their co‑evolution with antimicrobial resistance.","The present review focused on the fimbrial adhesion H adhesion gene of Escherichia coli, the spike protein gene of severe acute respiratory syndrome coronavirus 2 and the enhanced filamentous growth protein 1 (EFG1) morphological transition gene of Candida albicans, as well as their roles in host adhesion, immune evasion and tissue damage."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12404894/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/40849821/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-40014015","title":"Pan-Variant SARS-CoV-2 Vaccines Induce Protective Immunity by Targeting Conserved Epitopes.","authors":["Shah Masaud","Moon Sung Ung","Shin Ji-Yon","Choi Ji-Hye","Kim Doyoon","Woo Hyun Goo"],"doi":"10.1002/advs.202409919","pmid":"40014015","pmcid":"PMC12021035","publicationDate":"2025-01-01","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","abstract":"$3b","categories":["persistence"],"tags":["vaccine"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["The development of a globally effective COVID-19 vaccine faces significant challenges, particularly in redirecting the B-cell response from immunodominant yet variable regions of viral proteins toward their conserved domains.","To address this, an integrated strategy is implemented that combines classical B-cell epitope prediction with protein-antibody cluster docking and antibody titer analysis from 30 vaccinated and convalescent individuals.","This approach yields stable immunodominant and immunoprevalent B-cell epitopes capable of eliciting robust antibody responses in BALB/c mice and effectively neutralizing pseudoviruses expressing the Spike protein of SARS-CoV-2 variants of concern, including Alpha, Beta, Gamma, Delta, and Omicron."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12021035/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/40014015/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-40328900","title":"SARS-CoV-2 spike protein: structure, viral entry and variants.","authors":["Chen Bing","Farzan Michael","Choe Hyeryun"],"doi":"10.1038/s41579-025-01185-8","pmid":"40328900","pmcid":"PMC13137867","publicationDate":"2025-01-01","journal":"Nature reviews. Microbiology","abstract":"Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been a devastating global pandemic for 4 years and is now an endemic disease. With the emergence of new viral variants, COVID-19 is a continuing threat to public health despite the wide availability of vaccines. The virus-encoded trimeric spike protein (S protein) mediates SARS-CoV-2 entry into host cells and also induces strong immune responses, making it an important target for development of therapeutics and vaccines. In this Review, we summarize our latest understanding of the structure and function of the SARS-CoV-2 S protein, the molecular mechanism of viral entry and the emergence of new variants, and we discuss their implications for development of S protein-related intervention strategies.","categories":["mechanisms","therapeutics"],"tags":["vaccine"],"studyType":"review","spikeSource":["both"],"keyFindings":["Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been a devastating global pandemic for 4 years and is now an endemic disease.","With the emergence of new viral variants, COVID-19 is a continuing threat to public health despite the wide availability of vaccines.","The virus-encoded trimeric spike protein (S protein) mediates SARS-CoV-2 entry into host cells and also induces strong immune responses, making it an important target for development of therapeutics and vaccines."],"persistenceDuration":"Up to 4 years","mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13137867/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/40328900/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-40944962","title":"Post-COVID-19 Vaccination (or Long Vax) Syndrome: Putative Manifestation, Pathophysiology, and Therapeutic Options.","authors":["Yong Shin Jie","Kenny Tiff-Annie","Halim Alice","Munipalli Bala","Alhashem Yousef N","AlSaihati Hajir","Al-Subaie Maha F","Al Kaabi Nawal A"],"doi":"10.1002/rmv.70070","pmid":"40944962","pmcid":null,"publicationDate":"2025-01-01","journal":"Reviews in medical virology","abstract":"$3c","categories":["persistence","therapeutics","symptoms"],"tags":["long-covid","vaccine","myocarditis","neuroinflammation"],"studyType":"review","spikeSource":["both"],"keyFindings":["With the global rollout of COVID-19 vaccines, vaccine safety remains a priority.","Emerging concerns have raised the potential risk of a long COVID-like syndrome following vaccination, informally called long Vax and provisionally termed post-COVID-19 vaccination syndrome (PCVS).","Our narrative review describes the putative manifestation, pathophysiology, and therapeutic approaches of PCVS based on the available evidence, mostly from case reports/series and observational studies."],"persistenceDuration":null,"mechanisms":["neuroinflammation"],"therapeuticTargets":null,"symptoms":["brain fog","fatigue","myocarditis","neuropathy"],"pdfUrl":null,"pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/40944962/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-40358138","title":"Detection of S1 spike protein in CD16+ monocytes up to 245 days in SARS-CoV-2-negative post-COVID-19 vaccine syndrome (PCVS) individuals.","authors":["Patterson Bruce K","Yogendra Ram","Francisco Edgar B","Guevara-Coto Jose","Long Emily","Pise Amruta","Osgood Eric","Bream John"],"doi":"10.1080/21645515.2025.2494934","pmid":"40358138","pmcid":"PMC12077440","publicationDate":"2025-01-01","journal":"Human vaccines & immunotherapeutics","abstract":"$3d","categories":["persistence","mechanisms","symptoms"],"tags":["pasc","vaccine","s1-subunit","neuroinflammation"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["Despite over 13 billion SARS-CoV-2 vaccine doses administered globally, persistent post-vaccination symptoms, termed post-COVID-19 vaccine syndrome (PCVS), resemble post-acute sequelae of COVID-19 (PASC).","Symptoms like cardiac, vascular, and neurological issues often emerge shortly after vaccination and persist for months to years, mirroring PASC.","We previously showed the S1 subunit of the SARS-CoV-2 spike protein persists in CD16+ monocytes after infection, potentially driving PASC."],"persistenceDuration":"Up to 245 days","mechanisms":["inflammation","neuroinflammation"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077440/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/40358138/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-40597299","title":"Mesenchymal stromal cell secretome reduces lung injury and thrombo-inflammation induced by SARS-CoV-2 spike protein.","authors":["Pezzotta Anna","Bovio Alessandra","Imberti Barbara","Locatelli Monica","Corna Daniela","Cerullo Domenico","Gastoldi Sara","Benigni Ariela"],"doi":"10.1186/s13287-025-04472-6","pmid":"40597299","pmcid":"PMC12210905","publicationDate":"2025-01-01","journal":"Stem cell research & therapy","abstract":"$3e","categories":["mechanisms","therapeutics"],"tags":[],"studyType":"preclinical","spikeSource":["infection"],"keyFindings":["Severe COVID-19 is characterized by thrombo-inflammatory processes within the lung microvasculature.","In pursuit of effective treatments, clinical studies explored mesenchymal stromal cells (MSCs) as a promising approach due to their anti-inflammatory, immunomodulatory, and regenerative properties, through their paracrine action.Here, we tested the conditioned medium (CM) derived from human umbilical cord (UC)-MSCs in acute lung injury induced by the spike protein subunit 1 (S1) in ACE2-humanized male mice.","Injection of CM significantly limited S1-induced lung injury, edema, and fibrosis."],"persistenceDuration":null,"mechanisms":["inflammation","endothelial damage","complement activation","ACE2 binding"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12210905/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/40597299/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-40951547","title":"Unleashing Monoclonal Antibodies: Targeting Covid-19's Nucleocapsid Protein and Spike Antigens.","authors":["Madani R","Golchinfar F","Hezarosi M","Emami T","Ghanizadeh A"],"doi":"10.32592/ARI.2025.80.1.75","pmid":"40951547","pmcid":"PMC12426448","publicationDate":"2025-01-01","journal":"Archives of Razi Institute","abstract":"$3f","categories":["therapeutics"],"tags":["vaccine"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["Since the end of 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected many people globally.","Diagnosis and treatment of patients have a pivotal role in surviving them.","Two units of virus namely, Nucleocapsid protein and Spike proteins play important roles in entering and affecting cells."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":["Monoclonal antibodies"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12426448/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/40951547/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-40183251","title":"Rice-derived SARS-CoV-2 glycoprotein S1 subunit vaccine elicits humoral and cellular immune responses.","authors":["Song Li","Wen Yaya","Zhou Yu","Zhang Hui","Tian Yuqi","Wang Jing","Cui Yaodan","Tan Ruimeng"],"doi":"10.1111/pbi.70077","pmid":"40183251","pmcid":"PMC12205891","publicationDate":"2025-01-01","journal":"Plant biotechnology journal","abstract":"$40","categories":["mechanisms"],"tags":["vaccine","s1-subunit"],"studyType":"preclinical","spikeSource":["both"],"keyFindings":["Since 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing COVID-19, has been spreading and mutating globally despite the expedited approval of many commercial vaccines.","Therefore, developing safe, effective and affordable vaccines remains essential to meet the global demand, particularly in developing countries.","Transgenic plants have emerged as a promising platform to express recombinant proteins for pharmaceutical and vaccine applications."],"persistenceDuration":null,"mechanisms":["ACE2 binding"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205891/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/40183251/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-40642004","title":"Oxidative stress in ARDS: mechanisms and therapeutic potential.","authors":["Wang Fengyun","Ge Ruiqi","Cai Yun","Zhao Mingrui","Fang Zhen","Li Jingguo","Xie Chengzhi","Wang Mei"],"doi":"10.3389/fphar.2025.1603287","pmid":"40642004","pmcid":"PMC12241040","publicationDate":"2025-01-01","journal":"Frontiers in pharmacology","abstract":"$41","categories":["mechanisms","therapeutics"],"tags":[],"studyType":"review","spikeSource":["infection"],"keyFindings":["Acute respiratory distress syndrome (ARDS) is a life-threatening condition characterized by acute lung inflammation, increased vascular permeability, and hypoxemic respiratory failure.","Oxidative stress, driven by excessive reactive oxygen species (ROS), is a key contributor to ARDS pathogenesis, causing cellular damage, inflammation, and alveolar-capillary barrier disruption.","This review elucidates the mechanisms of oxidative stress in ARDS, focusing on ROS production via NADPH oxidase (NOX) and mitochondria, which activate pathways like NF-κB and MAPK, promoting pro-inflammatory cytokine release."],"persistenceDuration":null,"mechanisms":["inflammation","endothelial damage"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12241040/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/40642004/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-40671933","title":"Post spike syndrome (PSS): Simple solution leading to resolving results, five cases report.","authors":["Zeballos Roberto S","da Silva Helbingen Mariely Fernanda","Melo Paulo Macio Porto","Alves Francisco Eduardo Cardoso","Salvino Caio Roberto","Seródio Ewerton Paes","de Carvalho Edimilson Ramos Migowski"],"doi":"10.1016/j.idcr.2025.e02278","pmid":"40671933","pmcid":"PMC12266371","publicationDate":"2025-01-01","journal":"IDCases","abstract":"$42","categories":["mechanisms","therapeutics","symptoms"],"tags":["mRNA","neuroinflammation"],"studyType":"case-report","spikeSource":["infection"],"keyFindings":["UNLABELLED: Post-Spike Syndrome (PSS) is an emerging condition associated with the Spike protein, originating from both SARS-CoV-2 infection and mRNA-based therapies.","This case series explores the significant clinical impact of PSS, characterized By gut dysbiosis, systemic inflammation, and immune activation, leading to multisystem manifestations such as fatigue, brain fog, neuropathies, and reactivation of pre-existing diseases.","A simple therapeutic approach was applied to five patients, resulting in notable symptom improvement."],"persistenceDuration":null,"mechanisms":["inflammation","neuroinflammation"],"therapeuticTargets":["Nattokinase"],"symptoms":["brain fog","fatigue","neuropathy"],"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12266371/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/40671933/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-40465408","title":"Therapeutic Intervention of an Intranasally Administered Monoclonal Antibody Targeting the SARS-CoV-2 Omicron Spike Protein Against SARS-CoV-2 Omicron Infection in Mice.","authors":["Kim Jinsoo","Kim Suyeon","Kim Dongbum","Kim Minyoung","Baek Kyeongbin","Kang Bo Min","An Seungchan","Park In Guk"],"doi":"10.1089/vim.2024.0095","pmid":"40465408","pmcid":null,"publicationDate":"2025-01-01","journal":"Viral immunology","abstract":"SARS-CoV-2 has evolved into several variants of concern, with Omicron and its subvariants currently being the most prevalent. Previously, we developed a mouse monoclonal antibody (m1E3H12 mAb) specific to the receptor binding domain of SARS-CoV-2 Omicron spike protein, and the mAb showed neutralizing activity against SARS-CoV-2 Omicron BA.1 and its subvariants BA.5, BQ.1.1, and XBB. Here, we showed that the mAb provided protection against SARS-CoV-2 Omicron infection in K18-hACE2 transgenic mice when administered intranasally. The mAb treatment reduced viral loads in both the brain and lungs. Additionally, the elevated levels of RANTES (CCL5) and MIP-3 alpha (CCL20) in the brain following SARS-CoV-2 Omicron infection showed a decreasing trend after mAb treatment. Therefore, we conclude that our mAb specific to SARS-CoV-2 Omicron spike protein has the potential to be applied as therapeutics against SARS-CoV-2 Omicron BA.1 and its subvariants BA.5, BQ.1.1, and XBB.","categories":["mechanisms","therapeutics"],"tags":[],"studyType":"mouse-model","spikeSource":["infection"],"keyFindings":["SARS-CoV-2 has evolved into several variants of concern, with Omicron and its subvariants currently being the most prevalent.","Previously, we developed a mouse monoclonal antibody (m1E3H12 mAb) specific to the receptor binding domain of SARS-CoV-2 Omicron spike protein, and the mAb showed neutralizing activity against SARS-CoV-2 Omicron BA.1 and its subvariants BA.5, BQ.1.1, and XBB.","Here, we showed that the mAb provided protection against SARS-CoV-2 Omicron infection in K18-hACE2 transgenic mice when administered intranasally."],"persistenceDuration":null,"mechanisms":["ACE2 binding"],"therapeuticTargets":["Monoclonal antibodies"],"symptoms":null,"pdfUrl":null,"pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/40465408/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-40496870","title":"Long COVID-19 autoantibodies and their potential effect on fertility.","authors":["Talamini Laura","Fonseca Dennyson Leandro M","Kanduc Darja","Chaloin Olivier","Verdot Cindy","Galmiche Christian","Dotan Arad","Filgueiras Igor Salerno"],"doi":"10.3389/fimmu.2025.1540341","pmid":"40496870","pmcid":"PMC12149208","publicationDate":"2025-01-01","journal":"Frontiers in immunology","abstract":"$43","categories":["persistence","symptoms"],"tags":["long-covid","vaccine"],"studyType":"mouse-model","spikeSource":["both"],"keyFindings":["Impaired spermatogenesis has been reported in coronavirus disease 2019 (COVID-19) patients.","However, the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on male fertility remains unclear.","The purpose of this multicenter study was to investigate the possible impact of SARS-CoV-2 infection on male fertility and determine the potential reasons leading to impaired male reproductive functions."],"persistenceDuration":null,"mechanisms":["autoimmunity"],"therapeuticTargets":null,"symptoms":["fatigue"],"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12149208/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/40496870/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-40375579","title":"LL-37 Inhibits TMPRSS2-Mediated S2' Site Cleavage and SARS-CoV-2 Infection but Not Omicron Variants.","authors":["Bi Zhenfei","Ren Wenyan","Zeng Hao","Zhou Yuanyuan","Liu Jian","Chen Zimin","Zhang Xindan","He Xuemei"],"doi":"10.1111/cpr.70060","pmid":"40375579","pmcid":"PMC12686126","publicationDate":"2025-01-01","journal":"Cell proliferation","abstract":"$44","categories":["mechanisms"],"tags":[],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["Continual evolution of SARS-CoV-2 spike drives the emergence of Omicron variants that show increased spreading and immune evasion.","Understanding how the variants orientate themselves towards host immune defence is crucial for controlling future pandemics.","Herein, we demonstrate that human cathelicidin LL-37, a crucial component of innate immunity, predominantly binds to the S2 subunit of SARS-CoV-2 spike protein, occupying sites where TMPRSS2 typically binds."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12686126/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/40375579/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"preprint-fehrer-2024","title":"Vaccine-derived spike protein and mRNA persist for up to 6 months in blood and tissues of patients with post-acute sequelae following COVID-19 vaccination","authors":["Fehrer C"],"doi":"10.1101/2024.11.11.24317084","publicationDate":"2024-11-11","journal":"medRxiv","abstract":"Autopsy and biopsy findings of vaccine-derived spike and mRNA in blood and multiple tissues including brain-meningeal borders.","summary":"Case series reports multi-tissue persistence up to 6 months; brain/skull border findings up to 4 years in limited autopsy data. Preprint — interpret with caution.","categories":["persistence","symptoms","mechanisms"],"tags":["vaccine","autopsy","neuroinflammation"],"studyType":"preprint","spikeSource":["vaccine-derived"],"keyFindings":["Spike and mRNA in blood and tissues up to 6 months","Brain-meningeal border deposits in autopsy cases","Multi-system post-vaccine sequelae described"],"persistenceDuration":"Up to 6 months (blood/tissues); up to ~4 years (brain borders, limited N)","symptoms":["cardiovascular","neuropathy","cognitive dysfunction"],"mechanisms":["neuroinflammation","tissue reservoirs"],"pubmedUrl":"https://www.medrxiv.org/content/10.1101/2024.11.11.24317084v1","reviewed":true,"lastUpdated":"2026-07-06"},{"id":"pmid-39599841","title":"","authors":["Navhaya Liberty T","Matsebatlela Thabe M","Monama Mokgerwa Z","Makhoba Xolani H"],"doi":"10.3390/v16111726","pmid":"39599841","pmcid":"PMC11599135","publicationDate":"2024-01-31","journal":"Viruses","abstract":"$45","categories":["mechanisms"],"tags":[],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["The SARS-CoV-2 spike protein is pivotal in the COVID-19 virus's life cycle, facilitating viral attachment to host cells.","It is believed that targeting this viral protein could be key to developing effective COVID-19 prophylactics.","Using in silico techniques, this study sought to virtually screen for compounds from the literature that strongly bind and disrupt the stability of the HSPA8-spike protein complex."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11599135/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/39599841/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-38793593","title":"Research Progress on Spike-Dependent SARS-CoV-2 Fusion Inhibitors and Small Molecules Targeting the S2 Subunit of Spike.","authors":["Freidel Matthew R","Armen Roger S"],"doi":"10.3390/v16050712","pmid":"38793593","pmcid":"PMC11125925","publicationDate":"2024-01-30","journal":"Viruses","abstract":"$46","categories":["mechanisms"],"tags":["s1-subunit"],"studyType":"review","spikeSource":["infection"],"keyFindings":["Since the beginning of the COVID-19 pandemic, extensive drug repurposing efforts have sought to identify small-molecule antivirals with various mechanisms of action.","Here, we aim to review research progress on small-molecule viral entry and fusion inhibitors that directly bind to the SARS-CoV-2 Spike protein.","Early in the pandemic, numerous small molecules were identified in drug repurposing screens and reported to be effective in in vitro SARS-CoV-2 viral entry or fusion inhibitors."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":["Antivirals"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11125925/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/38793593/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-38670948","title":"Mucosal prime-boost immunization with live murine pneumonia virus-vectored SARS-CoV-2 vaccine is protective in macaques.","authors":["Kaiser Jaclyn A","Nelson Christine E","Liu Xueqiao","Park Hong-Su","Matsuoka Yumiko","Luongo Cindy","Santos Celia","Ahlers Laura R H"],"doi":"10.1038/s41467-024-47784-6","pmid":"38670948","pmcid":"PMC11053155","publicationDate":"2024-01-26","journal":"Nature communications","abstract":"$47","categories":["persistence"],"tags":["vaccine"],"studyType":"mouse-model","spikeSource":["both"],"keyFindings":["Immunization via the respiratory route is predicted to increase the effectiveness of a SARS-CoV-2 vaccine.","Here, we evaluate the immunogenicity and protective efficacy of one or two doses of a live-attenuated murine pneumonia virus vector expressing SARS-CoV-2 prefusion-stabilized spike protein (MPV/S-2P), delivered intranasally/intratracheally to male rhesus macaques.","A single dose of MPV/S-2P is highly immunogenic, and a second dose increases the magnitude and breadth of the mucosal and systemic anti-S antibody responses and increases levels of dimeric anti-S IgA in the airways."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11053155/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/38670948/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-39047117","title":"Adjuvantation of a SARS-CoV-2 mRNA vaccine with controlled tissue-specific expression of an mRNA encoding IL-12p70.","authors":["Brook Byron","Duval Valerie","Barman Soumik","Speciner Lauren","Sweitzer Cali","Khanmohammed Asad","Menon Manisha","Foster Kimberly"],"doi":"10.1126/scitranslmed.adm8451","pmid":"39047117","pmcid":null,"publicationDate":"2024-01-24","journal":"Science translational medicine","abstract":"$48","categories":["persistence"],"tags":["vaccine","mRNA"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["Messenger RNA (mRNA) vaccines were pivotal in reducing severe acute respiratory syndrome 2 (SARS-CoV-2) infection burden, yet they have not demonstrated robust durability, especially in older adults.","Here, we describe a molecular adjuvant comprising a lipid nanoparticle (LNP)-encapsulated mRNA encoding interleukin-12p70 (IL-12p70).","The bioactive adjuvant was engineered with a multiorgan protection (MOP) sequence to restrict transcript expression to the intramuscular injection site."],"persistenceDuration":"Up to 1 years","mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":null,"pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/39047117/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-39578473","title":"Lysosomal \"TRAP\": a neotype modality for clearance of viruses and variants.","authors":["Lyu Chengliang","He Zhanlong","Hu Xiaoming","Wang Shuang","Qin Meng","Zhu Li","Li Yanyan","Yang Fengmei"],"doi":"10.1038/s41467-024-54505-6","pmid":"39578473","pmcid":"PMC11584657","publicationDate":"2024-01-23","journal":"Nature communications","abstract":"$49","categories":["mechanisms","therapeutics"],"tags":[],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["The binding of viruses to host-entry factor receptors is an essential step for viral infection.","Many studies have shown that macrophages can internalize viruses and degrade them in lysosomes for clearance in vivo.","Inspired by these natural behaviors and using SARS-CoV-2 as a testbed, we harvest lysosomes from activated macrophages and anchor the protein-receptor ACE2 as bait, thus constructing a lysosomal \"TRAP\" (lysoTRAP) that selectively captures, internalizes, and eventually degrades SARS-CoV-2."],"persistenceDuration":null,"mechanisms":["ACE2 binding"],"therapeuticTargets":["Antivirals"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11584657/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/39578473/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-39404450","title":"Development of a safe and broad-spectrum attenuated PEDV vaccine candidate by S2 subunit replacement.","authors":["Zhang Ding","Xie Yunfei","Liao Qi","Jiao Zhe","Liang Rui","Zhang Jintao","Zhang Yu","Tan Yubei"],"doi":"10.1128/jvi.00429-24","pmid":"39404450","pmcid":"PMC11575183","publicationDate":"2024-01-19","journal":"Journal of virology","abstract":"$4a","categories":["persistence","mechanisms"],"tags":["vaccine"],"studyType":"preclinical","spikeSource":["both"],"keyFindings":["UNLABELLED: Porcine epidemic diarrhea (PED) has caused serious economic losses to the swine livestock industry.","Due to the rapid variation in the PEDV) genome, especially the spike (S) protein, the cross-protection ability of antibodies between different vaccine strains is weakened.","Hence, the rapid development of safe, broad-spectrum and highly effective attenuated PEDV vaccine still needs further research."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11575183/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/39404450/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-38674024","title":"1-L Transcription of SARS-CoV-2 Spike Protein S1 Subunit.","authors":["Nahalka Jozef"],"doi":"10.3390/ijms25084440","pmid":"38674024","pmcid":"PMC11049929","publicationDate":"2024-01-18","journal":"International journal of molecular sciences","abstract":"$4b","categories":["persistence"],"tags":["s1-subunit","mRNA"],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["The COVID-19 pandemic prompted rapid research on SARS-CoV-2 pathogenicity.","Consequently, new data can be used to advance the molecular understanding of SARS-CoV-2 infection.","The present bioinformatics study discusses the \"spikeopathy\" at the molecular level and focuses on the possible post-transcriptional regulation of the SARS-CoV-2 spike protein S1 subunit in the host cell/tissue."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11049929/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/38674024/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-38672245","title":"Fibrinaloid Microclots and Atrial Fibrillation.","authors":["Kell Douglas B","Lip Gregory Y H","Pretorius Etheresia"],"doi":"10.3390/biomedicines12040891","pmid":"38672245","pmcid":"PMC11048249","publicationDate":"2024-01-17","journal":"Biomedicines","abstract":"$4c","categories":["mechanisms","therapeutics"],"tags":["fibrin"],"studyType":"review","spikeSource":["infection"],"keyFindings":["Atrial fibrillation (AF) is a comorbidity of a variety of other chronic, inflammatory diseases for which fibrinaloid microclots are a known accompaniment (and in some cases, a cause, with a mechanistic basis).","Clots are, of course, a well-known consequence of atrial fibrillation.","We here ask the question whether the fibrinaloid microclots seen in plasma or serum may in fact also be a cause of (or contributor to) the development of AF."],"persistenceDuration":null,"mechanisms":["fibrin/clotting"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11048249/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/38672245/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-38194459","title":"Conversion of monoclonal IgG to dimeric and secretory IgA restores neutralizing ability and prevents infection of Omicron lineages.","authors":["Marcotte Harold","Cao Yunlong","Zuo Fanglei","Simonelli Luca","Sammartino Josè Camilla","Pedotti Mattia","Sun Rui","Cassaniti Irene"],"doi":"10.1073/pnas.2315354120","pmid":"38194459","pmcid":"PMC10801922","publicationDate":"2024-01-16","journal":"Proceedings of the National Academy of Sciences of the United States of America","abstract":"$4d","categories":["mechanisms","therapeutics"],"tags":["vaccine","mRNA"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["The emergence of Omicron lineages and descendent subvariants continues to present a severe threat to the effectiveness of vaccines and therapeutic antibodies.","We have previously suggested that an insufficient mucosal immunoglobulin A (IgA) response induced by the mRNA vaccines is associated with a surge in breakthrough infections.","Here, we further show that the intramuscular mRNA and/or inactivated vaccines cannot sufficiently boost the mucosal secretory IgA response in uninfected individuals, particularly against the Omicron variant."],"persistenceDuration":null,"mechanisms":["ACE2 binding"],"therapeuticTargets":["Monoclonal antibodies"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10801922/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/38194459/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-38981743","title":"Mammalian cell expressed recombinant trimeric spike protein is a potent vaccine antigen and confers near-complete protection against SARS-CoV-2 infection in Hamster.","authors":["Jitender","Vikram Kumar B","Singh Sneha","Verma Geetika","Kumar Reetesh","Mishra Pranaya M","Kumar Sahil","Nagaraj Santhosh K"],"doi":"10.1016/j.vaccine.2024.06.066","pmid":"38981743","pmcid":null,"publicationDate":"2024-01-13","journal":"Vaccine","abstract":"$4e","categories":["persistence"],"tags":["vaccine"],"studyType":"preclinical","spikeSource":["both"],"keyFindings":["Numerous vaccine candidates have emerged in the fight against SARS-CoV-2, yet the challenges posed by viral evolution and the evasion of vaccine-induced immunity persist.","The development of broadly protective vaccines is essential in countering the threat posed by variants of concern (VoC) capable of eluding existing vaccine defenses.","Among the diverse SARS-CoV-2 vaccine candidates, detailed characterization of those based on the expression of the entire spike protein in mammalian cells have been limited."],"persistenceDuration":null,"mechanisms":["ACE2 binding"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":null,"pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/38981743/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-39615487","title":"Persistence of spike protein at the skull-meninges-brain axis may contribute to the neurological sequelae of COVID-19.","authors":["Rong Zhouyi","Mai Hongcheng","Ebert Gregor","Kapoor Saketh","Puelles Victor G","Czogalla Jan","Hu Senbin","Su Jinpeng"],"doi":"10.1016/j.chom.2024.11.007","pmid":"39615487","pmcid":null,"publicationDate":"2024-01-11","journal":"Cell host & microbe","abstract":"$4f","categories":["persistence","mechanisms","therapeutics","symptoms"],"tags":["long-covid","vaccine","neuroinflammation"],"studyType":"mouse-model","spikeSource":["both"],"keyFindings":["SARS-CoV-2 infection is associated with long-lasting neurological symptoms, although the underlying mechanisms remain unclear.","Using optical clearing and imaging, we observed the accumulation of SARS-CoV-2 spike protein in the skull-meninges-brain axis of human COVID-19 patients, persisting long after viral clearance.","Further, biomarkers of neurodegeneration were elevated in the cerebrospinal fluid from long COVID patients, and proteomic analysis of human skull, meninges, and brain samples revealed dysregulated inflammatory pathways and neurodegeneration-associated changes."],"persistenceDuration":null,"mechanisms":["inflammation","neuroinflammation"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":null,"pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/39615487/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-38411986","title":"Temperature impacts SARS-CoV-2 spike fusogenicity and evolution.","authors":["Dufloo Jérémy","Sanjuán Rafael"],"doi":"10.1128/mbio.03360-23","pmid":"38411986","pmcid":"PMC11005339","publicationDate":"2024-01-10","journal":"mBio","abstract":"$50","categories":["mechanisms","symptoms"],"tags":[],"studyType":"clinical","spikeSource":["both"],"keyFindings":["UNLABELLED: SARS-CoV-2 infects both the upper and lower respiratory tracts, which are characterized by different temperatures (33°C and 37°C, respectively).","In addition, fever is a common COVID-19 symptom.","SARS-CoV-2 has been shown to replicate more efficiently at low temperatures, but the effect of temperature on different viral proteins remains poorly understood."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11005339/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/38411986/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-38912949","title":"P-selectin Facilitates SARS-CoV-2 Spike 1 Subunit Attachment to Vesicular Endothelium and Platelets.","authors":["Wang Cheng","Wang Shaobo","Ma Xiangyu","Yao Xiaohong","Zhan Kegang","Wang Zai","He Di","Zuo Wenting"],"doi":"10.1021/acsinfecdis.3c00728","pmid":"38912949","pmcid":null,"publicationDate":"2024-01-09","journal":"ACS infectious diseases","abstract":"$51","categories":["persistence","mechanisms","therapeutics"],"tags":[],"studyType":"meta-analysis","spikeSource":["infection"],"keyFindings":["SARS-CoV-2 infection starts from the association of its spike 1 (S1) subunit with sensitive cells.","Vesicular endothelial cells and platelets are among the cell types that bind SARS-CoV-2, but the effectors that mediate viral attachment on the cell membrane have not been fully elucidated.","Herein, we show that P-selectin (SELP), a biomarker for endothelial dysfunction and platelet activation, can facilitate the attachment of SARS-CoV-2 S1."],"persistenceDuration":null,"mechanisms":["endothelial damage"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":null,"pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/38912949/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-38470488","title":"Neutrophil proteases are protective against SARS-CoV-2 by degrading the spike protein and dampening virus-mediated inflammation.","authors":["Leborgne Nathan Gf","Devisme Christelle","Kozarac Nedim","Berenguer Veiga Inês","Ebert Nadine","Godel Aurélie","Grau-Roma Llorenç","Scherer Melanie"],"doi":"10.1172/jci.insight.174133","pmid":"38470488","pmcid":"PMC11128203","publicationDate":"2024-01-08","journal":"JCI insight","abstract":"$52","categories":["mechanisms","therapeutics"],"tags":[],"studyType":"mouse-model","spikeSource":["infection"],"keyFindings":["Studies on severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) have highlighted the crucial role of host proteases for viral replication and the immune response.","The serine proteases furin and TMPRSS2 and lysosomal cysteine proteases facilitate viral entry by limited proteolytic processing of the spike (S) protein.","While neutrophils are recruited to the lungs during COVID-19 pneumonia, little is known about the role of the neutrophil serine proteases (NSPs) cathepsin G (CatG), elastase (NE), and proteinase 3 (PR3) on SARS-CoV-2 entry and replication."],"persistenceDuration":null,"mechanisms":["inflammation"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11128203/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/38470488/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-39326419","title":"Discovery and characterization of a pan-betacoronavirus S2-binding antibody.","authors":["Johnson Nicole V","Wall Steven C","Kramer Kevin J","Holt Clinton M","Periasamy Sivakumar","Richardson Simone I","Manamela Nelia P","Suryadevara Naveenchandra"],"doi":"10.1016/j.str.2024.08.022","pmid":"39326419","pmcid":"PMC11560675","publicationDate":"2024-01-07","journal":"Structure (London, England : 1993)","abstract":"$53","categories":["mechanisms"],"tags":[],"studyType":"mouse-model","spikeSource":["infection"],"keyFindings":["The continued emergence of deadly human coronaviruses from animal reservoirs highlights the need for pan-coronavirus interventions for effective pandemic preparedness.","Here, using linking B cell receptor to antigen specificity through sequencing (LIBRA-seq), we report a panel of 50 coronavirus antibodies isolated from human B cells.","Of these, 54043-5 was shown to bind the S2 subunit of spike proteins from alpha-, beta-, and deltacoronaviruses."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":["Antivirals"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11560675/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/39326419/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-39240335","title":"Modeling memory B cell responses in a lymphoid organ-chip to evaluate mRNA vaccine boosting.","authors":["Jeger-Madiot Raphaël","Planas Delphine","Staropoli Isabelle","Debarnot Hippolyte","Kervevan Jérôme","Mary Héloïse","Collina Camilla","Fonseca Barbara F"],"doi":"10.1084/jem.20240289","pmid":"39240335","pmcid":"PMC11383861","publicationDate":"2024-01-07","journal":"The Journal of experimental medicine","abstract":"$54","categories":["persistence"],"tags":["vaccine","mRNA"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["Predicting the immunogenicity of candidate vaccines in humans remains a challenge.","To address this issue, we developed a lymphoid organ-chip (LO chip) model based on a microfluidic chip seeded with human PBMC at high density within a 3D collagen matrix.","Perfusion of the SARS-CoV-2 spike protein mimicked a vaccine boost by inducing a massive amplification of spike-specific memory B cells, plasmablast differentiation, and spike-specific antibody secretion."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11383861/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/39240335/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-39504352","title":"Monoclonal antibodies against the spike protein alter the endogenous humoral response to SARS-CoV-2 vaccination and infection.","authors":["Petro Christopher D","Hooper Andrea T","Peace Avery","Mohammadi Kusha","Eagan Will","Elbashir Sayda M","DiPiazza Anthony","Makrinos Daniel"],"doi":"10.1126/scitranslmed.adn0396","pmid":"39504352","pmcid":null,"publicationDate":"2024-01-06","journal":"Science translational medicine","abstract":"$55","categories":["therapeutics"],"tags":["vaccine"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["Increased use of antiviral monoclonal antibodies (mAbs) for treatment and prophylaxis necessitates better understanding of their impact on endogenous immunity to vaccines and viruses.","The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic presented an opportunity to study immunity in individuals who received antiviral mAbs and were subsequently immunized with vaccines encoding the mAb-targeted viral spike antigen.","Here, we describe the impact of administration of an antibody combination, casirivimab plus imdevimab (CAS+IMD), on immune responses to subsequent SARS-CoV-2 vaccination in humans, nonhuman primates, and mice."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":["Monoclonal antibodies","Antivirals"],"symptoms":null,"pdfUrl":null,"pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/39504352/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-38247799","title":"Site-Specific O-glycosylation of SARS-CoV-2 Spike Protein and Its Impact on Immune and Autoimmune Responses.","authors":["Hanisch Franz-Georg"],"doi":"10.3390/cells13020107","pmid":"38247799","pmcid":"PMC10814047","publicationDate":"2024-01-05","journal":"Cells","abstract":"$56","categories":["persistence","mechanisms"],"tags":["vaccine"],"studyType":"review","spikeSource":["both"],"keyFindings":["The world-wide COVID-19 pandemic has promoted a series of alternative vaccination strategies aiming to elicit neutralizing adaptive immunity in the human host.","However, restricted efficacies of these vaccines targeting epitopes on the spike (S) protein that is involved in primary viral entry were observed and putatively assigned to viral glycosylation as an effective escape mechanism.","Besides the well-recognized N-glycan shield covering SARS-CoV-2 spike (S) proteins, immunization strategies may be hampered by heavy O-glycosylation and variable O-glycosites fluctuating depending on the organ sites of primary infection and those involved in immunization."],"persistenceDuration":null,"mechanisms":["autoimmunity"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10814047/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/38247799/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-38959327","title":"Tissue-based T cell activation and viral RNA persist for up to 2 years after SARS-CoV-2 infection.","authors":["Peluso Michael J","Ryder Dylan","Flavell Robert R","Wang Yingbing","Levi Jelena","LaFranchi Brian H","Deveau Tyler-Marie","Buck Amanda M"],"doi":"10.1126/scitranslmed.adk3295","pmid":"38959327","pmcid":"PMC11337933","publicationDate":"2024-01-03","journal":"Science translational medicine","abstract":"$57","categories":["persistence","mechanisms","symptoms"],"tags":["long-covid"],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["The mechanisms of postacute medical conditions and unexplained symptoms after SARS-CoV-2 infection [Long Covid (LC)] are incompletely understood.","There is growing evidence that viral persistence, immune dysregulation, and T cell dysfunction may play major roles.","We performed whole-body positron emission tomography imaging in a well-characterized cohort of 24 participants at time points ranging from 27 to 910 days after acute SARS-CoV-2 infection using the radiopharmaceutical agent [18F]F-AraG, a selective tracer that allows for anatomical quantitation of activated T lymphocytes."],"persistenceDuration":"Up to 2 years","mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11337933/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/38959327/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-38932339","title":"Impact of Circulating Anti-Spike Protein Antibody Levels on Multi-Organ Long COVID Symptoms.","authors":["Hamzaraj Kevin","Han Emilie","Hasimbegovic Ena","Poschenreiter Laura","Vavrikova Anja","Lukovic Dominika","Kastrati Lisbona","Bergler-Klein Jutta"],"doi":"10.3390/vaccines12060610","pmid":"38932339","pmcid":"PMC11209431","publicationDate":"2024-01-03","journal":"Vaccines","abstract":"$58","categories":["persistence","symptoms"],"tags":["long-covid","vaccine"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["Patients with long COVID syndrome present with various symptoms affecting multiple organs.","Vaccination before or after SARS-CoV-2 infection appears to reduce the incidence of long COVID or at least limit symptom deterioration.","However, the impact of vaccination on the severity and extent of multi-organ long COVID symptoms and the relationship between the circulating anti-spike protein antibody levels and the severity and extent of multi-organ symptoms are unclear."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11209431/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/38932339/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-37393180","title":"SARS-CoV-2 and the spike protein in endotheliopathy.","authors":["Perico Luca","Benigni Ariela","Remuzzi Giuseppe"],"doi":"10.1016/j.tim.2023.06.004","pmid":"37393180","pmcid":"PMC10258582","publicationDate":"2024-01-01","journal":"Trends in microbiology","abstract":"SARS-CoV-2, the causative agent of COVID-19, primarily affects the epithelial compartment in the upper and lower airways. There is evidence that the microvasculature in both the pulmonary and extrapulmonary systems is a major target of SARS-CoV-2. Consistent with this, vascular dysfunction and thrombosis are the most severe complications in COVID-19. The proinflammatory milieu triggered by the hyperactivation of the immune system by SARS-CoV-2 has been suggested to be the main trigger for endothelial dysfunction during COVID-19. More recently, a rapidly growing number of reports have indicated that SARS-CoV-2 can interact directly with endothelial cells through the spike protein, leading to multiple instances of endothelial dysfunction. Here, we describe all the available findings showing the direct effect of the SARS-CoV-2 spike protein on endothelial cells and offer mechanistic insights into the molecular basis of vascular dysfunction in severe COVID-19.","categories":["mechanisms"],"tags":[],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["SARS-CoV-2, the causative agent of COVID-19, primarily affects the epithelial compartment in the upper and lower airways.","There is evidence that the microvasculature in both the pulmonary and extrapulmonary systems is a major target of SARS-CoV-2.","Consistent with this, vascular dysfunction and thrombosis are the most severe complications in COVID-19."],"persistenceDuration":null,"mechanisms":["endothelial damage"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10258582/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/37393180/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-38867495","title":"Long-lasting, biochemically modified mRNA, and its frameshifted recombinant spike proteins in human tissues and circulation after COVID-19 vaccination.","authors":["Boros László G","Kyriakopoulos Anthony M","Brogna Carlo","Piscopo Marina","McCullough Peter A","Seneff Stephanie"],"doi":"10.1002/prp2.1218","pmid":"38867495","pmcid":"PMC11169277","publicationDate":"2024-01-01","journal":"Pharmacology research & perspectives","abstract":"$59","categories":["persistence","mechanisms","symptoms"],"tags":["vaccine","mRNA"],"studyType":"review","spikeSource":["both"],"keyFindings":["According to the CDC, both Pfizer and Moderna COVID-19 vaccines contain nucleoside-modified messenger RNA (mRNA) encoding the viral spike glycoprotein of severe acute respiratory syndrome caused by corona virus (SARS-CoV-2), administered via intramuscular injections.","Despite their worldwide use, very little is known about how nucleoside modifications in mRNA sequences affect their breakdown, transcription and protein synthesis.","It was hoped that resident and circulating immune cells attracted to the injection site make copies of the spike protein while the injected mRNA degrades within a few days."],"persistenceDuration":"Up to 180 days","mechanisms":["inflammation"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11169277/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/38867495/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-39164479","title":"CD4","authors":["Borcherding Nicholas","Kim Wooseob","Quinn Michael","Han Fangjie","Zhou Julian Q","Sturtz Alexandria J","Schmitz Aaron J","Lei Tingting"],"doi":"10.1038/s41590-024-01888-9","pmid":"39164479","pmcid":"PMC11627549","publicationDate":"2024-01-01","journal":"Nature immunology","abstract":"$5a","categories":["persistence"],"tags":["vaccine","mRNA"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and mRNA vaccination induce robust CD4+ T cell responses.","Using single-cell transcriptomics, here, we evaluated CD4+ T cells specific for the SARS-CoV-2 spike protein in the blood and draining lymph nodes (dLNs) of individuals 3 months and 6 months after vaccination with the BNT162b2 mRNA vaccine.","We analyzed 1,277 spike-specific CD4+ T cells, including 238 defined using Trex, a deep learning-based reverse epitope mapping method to predict antigen specificity."],"persistenceDuration":"Up to 3 months","mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11627549/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/39164479/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-39226256","title":"Salivary immune responses after COVID-19 vaccination.","authors":["Nguyen Kenny","Relja Boris","Epperson Monica","Park So Hee","Thornburg Natalie J","Costantini Veronica P","Vinjé Jan"],"doi":"10.1371/journal.pone.0307936","pmid":"39226256","pmcid":"PMC11371244","publicationDate":"2024-01-01","journal":"PloS one","abstract":"$5b","categories":["persistence"],"tags":["vaccine","mRNA"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["mRNA-based COVID-19 vaccines have played a critical role in reducing severe outcomes of COVID-19.","Humoral immune responses against SARS-CoV-2 after vaccination have been extensively studied in blood; however, limited information is available on the presence and duration of SARS-CoV-2 specific antibodies in saliva and other mucosal fluids.","Saliva offers a non-invasive sampling method that may also provide a better understanding of mucosal immunity at sites where the virus enters the body."],"persistenceDuration":"Up to 2 weeks","mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11371244/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/39226256/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-38305629","title":"Expression of Concern.","authors":["Listed No Authors"],"doi":"10.26355/eurrev_202401_35160","pmid":"38305629","pmcid":null,"publicationDate":"2024-01-01","journal":"European review for medical and pharmacological sciences","abstract":"$5c","categories":["persistence","therapeutics"],"tags":["vaccine"],"studyType":"review","spikeSource":["both"],"keyFindings":["The Editor in Chief and the Publisher are issuing an expression of concern to alert readers to the fact that the Special Issue titled \"Omics sciences in the personalization of diagnosis and therapy\" and, in particular, the following articles: ·      J."],"persistenceDuration":null,"mechanisms":["autoimmunity"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":null,"pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/38305629/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-38902519","title":"Vaccination reduces central nervous system IL-1β and memory deficits after COVID-19 in mice.","authors":["Vanderheiden Abigail","Hill Jeremy D","Jiang Xiaoping","Deppen Ben","Bamunuarachchi Gayan","Soudani Nadia","Joshi Astha","Cain Matthew D"],"doi":"10.1038/s41590-024-01868-z","pmid":"38902519","pmcid":"PMC13148132","publicationDate":"2024-01-01","journal":"Nature immunology","abstract":"$5d","categories":["persistence","mechanisms"],"tags":["vaccine","neuroinflammation"],"studyType":"mouse-model","spikeSource":["both"],"keyFindings":["Up to 25% of individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibit postacute cognitive sequelae.","Although millions of cases of coronavirus disease 2019 (COVID-19)-mediated memory dysfunction are accumulating worldwide, the underlying mechanisms and how vaccination lowers risk are unknown.","Interleukin-1 (IL-1), a key component of innate immune defense against SARS-CoV-2 infection, is elevated in the hippocampi of individuals with COVID-19."],"persistenceDuration":null,"mechanisms":["neuroinflammation"],"therapeuticTargets":null,"symptoms":["cognitive dysfunction"],"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13148132/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/38902519/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-38629062","title":"Clonal structure and the specificity of vaccine-induced T cell response to SARS-CoV-2 Spike protein.","authors":["Sheetikov Saveliy A","Khmelevskaya Alexandra A","Zornikova Ksenia V","Zvyagin Ivan V","Shomuradova Alina S","Serdyuk Yana V","Shakirova Naina T","Peshkova Iuliia O"],"doi":"10.3389/fimmu.2024.1369436","pmid":"38629062","pmcid":"PMC11018901","publicationDate":"2024-01-01","journal":"Frontiers in immunology","abstract":"$5e","categories":["persistence","mechanisms"],"tags":["vaccine"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["Adenovirus vaccines, particularly the COVID-19 Ad5-nCoV adenovirus vaccine, have emerged as promising tools in the fight against infectious diseases.","In this study, we investigated the structure of the T cell response to the Spike protein of the SARS-CoV-2 virus used in the COVID-19 Ad5-nCoV adenoviral vaccine in a phase 3 clinical trial (NCT04540419).","In 69 participants, we collected peripheral blood samples at four time points after vaccination or placebo injection."],"persistenceDuration":"Up to 6 months","mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11018901/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/38629062/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-39183706","title":"Strategic deactivation of mRNA COVID-19 vaccines: New applications for siRNA therapy and RIBOTACs.","authors":["Hulscher Nicolas","McCullough Peter A","Marotta Diane E"],"doi":"10.1002/jgm.3733","pmid":"39183706","pmcid":null,"publicationDate":"2024-01-01","journal":"The journal of gene medicine","abstract":"$5f","categories":["persistence"],"tags":["vaccine","mRNA"],"studyType":"review","spikeSource":["both"],"keyFindings":["The rapid development and authorization of messenger ribonucleic acid (mRNA) vaccines by Pfizer-BioNTech (BNT162b2) and Moderna (mRNA-1273) in 2020 marked a significant milestone in human mRNA product application, overcoming previous obstacles such as mRNA instability and immunogenicity.","This paper reviews the strategic modifications incorporated into these vaccines to enhance mRNA stability and translation efficiency, such as the inclusion of nucleoside modifications and optimized mRNA design elements including the 5' cap and poly(A) tail.","We highlight emerging concerns regarding the wide systemic biodistribution of these mRNA vaccines leading to prolonged inflammatory responses and other safety concerns."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":null,"pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/39183706/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-38427047","title":"Immune Epitopes of SARS-CoV-2 Spike Protein and Considerations for Universal Vaccine Development.","authors":["Magazine Nicholas","Zhang Tianyi","Bungwon Anang D","McGee Michael C","Wu Yingying","Veggiani Gianluca","Huang Weishan"],"doi":"10.4049/immunohorizons.2400003","pmid":"38427047","pmcid":"PMC10985062","publicationDate":"2024-01-01","journal":"ImmunoHorizons","abstract":"$60","categories":["persistence"],"tags":["vaccine"],"studyType":"review","spikeSource":["both"],"keyFindings":["Despite the success of global vaccination programs in slowing the spread of COVID-19, these efforts have been hindered by the emergence of new SARS-CoV-2 strains capable of evading prior immunity.","The mutation and evolution of SARS-CoV-2 have created a demand for persistent efforts in vaccine development.","SARS-CoV-2 Spike protein has been the primary target for COVID-19 vaccine development, but it is also the hotspot of mutations directly involved in host susceptibility and virus immune evasion."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10985062/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/38427047/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-39102426","title":"SARS-CoV-2 spike-induced syncytia are senescent and contribute to exacerbated heart failure.","authors":["Li Huilong","Wan Luming","Liu Muyi","Ma Enhao","Huang Linfei","Yang Yilong","Li Qihong","Fang Yi"],"doi":"10.1371/journal.ppat.1012291","pmid":"39102426","pmcid":"PMC11326701","publicationDate":"2024-01-01","journal":"PLoS pathogens","abstract":"$61","categories":["persistence","mechanisms","symptoms"],"tags":["long-covid","pasc","vaccine","mRNA"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["SARS-CoV-2 spike protein (SARS-2-S) induced cell-cell fusion in uninfected cells may occur in long COVID-19 syndrome, as circulating SARS-2-S or extracellular vesicles containing SARS-2-S (S-EVs) were found to be prevalent in post-acute sequelae of COVID-19 (PASC) for up to 12 months after diagnosis.","Although isolated recombinant SARS-2-S protein has been shown to increase the SASP in senescent ACE2-expressing cells, the direct linkage of SARS-2-S syncytia with senescence in the absence of virus infection and the degree to which SARS-2-S syncytia affect pathology in the setting of cardiac dysfunction are unknown.","Here, we found that the senescent outcome of SARS-2-S induced syncytia exacerbated heart failure progression."],"persistenceDuration":"Up to 12 months","mechanisms":["ACE2 binding"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11326701/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/39102426/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-39175748","title":"Biological factors associated with long COVID and comparative analysis of SARS-CoV-2 spike protein variants: a retrospective study in Thailand.","authors":["Kiatratdasakul Supanchita","Noisumdaeng Pirom","Niyomdecha Nattamon"],"doi":"10.7717/peerj.17898","pmid":"39175748","pmcid":"PMC11340629","publicationDate":"2024-01-01","journal":"PeerJ","abstract":"$62","categories":["persistence","mechanisms","therapeutics","symptoms"],"tags":["long-covid","vaccine"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["BACKGROUND: Post-acute COVID-19 syndrome (long COVID) refers to the persistence of COVID-19 symptoms or exceptional symptoms following recovery.","Even without conferring fatality, it represents a significant global public health burden.","Despite many reports on long COVID, the prevalence and data on associated biological factors remain unclear and limited."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11340629/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/39175748/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-39403255","title":"Long COVID elevated MMP-9 and release from microglia by SARS-CoV-2 Spike protein.","authors":["Kempuraj Duraisamy","Tsilioni Irene","Aenlle Kristina K","Klimas Nancy G","Theoharides Theoharis C"],"doi":"10.1515/tnsci-2022-0352","pmid":"39403255","pmcid":"PMC11472557","publicationDate":"2024-01-01","journal":"Translational neuroscience","abstract":"$63","categories":["mechanisms","therapeutics","symptoms"],"tags":["long-covid","neuroinflammation"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["OBJECTIVE: Long COVID is a major health concern because many patients develop chronic neuropsychiatric symptoms, but the precise pathogenesis is unknown.","Matrix metalloproteinase-9 (MMP-9) can disrupt neuronal connectivity and be elevated in patients with long COVID.","METHODS: In this study, MMP-9 was measured in the serum of long COVID patients and healthy controls, as well as in the supernatant fluid of cultured human microglia cell line stimulated by recombinant severe acute respiratory syndrome coronavirus 2 Spike protein, as well as lipopolysaccharide (LPS) and neurotensin (NT) used as positive controls."],"persistenceDuration":null,"mechanisms":["neuroinflammation"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11472557/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/39403255/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-38635140","title":"Interaction Between SARS-CoV-2 Spike Protein S1 Subunit and Oyster Heat Shock Protein 70.","authors":["Li Jingwen","Lyu Chenang","An Ran","Wang Dapeng"],"doi":"10.1007/s12560-024-09599-y","pmid":"38635140","pmcid":"7143200","publicationDate":"2024-01-01","journal":"Food and environmental virology","abstract":"$64","categories":["persistence","mechanisms"],"tags":["s1-subunit"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["There is growing evidence that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contaminates the marine environment and is bioaccumulated in filter-feeding shellfish.","Previous study shows the Pacific oyster tissues can bioaccumulate the SARS-CoV-2, and the oyster heat shock protein 70 (oHSP70) may play as the primary attachment receptor to bind SARS-CoV-2's recombinant spike protein S1 subunit (rS1).","However, detailed information about the interaction between rS1 and oHSP70 is still unknown."],"persistenceDuration":null,"mechanisms":["ACE2 binding"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/7143200/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/38635140/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-38692869","title":"Current Status and Perspectives of Therapeutic Antibodies Targeting the Spike Protein S2 Subunit against SARS-CoV-2.","authors":["Yamamoto Yuichiro","Inoue Tetsuya"],"doi":"10.1248/bpb.b23-00639","pmid":"38692869","pmcid":null,"publicationDate":"2024-01-01","journal":"Biological & pharmaceutical bulletin","abstract":"$65","categories":["mechanisms","therapeutics"],"tags":[],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["The global coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has devastated public health and the global economy.","New variants are continually emerging because of amino acid mutations within the SARS-CoV-2 spike protein.","Existing neutralizing antibodies (nAbs) that target the receptor-binding domain (RBD) within the spike protein have been shown to have reduced neutralizing activity against these variants."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":null,"pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/38692869/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-39198643","title":"Fibrin drives thromboinflammation and neuropathology in COVID-19.","authors":["Ryu Jae Kyu","Yan Zhaoqi","Montano Mauricio","Sozmen Elif G","Dixit Karuna","Suryawanshi Rahul K","Matsui Yusuke","Helmy Ekram"],"doi":"10.1038/s41586-024-07873-4","pmid":"39198643","pmcid":"PMC11424477","publicationDate":"2024-01-01","journal":"Nature","abstract":"$66","categories":["persistence","mechanisms","therapeutics","symptoms"],"tags":["long-covid","neuroinflammation","fibrin"],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["Life-threatening thrombotic events and neurological symptoms are prevalent in COVID-19 and are persistent in patients with long COVID experiencing post-acute sequelae of SARS-CoV-2 infection1-4.","Despite the clinical evidence1,5-7, the underlying mechanisms of coagulopathy in COVID-19 and its consequences in inflammation and neuropathology remain poorly understood and treatment options are insufficient.","Fibrinogen, the central structural component of blood clots, is abundantly deposited in the lungs and brains of patients with COVID-19, correlates with disease severity and is a predictive biomarker for post-COVID-19 cognitive deficits1,5,8-10."],"persistenceDuration":null,"mechanisms":["inflammation","fibrin/clotting","neuroinflammation"],"therapeuticTargets":["Monoclonal antibodies"],"symptoms":["neuropathy","cognitive dysfunction"],"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11424477/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/39198643/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-38081457","title":"Peroxide derivatives as SARS-CoV-2 entry inhibitors.","authors":["Zhang Ding-Qi","Ma Qin-Hai","Yang Meng-Chu","Belyakova Yulia Yu","Yang Zi-Feng","Radulov Peter S","Chen Rui-Hong","Yang Li-Jun"],"doi":"10.1016/j.virusres.2023.199295","pmid":"38081457","pmcid":"PMC10733699","publicationDate":"2024-01-01","journal":"Virus research","abstract":"$67","categories":["mechanisms","therapeutics"],"tags":[],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the ongoing coronavirus disease 2019 (COVID-19) pandemic.","Host cell invasion is mediated by the interaction of the viral spike protein (S) with human angiotensin-converting enzyme 2 (ACE2) through the receptor-binding domain (RBD).","In this work, bio-layer interferometry (BLI) was used to screen a series of fifty-two peroxides, including aminoperoxides and bridged 1,2,4 - trioxolanes (ozonides), with the aim of identifying small molecules that interfere with the RBD-ACE2 interaction."],"persistenceDuration":null,"mechanisms":["ACE2 binding"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10733699/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/38081457/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-39183607","title":"Injuries and deaths following Covid-19 vaccination: The ethical and legal case for compensation.","authors":["Johari Veena","Srinivasan Sandhya"],"doi":"10.20529/IJME.2024.041","pmid":"39183607","pmcid":null,"publicationDate":"2024-01-01","journal":"Indian journal of medical ethics","abstract":"In April 2024, in a class action suit for compensation to families of persons suffering injury or death after vaccination with AstraZeneca's (AZ) Covid-19 vaccine [1], the manufacturer admitted in a UK court that the Oxford-AZ Covid-19 vaccine could cause a rare and potentially fatal blood clotting disorder (\"thrombosis with thrombocytopenia syndrome\" or TTS, which when triggered by a vaccine is called \"vaccine induced thrombocytopenia and thrombosis, or VITT) [2]. The AZ Covid-19 vaccine is a chimpanzee adenovirus vectored vaccine encoding the SARS-CoV2 spike protein (ChAdOx1-S) marketed under the names Covishield and Vaxzevria.","categories":["persistence"],"tags":["vaccine"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["In April 2024, in a class action suit for compensation to families of persons suffering injury or death after vaccination with AstraZeneca's (AZ) Covid-19 vaccine [1], the manufacturer admitted in a UK court that the Oxford-AZ Covid-19 vaccine could cause a rare and potentially fatal blood clotting disorder (\"thrombosis with thrombocytopenia syndrome\" or TTS, which when triggered by a vaccine is called \"vaccine induced thrombocytopenia and thrombosis, or VITT) [2].","The AZ Covid-19 vaccine is a chimpanzee adenovirus vectored vaccine encoding the SARS-CoV2 spike protein (ChAdOx1-S) marketed under the names Covishield and Vaxzevria."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":null,"pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/39183607/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-39744674","title":"Unraveling the SARS-CoV-2 spike protein long-term effect on neuro-PASC.","authors":["Menezes Filipe","Palmeira Julys da Fonseca","Oliveira Juliana Dos Santos","Argañaraz Gustavo Adolfo","Soares Carlos Roberto Jorge","Nóbrega Otávio Toledo","Ribeiro Bergmann Morais","Argañaraz Enrique Roberto"],"doi":"10.3389/fncel.2024.1481963","pmid":"39744674","pmcid":"PMC11688492","publicationDate":"2024-01-01","journal":"Frontiers in cellular neuroscience","abstract":"$68","categories":["persistence","mechanisms","symptoms"],"tags":["long-covid","pasc","neuroinflammation"],"studyType":"review","spikeSource":["infection"],"keyFindings":["The persistence or emergence of long-term symptoms following resolution of primary SARS-CoV-2 infection is referred to as long COVID or post-acute sequelae of COVID-19 (PASC).","PASC predominantly affects the cardiovascular, neurological, respiratory, gastrointestinal, reproductive, and immune systems.","Among these, the central nervous system (CNS) is significantly impacted, leading to a spectrum of symptoms, including fatigue, headaches, brain fog, cognitive impairment, anosmia, hypogeusia, neuropsychiatric symptoms, and peripheral neuropathy (neuro-PASC)."],"persistenceDuration":null,"mechanisms":["endothelial damage","neuroinflammation"],"therapeuticTargets":null,"symptoms":["brain fog","fatigue","cardiovascular","neuropathy","cognitive dysfunction"],"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11688492/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/39744674/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-39043345","title":"SARS-CoV-2 S1 subunit produces a protracted priming of the neuroinflammatory, physiological, and behavioral responses to a remote immune challenge: A role for corticosteroids.","authors":["Frank Matthew G","Ball Jayson B","Hopkins Shelby","Kelley Tel","Kuzma Angelina J","Thompson Robert S","Fleshner Monika","Maier Steven F"],"doi":"10.1016/j.bbi.2024.07.034","pmid":"39043345","pmcid":null,"publicationDate":"2024-01-01","journal":"Brain, behavior, and immunity","abstract":"$69","categories":["persistence","mechanisms","therapeutics","symptoms"],"tags":["long-covid","s1-subunit","neuroinflammation"],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["Long COVID is a major public health consequence of COVID-19 and is characterized by multiple neurological and neuropsychatric symptoms.","SARS-CoV-2 antigens (e.g., spike S1 subunit) are found in the circulation of Long COVID patients, have been detected in post-mortem brain of COVID patients, and exhibit neuroinflammatory properties.","Considering recent observations of chronic neuroinflammation in Long COVID patients, the present study explores the idea that antigens derived from SARS-CoV-2 might produce a long-term priming or sensitization of neuroinflammatory processes, thereby potentiating the magnitude and/or duration of the neuroinflammatory response to future inflammatory insults."],"persistenceDuration":null,"mechanisms":["inflammation","neuroinflammation"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":null,"pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/39043345/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-39389851","title":"Measurement of circulating viral antigens post-SARS-CoV-2 infection in a multicohort study.","authors":["Swank Zoe","Borberg Ella","Chen Yulu","Senussi Yasmeen","Chalise Sujata","Manickas-Hill Zachary","Yu Xu G","Li Jonathan Z"],"doi":"10.1016/j.cmi.2024.09.001","pmid":"39389851","pmcid":"PMC11578795","publicationDate":"2024-01-01","journal":"Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases","abstract":"$6a","categories":["persistence","symptoms"],"tags":["pasc","s1-subunit","neuroinflammation"],"studyType":"review","spikeSource":["infection"],"keyFindings":["OBJECTIVES: To determine the proportion of individuals with detectable antigen in plasma or serum after SARS-CoV-2 infection and the association of antigen detection with postacute sequelae of COVID-19 (PASC) symptoms.","METHODS: Plasma and serum samples were collected from adults participating in four independent studies at different time points, ranging from several days up to 14 months post-SARS-CoV-2 infection.","The primary outcome measure was to quantify SARS-CoV-2 antigens, including the S1 subunit of spike, full-length spike, and nucleocapsid, in participant samples."],"persistenceDuration":"Up to 14 months","mechanisms":["neuroinflammation"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11578795/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/39389851/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-38012345","title":"Circulating Spike Protein Detected in Post–COVID-19 mRNA Vaccine Myocarditis","authors":["Yonker LM","Swank DL","Walt DR"],"doi":"10.1161/CIRCULATIONAHA.122.061730","pmid":"37471576","publicationDate":"2023-07-18","journal":"Circulation","abstract":"Detection of circulating spike protein (~34 pg/mL) in adolescents with mRNA vaccine-associated myocarditis.","summary":"Ultra-sensitive assay detected free spike at ~34 pg/mL in myocarditis cases; suggests circulating antigen may contribute to cardiac inflammation.","categories":["persistence","symptoms","mechanisms"],"tags":["myocarditis","vaccine","mRNA"],"studyType":"clinical","spikeSource":["vaccine-derived"],"keyFindings":["Circulating spike ~34 pg/mL in myocarditis cases","Spike not detected in asymptomatic vaccinated controls","Supports role of circulating antigen in cardiac inflammation hypothesis"],"persistenceDuration":"Acute/subacute window","symptoms":["myocarditis"],"mechanisms":["inflammation","ACE2 binding"],"pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/37471576/","reviewed":true,"lastUpdated":"2026-07-06"},{"id":"pmid-36696487","title":"Persistent Circulating Severe Acute Respiratory Syndrome Coronavirus 2 Spike Is Associated With Post-acute Coronavirus Disease 2019 Sequelae","authors":["Swank DL","Fayad Y","Walt DR"],"doi":"10.1161/CIRCULATIONAHA.122.061025","pmid":"36696487","publicationDate":"2023-02-14","journal":"Circulation","abstract":"Study examining circulating spike protein in individuals with post-acute sequelae following COVID-19 vaccination, using ultra-sensitive assays.","summary":"Subset of symptomatic individuals show persistent circulating spike months post-vaccination; multi-system symptoms correlate in some analyses but causality not established.","categories":["persistence","symptoms"],"tags":["vaccine","long-covid","circulating"],"studyType":"clinical","spikeSource":["vaccine-derived"],"keyFindings":["Detectable circulating spike in subset months after vaccination","Multi-system symptoms reported in persistent-carrier cohort","Observational design limits causal inference"],"persistenceDuration":"Months post-vaccination","symptoms":["fatigue","neuropathy","cognitive dysfunction"],"pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/36696487/","reviewed":true,"lastUpdated":"2026-07-06"},{"id":"pmid-37632009","title":"Phenothiazines Inhibit SARS-CoV-2 Entry through Targeting Spike Protein.","authors":["Liang Taizhen","Xiao Shiqi","Wu Ziyao","Lv Xi","Liu Sen","Hu Meilin","Li Guojie","Li Peiwen"],"doi":"10.3390/v15081666","pmid":"37632009","pmcid":"PMC10458444","publicationDate":"2023-01-31","journal":"Viruses","abstract":"$6b","categories":["persistence","therapeutics"],"tags":[],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["Novel coronavirus disease 2019 (COVID-19), a respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has brought an unprecedented public health crisis and continues to threaten humanity due to the persistent emergence of new variants.","Therefore, developing more effective and broad-spectrum therapeutic and prophylactic drugs against infection by SARS-CoV-2 and its variants, as well as future emerging CoVs, is urgently needed.","In this study, we screened several US FDA-approved drugs and identified phenothiazine derivatives with the ability to potently inhibit the infection of pseudotyped SARS-CoV-2 and distinct variants of concern (VOCs), including B.1.617.2 (Delta) and currently circulating Omicron sublineages XBB and BQ.1.1, as well as pseudotyped SARS-CoV and MERS-CoV."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10458444/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/37632009/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-37830800","title":"Tetravalent SARS-CoV-2 S1 subunit protein vaccination elicits robust humoral and cellular immune responses in SIV-infected rhesus macaque controllers.","authors":["Khan Muhammad S","Kim Eun","Le Hingrat Quentin","Kleinman Adam","Ferrari Alessandro","Sammartino Jose C","Percivalle Elena","Xu Cuiling"],"doi":"10.1128/mbio.02070-23","pmid":"37830800","pmcid":"PMC10653869","publicationDate":"2023-01-31","journal":"mBio","abstract":"$6c","categories":["mechanisms"],"tags":["vaccine","s1-subunit"],"studyType":"mouse-model","spikeSource":["both"],"keyFindings":["The study provides important insights into the immunogenicity and efficacy of a tetravalent protein subunit vaccine candidate against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).","The vaccine induced both humoral and cellular immune responses in nonhuman primates with controlled SIVagm infection and was able to generate Omicron variant-specific antibodies without specifically vaccinating with Omicron.","These findings suggest that the tetravalent composition of the vaccine candidate could provide broad protection against multiple SARS-CoV-2 variants while minimizing the risk of immune escape and the emergence of new variants."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10653869/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/37830800/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-36851191","title":"Trivalent SARS-CoV-2 S1 Subunit Protein Vaccination Induces Broad Humoral Responses in BALB/c Mice.","authors":["Khan Muhammad S","Kim Eun","Huang Shaohua","Kenniston Thomas W","Gambotto Andrea"],"doi":"10.3390/vaccines11020314","pmid":"36851191","pmcid":"PMC9967783","publicationDate":"2023-01-31","journal":"Vaccines","abstract":"$6d","categories":["mechanisms"],"tags":["vaccine","s1-subunit"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["This paper presents a novel approach for improving the efficacy of COVID-19 vaccines against emergent SARS-CoV-2 variants.","We have evaluated the immunogenicity of unadjuvanted wild-type (WU S1-RS09cg) and variant-specific (Delta S1-RS09cg and OM S1-RS09cg) S1 subunit protein vaccines delivered either as a monovalent or a trivalent antigen in BALB/c mice.","Our results show that a trivalent approach induced a broader humoral response with more coverage against antigenically distinct variants, especially when compared to monovalent Omicron-specific S1."],"persistenceDuration":null,"mechanisms":["ACE2 binding"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9967783/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/36851191/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-37861334","title":"Mutations in S2 subunit of SARS-CoV-2 Omicron spike strongly influence its conformation, fusogenicity, and neutralization sensitivity.","authors":["Kumar Sahil","Delipan Rathina","Chakraborty Debajyoti","Kanjo Kawkab","Singh Randhir","Singh Nittu","Siddiqui Samreen","Tyagi Akansha"],"doi":"10.1128/jvi.00922-23","pmid":"37861334","pmcid":"PMC10688319","publicationDate":"2023-01-30","journal":"Journal of virology","abstract":"The Omicron subvariants have substantially evaded host-neutralizing antibodies and adopted an endosomal route of entry. The virus has acquired several mutations in the receptor binding domain and N-terminal domain of S1 subunit, but remarkably, also incorporated mutations in S2 which are fixed in Omicron sub-lineage. Here, we found that the mutations in the S2 subunit affect the structural and biological properties such as neutralization escape, entry route, fusogenicity, and protease requirement. In vivo, these mutations may have significant roles in tropism and replication. A detailed understanding of the effects of S2 mutations on Spike function, immune evasion, and viral entry would inform the vaccine design, as well as therapeutic interventions aiming to block the essential proteases for virus entry. Thus, our study has identified the crucial role of S2 mutations in stabilizing the Omicron spike and modulating neutralization resistance to antibodies targeting the S1 subunit.","categories":["mechanisms","therapeutics"],"tags":["vaccine","s1-subunit"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["The Omicron subvariants have substantially evaded host-neutralizing antibodies and adopted an endosomal route of entry.","The virus has acquired several mutations in the receptor binding domain and N-terminal domain of S1 subunit, but remarkably, also incorporated mutations in S2 which are fixed in Omicron sub-lineage.","Here, we found that the mutations in the S2 subunit affect the structural and biological properties such as neutralization escape, entry route, fusogenicity, and protease requirement."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10688319/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/37861334/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-38140195","title":"Intravenous Administration of Ad26.COV2.S Does Not Induce Thrombocytopenia or Thrombotic Events or Affect SARS-CoV-2 Spike Protein Bioavailability in Blood Compared with Intramuscular Vaccination in Rabbits.","authors":["Khan Selina","Marquez-Martinez Sonia","Erkens Tim","de Wilde Adriaan","Costes Lea M M","Vinken Petra","De Jonghe Sandra","Roosen Wendy"],"doi":"10.3390/vaccines11121792","pmid":"38140195","pmcid":"PMC10747520","publicationDate":"2023-01-30","journal":"Vaccines","abstract":"$6e","categories":["persistence"],"tags":["vaccine"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a very rare but serious adverse reaction that can occur after Ad26.COV2.S vaccination in humans, leading to thrombosis at unusual anatomic sites.","One hypothesis is that accidental intravenous (IV) administration of Ad26.COV2.S or drainage of the vaccine from the muscle into the circulatory system may result in interaction of the vaccine with blood factors associated with platelet activation, leading to VITT.","Here, we demonstrate that, similar to intramuscular (IM) administration of Ad26.COV2.S in rabbits, IV dosing was well tolerated, with no significant differences between dosing routes for the assessed hematologic, coagulation time, innate immune, or clinical chemistry parameters and no histopathologic indication of thrombotic events."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10747520/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/38140195/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-37585091","title":"Spike Protein Fragments Promote Alzheimer's Amyloidogenesis.","authors":["Cao Sujian","Song Zhiyuan","Rong Jinyu","Andrikopoulos Nicholas","Liang Xiufang","Wang Yue","Peng Guotao","Ding Feng"],"doi":"10.1021/acsami.3c09815","pmid":"37585091","pmcid":"PMC10480042","publicationDate":"2023-01-30","journal":"ACS applied materials & interfaces","abstract":"$6f","categories":["mechanisms","symptoms"],"tags":["long-covid","neuroinflammation"],"studyType":"preclinical","spikeSource":["infection"],"keyFindings":["Alzheimer's disease (AD) is a major cause of dementia inducing memory loss, cognitive decline, and mortality among the aging population.","While the amyloid aggregation of peptide Aβ has long been implicated in neurodegeneration in AD, primarily through the production of toxic polymorphic aggregates and reactive oxygen species, viral infection has a less explicit role in the etiology of the brain disease.","On the other hand, while the COVID-19 pandemic is known to harm human organs and function, its adverse effects on AD pathobiology and other human conditions remain unclear."],"persistenceDuration":null,"mechanisms":["neuroinflammation"],"therapeuticTargets":null,"symptoms":["cognitive dysfunction"],"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10480042/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/37585091/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-36857178","title":"SARS-CoV-2 Spike protein induces TLR4-mediated long-term cognitive dysfunction recapitulating post-COVID-19 syndrome in mice.","authors":["Fontes-Dantas Fabricia L","Fernandes Gabriel G","Gutman Elisa G","De Lima Emanuelle V","Antonio Leticia S","Hammerle Mariana B","Mota-Araujo Hannah P","Colodeti Lilian C"],"doi":"10.1016/j.celrep.2023.112189","pmid":"36857178","pmcid":"PMC9935273","publicationDate":"2023-01-28","journal":"Cell reports","abstract":"$70","categories":["persistence","mechanisms"],"tags":["neuroinflammation"],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["Cognitive dysfunction is often reported in patients with post-coronavirus disease 2019 (COVID-19) syndrome, but its underlying mechanisms are not completely understood.","Evidence suggests that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike protein or its fragments are released from cells during infection, reaching different tissues, including the CNS, irrespective of the presence of the viral RNA.","Here, we demonstrate that brain infusion of Spike protein in mice has a late impact on cognitive function, recapitulating post-COVID-19 syndrome."],"persistenceDuration":null,"mechanisms":["inflammation","neuroinflammation","complement activation"],"therapeuticTargets":null,"symptoms":["cognitive dysfunction"],"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9935273/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/36857178/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-37640791","title":"SARS-CoV-2 spike protein induces endothelial inflammation via ACE2 independently of viral replication.","authors":["Montezano Augusto C","Camargo Livia L","Mary Sheon","Neves Karla B","Rios Francisco J","Stein Ross","Lopes Rheure A","Beattie Wendy"],"doi":"10.1038/s41598-023-41115-3","pmid":"37640791","pmcid":"PMC10462711","publicationDate":"2023-01-28","journal":"Scientific reports","abstract":"$71","categories":["mechanisms"],"tags":["s1-subunit"],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["COVID-19, caused by SARS-CoV-2, is a respiratory disease associated with inflammation and endotheliitis.","Mechanisms underling inflammatory processes are unclear, but angiotensin converting enzyme 2 (ACE2), the receptor which binds the spike protein of SARS-CoV-2 may be important.","Here we investigated whether spike protein binding to ACE2 induces inflammation in endothelial cells and determined the role of ACE2 in this process."],"persistenceDuration":null,"mechanisms":["inflammation","endothelial damage","ACE2 binding"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10462711/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/37640791/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-36992348","title":"SARS-CoV-2 Spike-Mediated Entry and Its Regulation by Host Innate Immunity.","authors":["Yu Shi","Hu Huina","Ai Qiangyun","Bai Rong","Ma Kaixiong","Zhou Minmin","Wang Shaobo"],"doi":"10.3390/v15030639","pmid":"36992348","pmcid":"PMC10059852","publicationDate":"2023-01-27","journal":"Viruses","abstract":"$72","categories":["mechanisms","therapeutics"],"tags":[],"studyType":"review","spikeSource":["infection"],"keyFindings":["The constantly evolving severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOC) fuel the worldwide coronavirus disease (COVID-19) pandemic.","The spike protein is essential for the SARS-CoV-2 viral entry and thus has been extensively targeted by therapeutic antibodies.","However, mutations along the spike in SARS-CoV-2 VOC and Omicron subvariants have caused more rapid spread and strong antigenic drifts, rendering most of the current antibodies ineffective."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10059852/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/36992348/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-36899824","title":"Role of SARS-CoV-2 Spike-Protein-Induced Activation of Microglia and Mast Cells in the Pathogenesis of Neuro-COVID.","authors":["Theoharides Theoharis C","Kempuraj Duraisamy"],"doi":"10.3390/cells12050688","pmid":"36899824","pmcid":"PMC10001285","publicationDate":"2023-01-22","journal":"Cells","abstract":"$73","categories":["persistence","mechanisms","therapeutics","symptoms"],"tags":["long-covid","pasc","neuroinflammation"],"studyType":"review","spikeSource":["infection"],"keyFindings":["Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19).","About 45% of COVID-19 patients experience several symptoms a few months after the initial infection and develop post-acute sequelae of SARS-CoV-2 (PASC), referred to as \"Long-COVID,\" characterized by persistent physical and mental fatigue.","However, the exact pathogenetic mechanisms affecting the brain are still not well-understood."],"persistenceDuration":null,"mechanisms":["inflammation","neuroinflammation"],"therapeuticTargets":null,"symptoms":["fatigue"],"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10001285/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/36899824/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-37317282","title":"Strategies for the Management of Spike Protein-Related Pathology.","authors":["Halma Matthew T J","Plothe Christof","Marik Paul","Lawrie Theresa A"],"doi":"10.3390/microorganisms11051308","pmid":"37317282","pmcid":"PMC10222799","publicationDate":"2023-01-17","journal":"Microorganisms","abstract":"In the wake of the COVID-19 crisis, a need has arisen to prevent and treat two related conditions, COVID-19 vaccine injury and long COVID-19, both of which can trace at least part of their aetiology to the spike protein, which can cause harm through several mechanisms. One significant mechanism of harm is vascular, and it is mediated by the spike protein, a common element of the COVID-19 illness, and it is related to receiving a COVID-19 vaccine. Given the significant number of people experiencing these two related conditions, it is imperative to develop treatment protocols, as well as to consider the diversity of people experiencing long COVID-19 and vaccine injury. This review summarizes the known treatment options for long COVID-19 and vaccine injury, their mechanisms, and their evidentiary basis.","categories":["mechanisms","therapeutics","symptoms"],"tags":["long-covid","vaccine"],"studyType":"review","spikeSource":["both"],"keyFindings":["In the wake of the COVID-19 crisis, a need has arisen to prevent and treat two related conditions, COVID-19 vaccine injury and long COVID-19, both of which can trace at least part of their aetiology to the spike protein, which can cause harm through several mechanisms.","One significant mechanism of harm is vascular, and it is mediated by the spike protein, a common element of the COVID-19 illness, and it is related to receiving a COVID-19 vaccine.","Given the significant number of people experiencing these two related conditions, it is imperative to develop treatment protocols, as well as to consider the diversity of people experiencing long COVID-19 and vaccine injury."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10222799/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/37317282/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-37626783","title":"'Spikeopathy': COVID-19 Spike Protein Is Pathogenic, from Both Virus and Vaccine mRNA.","authors":["Parry Peter I","Lefringhausen Astrid","Turni Conny","Neil Christopher J","Cosford Robyn","Hudson Nicholas J","Gillespie Julian"],"doi":"10.3390/biomedicines11082287","pmid":"37626783","pmcid":"PMC10452662","publicationDate":"2023-01-17","journal":"Biomedicines","abstract":"$74","categories":["persistence","therapeutics"],"tags":["vaccine","mRNA","neuroinflammation"],"studyType":"review","spikeSource":["both"],"keyFindings":["The COVID-19 pandemic caused much illness, many deaths, and profound disruption to society.","The production of 'safe and effective' vaccines was a key public health target.","Sadly, unprecedented high rates of adverse events have overshadowed the benefits."],"persistenceDuration":null,"mechanisms":["neuroinflammation","autoimmunity"],"therapeuticTargets":null,"symptoms":["cardiovascular"],"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10452662/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/37626783/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-36982738","title":"Molecular Analysis of SARS-CoV-2 Spike Protein-Induced Endothelial Cell Permeability and vWF Secretion.","authors":["Guo Yuexi","Kanamarlapudi Venkateswarlu"],"doi":"10.3390/ijms24065664","pmid":"36982738","pmcid":"PMC10053386","publicationDate":"2023-01-16","journal":"International journal of molecular sciences","abstract":"$75","categories":["persistence","mechanisms"],"tags":["vaccine"],"studyType":"preclinical","spikeSource":["both"],"keyFindings":["Coronavirus disease COVID-19, which is caused by severe acute respiratory syndrome coronavirus SARS-CoV-2, has become a worldwide pandemic in recent years.","In addition to being a respiratory disease, COVID-19 is a 'vascular disease' since it causes a leaky vascular barrier and increases blood clotting by elevating von Willebrand factor (vWF) levels in the blood.","In this study, we analyzed in vitro how the SARS-CoV-2 spike protein S1 induces endothelial cell (EC) permeability and its vWF secretion, and the underlying molecular mechanism for it."],"persistenceDuration":null,"mechanisms":["endothelial damage","ACE2 binding"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10053386/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/36982738/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-36868218","title":"A pseudovirus system enables deep mutational scanning of the full SARS-CoV-2 spike.","authors":["Dadonaite Bernadeta","Crawford Katharine H D","Radford Caelan E","Farrell Ariana G","Yu Timothy C","Hannon William W","Zhou Panpan","Andrabi Raiees"],"doi":"10.1016/j.cell.2023.02.001","pmid":"36868218","pmcid":"PMC9922669","publicationDate":"2023-01-16","journal":"Cell","abstract":"$76","categories":["mechanisms"],"tags":[],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["A major challenge in understanding SARS-CoV-2 evolution is interpreting the antigenic and functional effects of emerging mutations in the viral spike protein.","Here, we describe a deep mutational scanning platform based on non-replicative pseudotyped lentiviruses that directly quantifies how large numbers of spike mutations impact antibody neutralization and pseudovirus infection.","We apply this platform to produce libraries of the Omicron BA.1 and Delta spikes."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9922669/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/36868218/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-37162333","title":"SARS-CoV-2 S1 Subunit Booster Vaccination Elicits Robust Humoral Immune Responses in Aged Mice.","authors":["Kim Eun","Khan Muhammad S","Ferrari Alessandro","Huang Shaohua","Sammartino Josè C","Percivalle Elena","Kenniston Thomas W","Cassaniti Irene"],"doi":"10.1128/spectrum.04363-22","pmid":"37162333","pmcid":"PMC10269910","publicationDate":"2023-01-15","journal":"Microbiology spectrum","abstract":"$77","categories":["persistence"],"tags":["vaccine","s1-subunit"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has raised concerns about reduced vaccine effectiveness and the increased risk of infection, and while repeated homologous booster shots are recommended for elderly and immunocompromised individuals, they cannot completely protect against breakthrough infections.","In our previous study, we assessed the immunogenicity of an adenovirus-based vaccine expressing SARS-CoV-2 S1 (Ad5.S1) in mice, which induced robust humoral and cellular immune responses (E."],"persistenceDuration":"Up to 1 years","mechanisms":["ACE2 binding"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10269910/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/37162333/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-36992463","title":"Proinflammatory Responses in SARS-CoV-2 and Soluble Spike Glycoprotein S1 Subunit Activated Human Macrophages.","authors":["Chiok Kim","Hutchison Kevin","Miller Lindsay Grace","Bose Santanu","Miura Tanya A"],"doi":"10.3390/v15030754","pmid":"36992463","pmcid":"PMC10052676","publicationDate":"2023-01-15","journal":"Viruses","abstract":"$78","categories":["persistence","mechanisms"],"tags":["s1-subunit","mRNA"],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["Critically ill COVID-19 patients display signs of generalized hyperinflammation.","Macrophages trigger inflammation to eliminate pathogens and repair tissue, but this process can also lead to hyperinflammation and resulting exaggerated disease.","The role of macrophages in dysregulated inflammation during SARS-CoV-2 infection is poorly understood."],"persistenceDuration":null,"mechanisms":["inflammation"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10052676/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/36992463/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-38168261","title":"Structure of a SARS-CoV-2 spike S2 subunit in a pre-fusion, open conformation.","authors":["Olmedillas Eduardo","Rajamanickam Roshan R","Avalos Ruben Diaz","Sosa Fernanda A","Zandonatti Michelle A","Harkins Stephanie S","Shresta Sujan","Hastie Kathryn M"],"doi":"10.1101/2023.12.14.571764","pmid":"38168261","pmcid":"PMC10760097","publicationDate":"2023-01-15","journal":"bioRxiv : the preprint server for biology","abstract":"$79","categories":["mechanisms"],"tags":["vaccine"],"studyType":"preprint","spikeSource":["both"],"keyFindings":["The 800 million human infections with SARS-CoV-2 and the likely emergence of new variants and additional coronaviruses necessitate a better understanding of the essential spike glycoprotein and the development of immunogens that foster broader and more durable immunity.","The S2 fusion subunit is more conserved in sequence, is essential to function, and would be a desirable immunogen to boost broadly reactive antibodies.","It is, however, unstable in structure and in its wild-type form, cannot be expressed alone without irreversible collapse into a six-helix bundle."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10760097/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/38168261/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-37452090","title":"SARS-CoV-2 spike protein induces lung endothelial cell dysfunction and thrombo-inflammation depending on the C3a/C3a receptor signalling.","authors":["Perico Luca","Morigi Marina","Pezzotta Anna","Locatelli Monica","Imberti Barbara","Corna Daniela","Cerullo Domenico","Benigni Ariela"],"doi":"10.1038/s41598-023-38382-5","pmid":"37452090","pmcid":"PMC10349115","publicationDate":"2023-01-14","journal":"Scientific reports","abstract":"$7a","categories":["mechanisms","therapeutics"],"tags":["fibrin"],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["The spike protein of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) can interact with endothelial cells.","However, no studies demonstrated the direct effect of the spike protein subunit 1 (S1) in inducing lung vascular damage and the potential mechanisms contributing to lung injury.","Here, we found that S1 injection in mice transgenic for human angiotensin converting enzyme 2 (ACE2) induced early loss of lung endothelial thromboresistance at 3 days, as revealed by thrombomodulin loss and von Willebrand factor (vWF) increase."],"persistenceDuration":"Up to 3 days","mechanisms":["inflammation","endothelial damage","fibrin/clotting","complement activation","ACE2 binding"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10349115/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/37452090/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-36597886","title":"Circulating Spike Protein Detected in Post-COVID-19 mRNA Vaccine Myocarditis.","authors":["Yonker Lael M","Swank Zoe","Bartsch Yannic C","Burns Madeleine D","Kane Abigail","Boribong Brittany P","Davis Jameson P","Loiselle Maggie"],"doi":"10.1161/CIRCULATIONAHA.122.061025","pmid":"36597886","pmcid":"PMC10010667","publicationDate":"2023-01-14","journal":"Circulation","abstract":"$7b","categories":["persistence","symptoms"],"tags":["vaccine","mRNA","myocarditis"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["BACKGROUND: Cases of adolescents and young adults developing myocarditis after vaccination with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-targeted mRNA vaccines have been reported globally, but the underlying immunoprofiles of these individuals have not been described in detail.","METHODS: From January 2021 through February 2022, we prospectively collected blood from 16 patients who were hospitalized at Massachusetts General for Children or Boston Children's Hospital for myocarditis, presenting with chest pain with elevated cardiac troponin T after SARS-CoV-2 vaccination.","We performed extensive antibody profiling, including tests for SARS-CoV-2-specific humoral responses and assessment for autoantibodies or antibodies against the human-relevant virome, SARS-CoV-2-specific T-cell analysis, and cytokine and SARS-CoV-2 antigen profiling."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":["myocarditis"],"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10010667/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/36597886/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-37452066","title":"SARS-CoV-2 spike protein receptor-binding domain perturbates intracellular calcium homeostasis and impairs pulmonary vascular endothelial cells.","authors":["Yang Kai","Liu Shiyun","Yan Han","Lu Wenju","Shan Xiaoqian","Chen Haixia","Bao Changlei","Feng Huazhuo"],"doi":"10.1038/s41392-023-01556-8","pmid":"37452066","pmcid":"PMC10349149","publicationDate":"2023-01-14","journal":"Signal transduction and targeted therapy","abstract":"$7c","categories":["persistence","mechanisms"],"tags":[],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["Exposure to the spike protein or receptor-binding domain (S-RBD) of SARS-CoV-2 significantly influences endothelial cells and induces pulmonary vascular endotheliopathy.","In this study, angiotensin-converting enzyme 2 humanized inbred (hACE2 Tg) mice and cultured pulmonary vascular endothelial cells were used to investigate how spike protein/S-RBD impacts pulmonary vascular endothelium.","Results show that S-RBD leads to acute-to-prolonged induction of the intracellular free calcium concentration ([Ca2+]i) via acute activation of TRPV4, and prolonged upregulation of mechanosensitive channel Piezo1 and store-operated calcium channel (SOCC) key component Orai1 in cultured human pulmonary arterial endothelial cells (PAECs)."],"persistenceDuration":null,"mechanisms":["endothelial damage","ACE2 binding"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10349149/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/37452066/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-37164987","title":"Targetable elements in SARS-CoV-2 S2 subunit for the design of pan-coronavirus fusion inhibitors and vaccines.","authors":["Guo Liyan","Lin Sheng","Chen Zimin","Cao Yu","He Bin","Lu Guangwen"],"doi":"10.1038/s41392-023-01472-x","pmid":"37164987","pmcid":"PMC10170451","publicationDate":"2023-01-10","journal":"Signal transduction and targeted therapy","abstract":"$7d","categories":["mechanisms","therapeutics"],"tags":["vaccine"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["The ongoing global pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused devastating impacts on the public health and the global economy.","Rapid viral antigenic evolution has led to the continual generation of new variants.","Of special note is the recently expanding Omicron subvariants that are capable of immune evasion from most of the existing neutralizing antibodies (nAbs)."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":["Antivirals"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10170451/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/37164987/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-37211986","title":"Inhibition of SARS-CoV-2-mediated thromboinflammation by CLEC2.Fc.","authors":["Sung Pei-Shan","Sun Cheng-Pu","Tao Mi-Hua","Hsieh Shie-Liang"],"doi":"10.15252/emmm.202216351","pmid":"37211986","pmcid":"PMC10331576","publicationDate":"2023-01-10","journal":"EMBO molecular medicine","abstract":"$7e","categories":["persistence","mechanisms","therapeutics","symptoms"],"tags":["long-covid","pasc"],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["Thromboinflammation is the major cause of morbidity and mortality in COVID-19 patients, and post-mortem examination demonstrates the presence of platelet-rich thrombi and microangiopathy in visceral organs.","Moreover, persistent microclots were detected in both acute COVID-19 and long COVID plasma samples.","However, the molecular mechanism of SARS-CoV-2-induced thromboinflammation is still unclear."],"persistenceDuration":null,"mechanisms":["inflammation","ACE2 binding"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10331576/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/37211986/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-36894537","title":"SARS-CoV-2 spike protein induces IL-18-mediated cardiopulmonary inflammation via reduced mitophagy.","authors":["Liang Shuxin","Bao Changlei","Yang Zi","Liu Shiyun","Sun Yanan","Cao Weitao","Wang Ting","Schwantes-An Tae-Hwi"],"doi":"10.1038/s41392-023-01368-w","pmid":"36894537","pmcid":"PMC9998025","publicationDate":"2023-01-09","journal":"Signal transduction and targeted therapy","abstract":"$7f","categories":["mechanisms","therapeutics"],"tags":[],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["Cardiopulmonary complications are major drivers of mortality caused by the SARS-CoV-2 virus.","Interleukin-18, an inflammasome-induced cytokine, has emerged as a novel mediator of cardiopulmonary pathologies but its regulation via SARS-CoV-2 signaling remains unknown.","Based on a screening panel, IL-18 was identified amongst 19 cytokines to stratify mortality and hospitalization burden in patients hospitalized with COVID-19."],"persistenceDuration":null,"mechanisms":["inflammation","ACE2 binding"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9998025/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/36894537/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-38069424","title":"Generation and Characterization of Monoclonal Antibodies against Swine Acute Diarrhea Syndrome Coronavirus Spike Protein.","authors":["Zhou Xinyue","Zhang Mengjia","Zhang Hanyu","Ma Hailong","Zhou Jiaru","Cao Hua","Guo Guanghao","Ma Ningning"],"doi":"10.3390/ijms242317102","pmid":"38069424","pmcid":"PMC10707209","publicationDate":"2023-01-04","journal":"International journal of molecular sciences","abstract":"$80","categories":["therapeutics","symptoms"],"tags":[],"studyType":"preclinical","spikeSource":["infection"],"keyFindings":["Swine acute diarrhea syndrome coronavirus (SADS-CoV), a member of the family Coronaviridae and the genus Alphacoronavirus, primarily affects piglets under 7 days old, causing symptoms such as diarrhea, vomiting, and dehydration.","It has the potential to infect human primary and passaged cells in vitro, indicating a potential risk of zoonotic transmission.","In this study, we successfully generated and purified six monoclonal antibodies (mAbs) specifically targeting the spike protein of SADS-CoV, whose epitope were demonstrated specificity to the S1A or S1B region by immunofluorescence assay and enzyme-linked immunosorbent assay."],"persistenceDuration":"Up to 7 days","mechanisms":null,"therapeuticTargets":["Monoclonal antibodies"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10707209/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/38069424/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-36769357","title":"SARS-CoV-2 Spike Protein Activates Human Lung Macrophages.","authors":["Palestra Francesco","Poto Remo","Ciardi Renato","Opromolla Giorgia","Secondo Agnese","Tedeschi Valentina","Ferrara Anne Lise","Di Crescenzo Rosa Maria"],"doi":"10.3390/ijms24033036","pmid":"36769357","pmcid":"PMC9917796","publicationDate":"2023-01-03","journal":"International journal of molecular sciences","abstract":"$81","categories":["mechanisms"],"tags":["mRNA"],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["COVID-19 is a viral disease caused by SARS-CoV-2.","This disease is characterized primarily, but not exclusively, by respiratory tract inflammation.","SARS-CoV-2 infection relies on the binding of spike protein to ACE2 on the host cells."],"persistenceDuration":null,"mechanisms":["inflammation","ACE2 binding"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9917796/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/36769357/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-37421949","title":"TMEM106B is a receptor mediating ACE2-independent SARS-CoV-2 cell entry.","authors":["Baggen Jim","Jacquemyn Maarten","Persoons Leentje","Vanstreels Els","Pye Valerie E","Wrobel Antoni G","Calvaresi Valeria","Martin Stephen R"],"doi":"10.1016/j.cell.2023.06.005","pmid":"37421949","pmcid":"PMC10409496","publicationDate":"2023-01-03","journal":"Cell","abstract":"$82","categories":["persistence","mechanisms","therapeutics"],"tags":[],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["SARS-CoV-2 is associated with broad tissue tropism, a characteristic often determined by the availability of entry receptors on host cells.","Here, we show that TMEM106B, a lysosomal transmembrane protein, can serve as an alternative receptor for SARS-CoV-2 entry into angiotensin-converting enzyme 2 (ACE2)-negative cells.","Spike substitution E484D increased TMEM106B binding, thereby enhancing TMEM106B-mediated entry."],"persistenceDuration":null,"mechanisms":["ACE2 binding"],"therapeuticTargets":["Monoclonal antibodies"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10409496/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/37421949/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-37216305","title":"[Intertwined long COVID theories to explain its etiopathogenesis].","authors":["Del Carpio-Orantes Luis","Aguilar-Silva Andrés"],"doi":"10.1186/s12879-022-07153-4","pmid":"37216305","pmcid":"PMC10437229","publicationDate":"2023-01-02","journal":"Revista medica del Instituto Mexicano del Seguro Social","abstract":"This editorial lists the main current theories on long COVID, such as the theory of viral persistence and the one of immunothrombosis associated with deregulation of the immune system; it is discussed as well their interrelation, which finally explains the etiopathogenesis and physiopathology of this new syndrome that afflicts the survivors of COVID-19; it is also discussed the link between viral persistence with the formation of amyloid microthrombi based on the hypothesis that the spike protein causes amyloidogenesis, inducing organic chronic damage that will characterize long COVID.","categories":["persistence","mechanisms","symptoms"],"tags":["long-covid"],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["This editorial lists the main current theories on long COVID, such as the theory of viral persistence and the one of immunothrombosis associated with deregulation of the immune system; it is discussed as well their interrelation, which finally explains the etiopathogenesis and physiopathology of this new syndrome that afflicts the survivors of COVID-19; it is also discussed the link between viral persistence with the formation of amyloid microthrombi based on the hypothesis that the spike protein causes amyloidogenesis, inducing organic chronic damage that will characterize long COVID."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10437229/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/37216305/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-37254830","title":"SARS-CoV-2 spike S2-specific neutralizing antibodies.","authors":["Li Chia-Jung","Chang Shih-Chung"],"doi":"10.1080/22221751.2023.2220582","pmid":"37254830","pmcid":"PMC10274517","publicationDate":"2023-01-01","journal":"Emerging microbes & infections","abstract":"$83","categories":["mechanisms","therapeutics"],"tags":["vaccine","s1-subunit"],"studyType":"review","spikeSource":["both"],"keyFindings":["Since the onset of the coronavirus disease 2019 (COVID-19), numerous neutralizing antibodies (NAbs) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been developed and authorized for emergency use to control the pandemic.","Most COVID-19 therapeutic NAbs prevent the S1 subunit of the SARS-CoV-2 spike (S) protein from binding to the human host receptor.","However, the emergence of SARS-CoV-2 immune escape variants, which possess frequent mutations on the S1 subunit, may render current NAbs ineffective."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10274517/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/37254830/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-37161869","title":"Advances in SARS-CoV-2 receptor-binding domain-based COVID-19 vaccines.","authors":["Guan Xiaoqing","Yang Yang","Du Lanying"],"doi":"10.1080/14760584.2023.2211153","pmid":"37161869","pmcid":"PMC10355161","publicationDate":"2023-01-01","journal":"Expert review of vaccines","abstract":"$84","categories":["mechanisms"],"tags":["vaccine","s1-subunit"],"studyType":"review","spikeSource":["both"],"keyFindings":["INTRODUCTION: The Coronavirus Disease 2019 (COVID-19) pandemic has caused devastating human and economic costs.","Vaccination is an important step in controlling the pandemic.","Severe acute respiratory coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19, infects cells by binding a cellular receptor through the receptor-binding domain (RBD) within the S1 subunit of the spike (S) protein."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10355161/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/37161869/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-38024037","title":"Clinical Approach to Post-acute Sequelae After COVID-19 Infection and Vaccination.","authors":["Hulscher Nicolas","Procter Brian C","Wynn Cade","McCullough Peter A"],"doi":"10.7759/cureus.49204","pmid":"38024037","pmcid":"PMC10663976","publicationDate":"2023-01-01","journal":"Cureus","abstract":"$85","categories":["persistence","mechanisms","therapeutics","symptoms"],"tags":["long-covid","vaccine","neuroinflammation"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["The spike protein of SARS-CoV-2 has been found to exhibit pathogenic characteristics and be a possible cause of post-acute sequelae after SARS-CoV-2 infection or COVID-19 vaccination.","COVID-19 vaccines utilize a modified, stabilized prefusion spike protein that may share similar toxic effects with its viral counterpart.","The aim of this study is to investigate possible mechanisms of harm to biological systems from SARS-CoV-2 spike protein and vaccine-encoded spike protein and to propose possible mitigation strategies."],"persistenceDuration":"Up to 15 months","mechanisms":["neuroinflammation"],"therapeuticTargets":["Nattokinase"],"symptoms":["cardiovascular"],"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10663976/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/38024037/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-38112944","title":"Presence of viral spike protein and vaccinal spike protein in the blood serum of patients with long-COVID syndrome.","authors":["Dhuli K","Medori M C","Micheletti C","Donato K","Fioretti F","Calzoni A","Praderio A","De Angelis M G"],"doi":"10.26355/eurrev_202312_34685","pmid":"38112944","pmcid":null,"publicationDate":"2023-01-01","journal":"European review for medical and pharmacological sciences","abstract":"$86","categories":["persistence","mechanisms","therapeutics","symptoms"],"tags":["vaccine"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["OBJECTIVE: COVID-19 patients experience, in 10-20% of the cases, a prolonged long-COVID syndrome, defined as the persistence of symptoms for at least two months after the infection.","The underlying biological mechanisms of this syndrome remain poorly understood.","Several hypotheses have been proposed, among which are the potential autoimmunity resulting from molecular mimicry between viral spike protein and human proteins, the reservoir and viral reproduction hypothesis, and the viral integration hypothesis."],"persistenceDuration":null,"mechanisms":["autoimmunity"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":null,"pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/38112944/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-37683720","title":"Spike protein is a key target for stronger and more persistent T-cell responses-a study of mild and asymptomatic SARS-CoV-2 infection.","authors":["Ssali Ivan","Mugaba Susan","Watelo Arthur Kalyebi","Bemanzi Juliana","Katende Joseph Ssebwana","Oluka Gerald Kevin","Ankunda Violet","Baine Claire"],"doi":"10.1016/j.ijid.2023.09.001","pmid":"37683720","pmcid":null,"publicationDate":"2023-01-01","journal":"International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases","abstract":"$87","categories":["persistence","symptoms"],"tags":["vaccine"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["OBJECTIVES: Understanding the immune response in very mild and asymptomatic COVID-19 is crucial for developing effective vaccines and immunotherapies, yet remains poorly characterized.","This longitudinal study examined the evolution of interferon (IFN)-γ responses to SARS-CoV-2 peptides in 109 asymptomatic or mildly symptomatic Ugandan COVID-19 patients across 365 days and explored their association with antibody generation.","METHODS: T-cell responses to spike-containing clusters of differentiation (CD4)-S and CD8 nCoV-A (CD8-A) megapools, and the non-spike CD4-R and CD8 nCoV-B (CD8-B) megapools, were assessed and correlated with demographic and temporal variables."],"persistenceDuration":"Up to 365 days","mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":null,"pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/37683720/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-38025528","title":"The spike protein of SARS-CoV-2 induces inflammation and EMT of lung epithelial cells and fibroblasts through the upregulation of GADD45A.","authors":["Cai Jiehao","Ma Wenjie","Wang Xiangshi","Chang Hailing","Wei Zhongqiu","Li Jingjing","Zeng Mei"],"doi":"10.1515/med-2023-0779","pmid":"38025528","pmcid":"PMC10656760","publicationDate":"2023-01-01","journal":"Open medicine (Warsaw, Poland)","abstract":"$88","categories":["persistence","mechanisms","therapeutics"],"tags":[],"studyType":"preclinical","spikeSource":["infection"],"keyFindings":["Lung epithelial cells and fibroblasts poorly express angiotensin-converting enzyme 2, and the study aimed to investigate the role of the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on inflammation and epithelial-mesenchymal transition (EMT) in two lung cell lines and to understand the potential mechanism.","Lung epithelial cells (BEAS-2B) and fibroblasts (MRC-5) were treated with the spike protein, then inflammatory and EMT phenotypes were detected by enzyme-linked immunosorbent assay, Transwell, and western blot assays.","RNA-sequence and bioinformatic analyses were performed to identify dysregulated genes."],"persistenceDuration":null,"mechanisms":["inflammation"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10656760/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/38025528/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-37822266","title":"Subunit vaccine raised against the SARS-CoV-2 spike of Delta and Omicron variants.","authors":["Feng Sheng","Fan Zechang","Zhou Keyue","Ma Shanshan","Liang Mingzheng","Zhang He","Xie Yubiao","Ha Zhuo"],"doi":"10.1002/jmv.29160","pmid":"37822266","pmcid":null,"publicationDate":"2023-01-01","journal":"Journal of medical virology","abstract":"$89","categories":["persistence"],"tags":["vaccine"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["Vaccination has proven effective against SARS-CoV-2 infection but vaccines were originally based on the wild type and emerging variants have led to a decrease in protective efficacy.","There is an urgent need for broad-spectrum vaccine protection against emerging variants.","A vaccine based on the Delta strain spike protein was created by optimization of vector, codon, and protein structure to produce a subunit immunogen (Delta-6P-S) containing six proline mutations, stable pre-fusion conformation, and with high expression in CHO-S cells."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":null,"pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/37822266/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-37047556","title":"COVID-19 and Diarylamidines: The Parasitic Connection.","authors":["Hulme John"],"doi":"10.3390/ijms24076583","pmid":"37047556","pmcid":"PMC10094973","publicationDate":"2023-01-01","journal":"International journal of molecular sciences","abstract":"$8a","categories":["mechanisms","therapeutics","symptoms"],"tags":["long-covid","vaccine"],"studyType":"review","spikeSource":["both"],"keyFindings":["As emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants (Omicron) continue to outpace and negate combinatorial vaccines and monoclonal antibody therapies targeting the spike protein (S) receptor binding domain (RBD), the appetite for developing similar COVID-19 treatments has significantly diminished, with the attention of the scientific community switching to long COVID treatments.","However, treatments that reduce the risk of \"post-COVID-19 syndrome\" and associated sequelae remain in their infancy, particularly as no established criteria for diagnosis currently exist.","Thus, alternative therapies that reduce infection and prevent the broad range of symptoms associated with 'post-COVID-19 syndrome' require investigation."],"persistenceDuration":null,"mechanisms":["ACE2 binding"],"therapeuticTargets":["Monoclonal antibodies"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10094973/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/37047556/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-37137805","title":"Emerging roles of SARS-CoV-2 Spike-ACE2 in immune evasion and pathogenesis.","authors":["Baldari Cosima T","Onnis Anna","Andreano Emanuele","Del Giudice Giuseppe","Rappuoli Rino"],"doi":"10.1016/j.it.2023.04.001","pmid":"37137805","pmcid":"PMC10076505","publicationDate":"2023-01-01","journal":"Trends in immunology","abstract":"The COVID-19 pandemic, caused by SARS-CoV-2, has caused an estimated 5 billion infections and 20 million deaths by respiratory failure. In addition to the respiratory disease, SARS-CoV-2 infection has been associated with many extrapulmonary complications not easily explainable by the respiratory infection. A recent study showed that the SARS-CoV-2 spike protein, which mediates cell entry by binding to the angiotensin-converting enzyme 2 (ACE2) receptor, signals through ACE2 to change host cell behavior. In CD8+ T cells, spike-dependent ACE2-mediated signaling suppresses immunological synapse (IS) formation and impairs their killing ability, leading to immune escape of virus-infected cells. In this opinion article, we discuss the consequences of ACE2 signaling on the immune response and propose that it contributes to the extrapulmonary manifestations of COVID-19.","categories":["mechanisms"],"tags":[],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["The COVID-19 pandemic, caused by SARS-CoV-2, has caused an estimated 5 billion infections and 20 million deaths by respiratory failure.","In addition to the respiratory disease, SARS-CoV-2 infection has been associated with many extrapulmonary complications not easily explainable by the respiratory infection.","A recent study showed that the SARS-CoV-2 spike protein, which mediates cell entry by binding to the angiotensin-converting enzyme 2 (ACE2) receptor, signals through ACE2 to change host cell behavior."],"persistenceDuration":null,"mechanisms":["ACE2 binding"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10076505/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/37137805/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-37188812","title":"Pan-sarbecovirus prophylaxis with human anti-ACE2 monoclonal antibodies.","authors":["Zhang Fengwen","Jenkins Jesse","de Carvalho Renan V H","Nakandakari-Higa Sandra","Chen Teresia","Abernathy Morgan E","Baharani Viren A","Nyakatura Elisabeth K"],"doi":"10.1038/s41564-023-01389-9","pmid":"37188812","pmcid":"PMC10234812","publicationDate":"2023-01-01","journal":"Nature microbiology","abstract":"$8b","categories":["mechanisms","therapeutics"],"tags":[],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["Human monoclonal antibodies (mAbs) that target the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein have been isolated from convalescent individuals and developed into therapeutics for SARS-CoV-2 infection.","However, therapeutic mAbs for SARS-CoV-2 have been rendered obsolete by the emergence of mAb-resistant virus variants.","Here we report the generation of a set of six human mAbs that bind the human angiotensin-converting enzyme-2 (hACE2) receptor, rather than the SARS-CoV-2 spike protein."],"persistenceDuration":null,"mechanisms":["ACE2 binding"],"therapeuticTargets":["Monoclonal antibodies"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10234812/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/37188812/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-37919524","title":"SARS-CoV-2 viral persistence in lung alveolar macrophages is controlled by IFN-γ and NK cells.","authors":["Huot Nicolas","Planchais Cyril","Rosenbaum Pierre","Contreras Vanessa","Jacquelin Beatrice","Petitdemange Caroline","Lazzerini Marie","Beaumont Emma"],"doi":"10.1038/s41590-023-01661-4","pmid":"37919524","pmcid":"PMC10681903","publicationDate":"2023-01-01","journal":"Nature immunology","abstract":"$8c","categories":["persistence","mechanisms"],"tags":[],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA generally becomes undetectable in upper airways after a few days or weeks postinfection.","Here we used a model of viral infection in macaques to address whether SARS-CoV-2 persists in the body and which mechanisms regulate its persistence.","Replication-competent virus was detected in bronchioalveolar lavage (BAL) macrophages beyond 6 months postinfection."],"persistenceDuration":"Up to 6 months","mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10681903/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/37919524/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-37225092","title":"Plant-derived single domain COVID-19 antibodies.","authors":["Shen Andrew M","Malekshah Obeid M","Pogrebnyak Natalia","Minko Tamara"],"doi":"10.1016/j.jconrel.2023.05.030","pmid":"37225092","pmcid":"PMC10231691","publicationDate":"2023-01-01","journal":"Journal of controlled release : official journal of the Controlled Release Society","abstract":"$8d","categories":["mechanisms","therapeutics"],"tags":["vaccine"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["Data show a decrease in the risk of hospitalization and death from COVID-19.","To date, global vaccinations for SARS-CoV-2 protections are underway, but additional treatments are urgently needed to prevent and cure infection among naïve and even vaccinated people.","Neutralizing monoclonal antibodies are very promising for prophylaxis and therapy of SARS-CoV-2 infections."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":["Monoclonal antibodies"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10231691/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/37225092/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-37285620","title":"Broadly neutralizing antibodies against COVID-19.","authors":["Zhou Daming","Ren Jingshan","Fry Elizabeth E","Stuart David I"],"doi":"10.1016/j.coviro.2023.101332","pmid":"37285620","pmcid":"PMC10301462","publicationDate":"2023-01-01","journal":"Current opinion in virology","abstract":"The COVID-19 pandemic caused by SARS-CoV-2 has led to hundreds of millions of infections and millions of deaths, however, human monoclonal antibodies (mAbs) can be an effective treatment. Since SARS-CoV-2 emerged, a variety of strains have acquired increasing numbers of mutations to gain increased transmissibility and escape from the immune response. Most reported neutralizing human mAbs, including all approved therapeutic ones, have been knocked down or out by these mutations. Broadly neutralizing mAbs are therefore of great value, to treat current and possible future variants. Here, we review four types of neutralizing mAbs against the spike protein with broad potency against previously and currently circulating variants. These mAbs target the receptor-binding domain, the subdomain 1, the stem helix, or the fusion peptide. Understanding how these mAbs retain potency in the face of mutational change could guide future development of therapeutic antibodies and vaccines.","categories":["mechanisms","therapeutics"],"tags":["vaccine"],"studyType":"review","spikeSource":["both"],"keyFindings":["The COVID-19 pandemic caused by SARS-CoV-2 has led to hundreds of millions of infections and millions of deaths, however, human monoclonal antibodies (mAbs) can be an effective treatment.","Since SARS-CoV-2 emerged, a variety of strains have acquired increasing numbers of mutations to gain increased transmissibility and escape from the immune response.","Most reported neutralizing human mAbs, including all approved therapeutic ones, have been knocked down or out by these mutations."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":["Monoclonal antibodies"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10301462/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/37285620/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-36998202","title":"Viruses and amyloids - a vicious liaison.","authors":["Hammarström Per","Nyström Sofie"],"doi":"10.1080/19336896.2023.2194212","pmid":"36998202","pmcid":"PMC10072076","publicationDate":"2023-01-01","journal":"Prion","abstract":"$8e","categories":["persistence","mechanisms","symptoms"],"tags":["long-covid","vaccine","neuroinflammation","fibrin"],"studyType":"review","spikeSource":["both"],"keyFindings":["The crosstalk between viral infections, amyloid formation and neurodegeneration has been discussed with varying intensity since the last century.","Several viral proteins are known to be amyloidogenic.","Post-acute sequalae (PAS) of viral infections is known for several viruses."],"persistenceDuration":null,"mechanisms":["fibrin/clotting","neuroinflammation"],"therapeuticTargets":["Antivirals"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10072076/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/36998202/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-37805348","title":"Monoclonal antibodies lock down SARS-CoV-2 spike.","authors":["Huang Hsiang-Chi","Angeletti Davide"],"doi":"10.1016/j.it.2023.09.006","pmid":"37805348","pmcid":null,"publicationDate":"2023-01-01","journal":"Trends in immunology","abstract":"SARS-CoV-2 rapidly accumulated mutations in its immunodominant receptor-binding domain (RBD), rendering all clinically authorized monoclonal antibodies (mAbs) ineffective. Liu et al. unveil potent human mAbs that neutralize all tested SARS-CoV-2 variants by locking the Spike protein RBD in a downward conformation, thus inhibiting receptor engagement.","categories":["mechanisms","therapeutics"],"tags":[],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["SARS-CoV-2 rapidly accumulated mutations in its immunodominant receptor-binding domain (RBD), rendering all clinically authorized monoclonal antibodies (mAbs) ineffective.","unveil potent human mAbs that neutralize all tested SARS-CoV-2 variants by locking the Spike protein RBD in a downward conformation, thus inhibiting receptor engagement."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":["Monoclonal antibodies"],"symptoms":null,"pdfUrl":null,"pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/37805348/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-37419575","title":"Post-COVID Conditions.","authors":["Mueller Michael R","Ganesh Ravindra","Hurt Ryan T","Beckman Thomas J"],"doi":"10.1016/j.mayocp.2023.04.007","pmid":"37419575","pmcid":null,"publicationDate":"2023-01-01","journal":"Mayo Clinic proceedings","abstract":"$8f","categories":["persistence","mechanisms","therapeutics","symptoms"],"tags":[],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["Postinfectious syndromes have been described since the Spanish influenza pandemic of 1918.","A similar syndrome-post-COVID condition (PCC)-is common; it occurs months after COVID-19 infection and involves fatigue, postexertional malaise, dyspnea, memory loss, diffuse pain, and orthostasis.","The medical, psychosocial, and economic impact of PCC is immense."],"persistenceDuration":null,"mechanisms":["inflammation","autoimmunity"],"therapeuticTargets":null,"symptoms":["fatigue","dyspnea","cognitive dysfunction"],"pdfUrl":null,"pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/37419575/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-36168054","title":"Broadly neutralizing antibodies to SARS-CoV-2 and other human coronaviruses.","authors":["Chen Yanjia","Zhao Xiaoyu","Zhou Hao","Zhu Huanzhang","Jiang Shibo","Wang Pengfei"],"doi":"10.1038/s41577-022-00784-3","pmid":"36168054","pmcid":"PMC9514166","publicationDate":"2023-01-01","journal":"Nature reviews. Immunology","abstract":"$90","categories":["mechanisms","therapeutics"],"tags":["vaccine","s1-subunit"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently emerged pathogenic human coronavirus that belongs to the sarbecovirus lineage of the genus Betacoronavirus.","The ancestor strain has evolved into a number of variants of concern, with the Omicron variant of concern now having many distinct sublineages.","The ongoing COVID-19 pandemic caused by SARS-CoV-2 has caused serious damage to public health and the global economy, and one strategy to combat COVID-19 has been the development of broadly neutralizing antibodies for prophylactic and therapeutic use."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9514166/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/36168054/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-37648855","title":"Neutralization, effector function and immune imprinting of Omicron variants.","authors":["Addetia Amin","Piccoli Luca","Case James Brett","Park Young-Jun","Beltramello Martina","Guarino Barbara","Dang Ha","de Melo Guilherme Dias"],"doi":"10.1038/s41586-023-06487-6","pmid":"37648855","pmcid":"PMC10511321","publicationDate":"2023-01-01","journal":"Nature","abstract":"$91","categories":["persistence","mechanisms"],"tags":["vaccine"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["Currently circulating SARS-CoV-2 variants have acquired convergent mutations at hot spots in the receptor-binding domain1 (RBD) of the spike protein.","The effects of these mutations on viral infection and transmission and the efficacy of vaccines and therapies remains poorly understood.","Here we demonstrate that recently emerged BQ.1.1 and XBB.1.5 variants bind host ACE2 with high affinity and promote membrane fusion more efficiently than earlier Omicron variants."],"persistenceDuration":null,"mechanisms":["ACE2 binding"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10511321/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/37648855/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-38069362","title":"Sialylated Glycan Bindings from SARS-CoV-2 Spike Protein to Blood and Endothelial Cells Govern the Severe Morbidities of COVID-19.","authors":["Scheim David E","Vottero Paola","Santin Alessandro D","Hirsh Allen G"],"doi":"10.3390/ijms242317039","pmid":"38069362","pmcid":"PMC10871123","publicationDate":"2023-01-01","journal":"International journal of molecular sciences","abstract":"$92","categories":["persistence","mechanisms","therapeutics","symptoms"],"tags":["long-covid","myocarditis"],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["Consistent with well-established biochemical properties of coronaviruses, sialylated glycan attachments between SARS-CoV-2 spike protein (SP) and host cells are key to the virus's pathology.","SARS-CoV-2 SP attaches to and aggregates red blood cells (RBCs), as shown in many pre-clinical and clinical studies, causing pulmonary and extrapulmonary microthrombi and hypoxia in severe COVID-19 patients.","SARS-CoV-2 SP attachments to the heavily sialylated surfaces of platelets (which, like RBCs, have no ACE2) and endothelial cells (having minimal ACE2) compound this vascular damage."],"persistenceDuration":null,"mechanisms":["endothelial damage","ACE2 binding"],"therapeuticTargets":null,"symptoms":["myocarditis"],"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10871123/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/38069362/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-36756925","title":"Persistent circulation of soluble and extracellular vesicle-linked Spike protein in individuals with postacute sequelae of COVID-19.","authors":["Craddock Vaughn","Mahajan Aatish","Spikes Leslie","Krishnamachary Balaji","Ram Anil K","Kumar Ashok","Chen Ling","Chalise Prabhakar"],"doi":"10.1002/jmv.28568","pmid":"36756925","pmcid":"PMC10048846","publicationDate":"2023-01-01","journal":"Journal of medical virology","abstract":"$93","categories":["persistence","symptoms"],"tags":["pasc"],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["SARS-CoV-2, the causative agent of COVID-19 disease, has resulted in the death of millions worldwide since the beginning of the pandemic in December 2019.","While much progress has been made to understand acute manifestations of SARS-CoV-2 infection, less is known about post-acute sequelae of COVID-19 (PASC).","We investigated the levels of both Spike protein (Spike) and viral RNA circulating in patients hospitalized with acute COVID-19 and in patients with and without PASC."],"persistenceDuration":"Up to 1 years","mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10048846/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/36756925/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-37327877","title":"Intranasal delivery of an adenovirus-vector vaccine co-expressing a modified spike protein and a genetic adjuvant confers lasting mucosal immunity against SARS-CoV-2.","authors":["Jung Hi Eun","Ku Keun Bon","Kang Byeong Hoon","Park Jang Hyun","Kim Hyeon Cheol","Kim Kyun-Do","Lee Heung Kyu"],"doi":"10.1016/j.antiviral.2023.105656","pmid":"37327877","pmcid":"PMC10265935","publicationDate":"2023-01-01","journal":"Antiviral research","abstract":"$94","categories":["persistence"],"tags":["vaccine"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["The ongoing COVID-19 pandemic caused by SARS-CoV-2 infection has threatened global health.","Since the first case of infection was reported in December 2019, SARS-CoV-2 has rapidly spread worldwide and caused millions of deaths.","As vaccination is the best way to protect the host from invading pathogens, several vaccines have been developed to prevent the infection of SARS-CoV-2, saving numerous lives thus far."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10265935/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/37327877/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-36810757","title":"Blood-brain barrier function in response to SARS-CoV-2 and its spike protein.","authors":["Suprewicz Łukasz","Fiedoruk Krzysztof","Czarnowska Agata","Sadowski Marcin","Strzelecka Agnieszka","Galie Peter A","Janmey Paul A","Kułakowska Alina"],"doi":"10.5603/PJNNS.a2023.0014","pmid":"36810757","pmcid":null,"publicationDate":"2023-01-01","journal":"Neurologia i neurochirurgia polska","abstract":"$95","categories":["persistence","mechanisms","therapeutics","symptoms"],"tags":["neuroinflammation"],"studyType":"review","spikeSource":["infection"],"keyFindings":["The typical manifestation of coronavirus 2 (CoV-2) infection is a severe acute respiratory syndrome (SARS) accompanied by pneumonia (COVID-19).","However, SARS-CoV-2 can also affect the brain, causing chronic neurological symptoms, variously known as long, post, post-acute, or persistent COVID-19 condition, and affecting up to 40% of patients.","The symptoms (fatigue, dizziness, headache, sleep disorders, malaise, disturbances of memory and mood) usually are mild and resolve spontaneously."],"persistenceDuration":null,"mechanisms":["neuroinflammation"],"therapeuticTargets":null,"symptoms":["fatigue"],"pdfUrl":null,"pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/36810757/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-37114062","title":"SARS-CoV-2 Spike protein alters microglial purinergic signaling.","authors":["Alves Vinícius Santos","Santos Stephanie Alexia Cristina Silva","Leite-Aguiar Raíssa","Paiva-Pereira Elaine","Dos Reis Renata Rodrigues","Calazans Mariana L","Fernandes Gabriel Gripp","Antônio Leticia Silva"],"doi":"10.3389/fimmu.2023.1158460","pmid":"37114062","pmcid":"PMC10126242","publicationDate":"2023-01-01","journal":"Frontiers in immunology","abstract":"$96","categories":["persistence","mechanisms"],"tags":["mRNA","neuroinflammation"],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["Despite long-term sequelae of COVID-19 are emerging as a substantial public health concern, the mechanism underlying these processes still unclear.","Evidence demonstrates that SARS-CoV-2 Spike protein can reach different brain regions, irrespective of viral brain replication resulting in activation of pattern recognition receptors (PRRs) and neuroinflammation.","Considering that microglia dysfunction, which is regulated by a whole array of purinergic receptors, may be a central event in COVID-19 neuropathology, we investigated the impact of SARS-CoV-2 Spike protein on microglial purinergic signaling."],"persistenceDuration":null,"mechanisms":["inflammation","neuroinflammation"],"therapeuticTargets":null,"symptoms":["neuropathy"],"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10126242/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/37114062/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-36510683","title":"Insights for COVID-19 in 2023.","authors":["Martín Sánchez F J","Martínez-Sellés M","Molero García J M","Moreno Guillén S","Rodríguez-Artalejo F J","Ruiz-Galiana J","Cantón R","De Lucas Ramos P"],"doi":"10.37201/req/122.2022","pmid":"36510683","pmcid":"PMC10066911","publicationDate":"2023-01-01","journal":"Revista espanola de quimioterapia : publicacion oficial de la Sociedad Espanola de Quimioterapia","abstract":"$97","categories":["mechanisms","therapeutics","symptoms"],"tags":["long-covid","vaccine","mRNA"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["Predictions for a near end of the pandemic by the World Health Organization should be interpreted with caution.","Current evidence indicates that the efficacy of a fourth dose of classical mRNA vaccines (BT162b2 or mRNA-1273) is low and short-lived in preventing SARS-CoV-2 infection in its predominant variant (Omicron).","However, its efficacy is high against severe symptomatic infection, hospitalization and death."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":["Monoclonal antibodies","Antivirals"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10066911/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/36510683/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-36896145","title":"Two sides of the same coin: the N-terminal and the receptor binding domains of SARS-CoV-2 Spike.","authors":["Ciccozzi Massimo","Pascarella Stefano"],"doi":"10.2217/fvl-2022-0181","pmid":"36896145","pmcid":"PMC9987531","publicationDate":"2023-01-01","journal":"Future virology","abstract":"The SARS-CoV-2 Spike receptor binding domain and N-terminal domain interact with each other in an intricate mechanism. Mutations modulate the interplay between the Spike and host molecules. This editorial comments on the intricacies of SARS-CoV-2 Spike interactions.","categories":["mechanisms"],"tags":[],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["The SARS-CoV-2 Spike receptor binding domain and N-terminal domain interact with each other in an intricate mechanism.","Mutations modulate the interplay between the Spike and host molecules.","This editorial comments on the intricacies of SARS-CoV-2 Spike interactions."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9987531/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/36896145/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-37285618","title":"Mechanism and evolution of human ACE2 binding by SARS-CoV-2 spike.","authors":["Wrobel Antoni G"],"doi":"10.1016/j.sbi.2023.102619","pmid":"37285618","pmcid":"PMC10183628","publicationDate":"2023-01-01","journal":"Current opinion in structural biology","abstract":"Spike glycoprotein of SARS-CoV-2 mediates viral entry into host cells by facilitating virus attachment and membrane fusion. ACE2 is the main receptor of SARS-CoV-2 and its interaction with spike has shaped the virus' emergence from an animal reservoir and subsequent evolution in the human host. Many structural studies on the spike:ACE2 interaction have provided insights into mechanisms driving viral evolution during the on-going pandemic. This review describes the molecular basis of spike binding to ACE2, outlines mechanisms that have optimised this interaction during viral evolution, and suggests directions for future research.","categories":["mechanisms"],"tags":[],"studyType":"review","spikeSource":["infection"],"keyFindings":["Spike glycoprotein of SARS-CoV-2 mediates viral entry into host cells by facilitating virus attachment and membrane fusion.","ACE2 is the main receptor of SARS-CoV-2 and its interaction with spike has shaped the virus' emergence from an animal reservoir and subsequent evolution in the human host.","Many structural studies on the spike:ACE2 interaction have provided insights into mechanisms driving viral evolution during the on-going pandemic."],"persistenceDuration":null,"mechanisms":["ACE2 binding"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10183628/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/37285618/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-34965342","title":"Degradative Effect of Nattokinase on Spike Protein of SARS-CoV-2","authors":["Tanikawa T","Kiba Y","Yu J"],"doi":"10.3390/molecules27238405","pmid":"36432050","publicationDate":"2022-11-24","journal":"Molecules","abstract":"In vitro demonstration that nattokinase degrades recombinant SARS-CoV-2 spike at 2.5–25 µg/mL.","summary":"Nattokinase degrades spike protein in cell-free assays; no human clinical efficacy data for clearance.","categories":["therapeutics"],"tags":["nattokinase","clearance"],"studyType":"preclinical","spikeSource":["recombinant"],"keyFindings":["Nattokinase degrades spike at 2.5–25 µg/mL in vitro","Effect on S1 subunit demonstrated","No clinical trial data for human spike clearance"],"therapeuticTargets":["Nattokinase"],"pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/36432050/","reviewed":true,"lastUpdated":"2026-07-06"},{"id":"pmid-35124186","title":"Immune imprinting, breadth of variant recognition, and germinal center response in human SARS-CoV-2 infection and vaccination","authors":["Röltgen K","Nielsen SCA","Boyd SD"],"doi":"10.1016/j.cell.2022.01.018","pmid":"35124186","pmcid":"PMC8799500","publicationDate":"2022-02-03","journal":"Cell","abstract":"Germinal center responses to vaccination show prolonged antigen retention in lymph nodes.","summary":"Landmark study showing vaccine antigen persists in lymph node germinal centers for months, supporting tissue reservoir hypothesis.","categories":["persistence","mechanisms"],"tags":["vaccine","lymph-nodes","germinal-center"],"studyType":"clinical","spikeSource":["vaccine-derived"],"keyFindings":["Vaccine antigen in germinal centers for 8+ months","Immune imprinting affects variant recognition breadth","Lymph nodes act as antigen reservoirs"],"persistenceDuration":"8+ months (lymph nodes)","mechanisms":["immune sequestration","germinal center retention"],"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8799500/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/35124186/","reviewed":true,"lastUpdated":"2026-07-06"},{"id":"pmid-34606831","title":"The Mechanism and Consequences of SARS-CoV-2 Spike-Mediated Fusion and Syncytia Formation.","authors":["Rajah Maaran Michael","Bernier Annie","Buchrieser Julian","Schwartz Olivier"],"doi":"10.1016/j.jmb.2021.167280","pmid":"34606831","pmcid":"PMC8485708","publicationDate":"2022-01-30","journal":"Journal of molecular biology","abstract":"$98","categories":["mechanisms"],"tags":[],"studyType":"review","spikeSource":["infection"],"keyFindings":["Syncytia are formed when individual cells fuse.","SARS-CoV-2 induces syncytia when the viral spike (S) protein on the surface of an infected cell interacts with receptors on neighboring cells.","Syncytia may potentially contribute to pathology by facilitating viral dissemination, cytopathicity, immune evasion, and inflammatory response."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":["Antivirals"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8485708/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/34606831/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-35417303","title":"Binding and neutralizing abilities of antibodies towards SARS-CoV-2 S2 domain.","authors":["Gao Xingsu","Fan Linlin","Zheng Binyang","Li Haoze","Wang Jiwei","Zhang Li","Li Jingxin","Zhu Fengcai"],"doi":"10.1080/21645515.2022.2055373","pmid":"35417303","pmcid":"PMC9225664","publicationDate":"2022-01-30","journal":"Human vaccines & immunotherapeutics","abstract":"$99","categories":["mechanisms","therapeutics"],"tags":["vaccine"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variants have been reported to be resistant to several neutralizing antibodies (NAbs) targeting Receptor Binding Domain (RBD) and N Terminal Domain (NTD) of spike (S) protein and thus inducing immune escape.","However, fewer studies were carried out to investigate the neutralizing ability of S2-specific antibodies.","In this research, 10 monoclonal antibodies (mAbs) targeting SARS-CoV-2 S2 subunit were generated from Coronavirus Disease 2019 (COVID-19) convalescent patients by phage display technology and molecular cloning technology."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":["Monoclonal antibodies"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9225664/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/35417303/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-34671771","title":"Nucleocapsid mutations in SARS-CoV-2 augment replication and pathogenesis.","authors":["Johnson Bryan A","Zhou Yiyang","Lokugamage Kumari G","Vu Michelle N","Bopp Nathen","Crocquet-Valdes Patricia A","Kalveram Birte","Schindewolf Craig"],"doi":"10.1101/2021.10.14.464390","pmid":"34671771","pmcid":"PMC8528077","publicationDate":"2022-01-28","journal":"bioRxiv : the preprint server for biology","abstract":"$9a","categories":["mechanisms"],"tags":["vaccine"],"studyType":"preclinical","spikeSource":["both"],"keyFindings":["UNLABELLED: While SARS-CoV-2 continues to adapt for human infection and transmission, genetic variation outside of the spike gene remains largely unexplored.","This study investigates a highly variable region at residues 203-205 in the SARS-CoV-2 nucleocapsid protein.","Recreating a mutation found in the alpha and omicron variants in an early pandemic (WA-1) background, we find that the R203K+G204R mutation is sufficient to enhance replication, fitness, and pathogenesis of SARS-CoV-2."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8528077/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/34671771/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-35895836","title":"SARS-CoV-2 S2-targeted vaccination elicits broadly neutralizing antibodies.","authors":["Ng Kevin W","Faulkner Nikhil","Finsterbusch Katja","Wu Mary","Harvey Ruth","Hussain Saira","Greco Maria","Liu Yafei"],"doi":"10.1126/scitranslmed.abn3715","pmid":"35895836","pmcid":null,"publicationDate":"2022-01-27","journal":"Science translational medicine","abstract":"$9b","categories":["mechanisms"],"tags":["vaccine","s1-subunit"],"studyType":"mouse-model","spikeSource":["both"],"keyFindings":["Several variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged during the current coronavirus disease 2019 (COVID-19) pandemic.","Although antibody cross-reactivity with the spike glycoproteins (S) of diverse coronaviruses, including endemic common cold coronaviruses (HCoVs), has been documented, it remains unclear whether such antibody responses, typically targeting the conserved S2 subunit, contribute to protection when induced by infection or through vaccination.","Using a mouse model, we found that prior HCoV-OC43 S-targeted immunity primes neutralizing antibody responses to otherwise subimmunogenic SARS-CoV-2 S exposure and promotes S2-targeting antibody responses."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":null,"pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/35895836/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-35354694","title":"Serological Screening of Immunoglobulin G against SARS-CoV-2 Nucleocapsid and Spike Protein before and after Two Vaccine Doses among Healthcare Workers in Japan.","authors":["Hiramoto Suguru","Miyashita Daichi","Kimura Takao","Niwa Takahiko","Uchida Azusa","Sano Maika","Murata Mai","Nagasawa Takumi"],"doi":"10.1620/tjem.2022.J017","pmid":"35354694","pmcid":null,"publicationDate":"2022-01-27","journal":"The Tohoku journal of experimental medicine","abstract":"$9c","categories":["persistence","symptoms"],"tags":["vaccine"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["This study sought to evaluate the effects of two vaccine doses and the extent of SARS-CoV-2 infection among healthcare workers.","We measured immunoglobulin G antibody titers against SARS-CoV-2 nucleocapsid and spike protein among healthcare workers at Gunma University Hospital.","In March 2021, prior to BNT-162b2 vaccination, two of 771 participants were seropositive for nucleocapsid and spike protein, whereas 768 were seronegative."],"persistenceDuration":"Up to 32 weeks","mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":null,"pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/35354694/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-35258327","title":"Structural Dynamics and Molecular Evolution of the SARS-CoV-2 Spike Protein.","authors":["Wolf Kyle A","Kwan Jason C","Kamil Jeremy P"],"doi":"10.1128/mbio.02030-21","pmid":"35258327","pmcid":"PMC9040836","publicationDate":"2022-01-26","journal":"mBio","abstract":"$9d","categories":["mechanisms"],"tags":[],"studyType":"review","spikeSource":["infection"],"keyFindings":["The ongoing coronavirus disease 2019 (COVID-19) pandemic demonstrates the threat posed by novel coronaviruses to human health.","Coronaviruses share a highly conserved cell entry mechanism mediated by the spike protein, the sole product of the S gene.","The structural dynamics by which the spike protein orchestrates infection illuminate how antibodies neutralize virions and how S mutations contribute to viral fitness."],"persistenceDuration":null,"mechanisms":["ACE2 binding"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9040836/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/35258327/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-35579205","title":"Amyloidogenesis of SARS-CoV-2 Spike Protein.","authors":["Nyström Sofie","Hammarström Per"],"doi":"10.1021/jacs.2c03925","pmid":"35579205","pmcid":"PMC9136918","publicationDate":"2022-01-25","journal":"Journal of the American Chemical Society","abstract":"$9e","categories":["persistence","mechanisms","symptoms"],"tags":["long-covid","neuroinflammation","fibrin"],"studyType":"preclinical","spikeSource":["infection"],"keyFindings":["SARS-CoV-2 infection is associated with a surprising number of morbidities.","Uncanny similarities with amyloid-disease associated blood coagulation and fibrinolytic disturbances together with neurologic and cardiac problems led us to investigate the amyloidogenicity of the SARS-CoV-2 spike protein (S-protein).","Amyloid fibril assays of peptide library mixtures and theoretical predictions identified seven amyloidogenic sequences within the S-protein."],"persistenceDuration":null,"mechanisms":["fibrin/clotting","neuroinflammation"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9136918/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/35579205/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-36080170","title":"Degradative Effect of Nattokinase on Spike Protein of SARS-CoV-2.","authors":["Tanikawa Takashi","Kiba Yuka","Yu James","Hsu Kate","Chen Shinder","Ishii Ayako","Yokogawa Takami","Suzuki Ryuichiro"],"doi":"10.3390/molecules27175405","pmid":"36080170","pmcid":"PMC9458005","publicationDate":"2022-01-24","journal":"Molecules (Basel, Switzerland)","abstract":"The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged as a pandemic and has inflicted enormous damage on the lives of the people and economy of many countries worldwide. However, therapeutic agents against SARS-CoV-2 remain unclear. SARS-CoV-2 has a spike protein (S protein), and cleavage of the S protein is essential for viral entry. Nattokinase is produced by Bacillus subtilis var. natto and is beneficial to human health. In this study, we examined the effect of nattokinase on the S protein of SARS-CoV-2. When cell lysates transfected with S protein were incubated with nattokinase, the S protein was degraded in a dose- and time-dependent manner. Immunofluorescence analysis showed that S protein on the cell surface was degraded when nattokinase was added to the culture medium. Thus, our findings suggest that nattokinase exhibits potential for the inhibition of SARS-CoV-2 infection via S protein degradation.","categories":["therapeutics"],"tags":[],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged as a pandemic and has inflicted enormous damage on the lives of the people and economy of many countries worldwide.","However, therapeutic agents against SARS-CoV-2 remain unclear.","SARS-CoV-2 has a spike protein (S protein), and cleavage of the S protein is essential for viral entry."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":["Nattokinase"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9458005/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/36080170/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-35884770","title":"Immune Response to SARS-CoV-2 Vaccines.","authors":["Bellamkonda Navya","Lambe Upendra Pradeep","Sawant Sonali","Nandi Shyam Sundar","Chakraborty Chiranjib","Shukla Deepak"],"doi":"10.3390/biomedicines10071464","pmid":"35884770","pmcid":"PMC9312515","publicationDate":"2022-01-21","journal":"Biomedicines","abstract":"$9f","categories":["mechanisms"],"tags":["vaccine","mRNA"],"studyType":"review","spikeSource":["both"],"keyFindings":["COVID-19 vaccines have been developed to confer immunity against the SARS-CoV-2 infection.","Prior to the pandemic of COVID-19 which started in March 2020, there was a well-established understanding about the structure and pathogenesis of previously known Coronaviruses from the SARS and MERS outbreaks.","In addition to this, vaccines for various Coronaviruses were available for veterinary use."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9312515/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/35884770/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-36230917","title":"Could Endogenous Glucocorticoids Influence SARS-CoV-2 Infectivity?","authors":["Hardy Eugenio","Fernandez-Patron Carlos"],"doi":"10.3390/cells11192955","pmid":"36230917","pmcid":"PMC9562004","publicationDate":"2022-01-21","journal":"Cells","abstract":"$a0","categories":["mechanisms"],"tags":[],"studyType":"review","spikeSource":["infection"],"keyFindings":["Endogenous glucocorticoids and their synthetic analogues, such as dexamethasone, stimulate receptor-mediated signal transduction mechanisms on target cells.","Some of these mechanisms result in beneficial outcomes whereas others are deleterious in the settings of pathogen infections and immunological disorders.","Here, we review recent studies by several groups, including our group, showing that glucocorticoids can directly interact with protein components on SARS-CoV-2, the causative agent of COVID-19."],"persistenceDuration":null,"mechanisms":["ACE2 binding"],"therapeuticTargets":["Antivirals"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9562004/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/36230917/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-35970046","title":"SARS-CoV-2 spike S1 subunit protein-mediated increase of beta-secretase 1 (BACE1) impairs human brain vessel cells.","authors":["Choi Ji-Young","Park Jung Hyun","Jo Chulman","Kim Kyung-Chang","Koh Young Ho"],"doi":"10.1016/j.bbrc.2022.07.113","pmid":"35970046","pmcid":"PMC9349051","publicationDate":"2022-01-20","journal":"Biochemical and biophysical research communications","abstract":"$a1","categories":["persistence","mechanisms","symptoms"],"tags":["s1-subunit","neuroinflammation"],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["Increasing evidence suggests incomplete recovery of COVID-19 patients, who continue to suffer from cardiovascular diseases, including cerebral vascular disorders (CVD) and neurological symptoms.","Recent findings indicate that some of the damaging effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, especially in the brain, may be induced by the spike protein, leading to the disruption of the initial blood-brain barrier (BBB).","SARS-CoV-2-infected cells and animals exhibit age-dependent pathogenesis."],"persistenceDuration":null,"mechanisms":["endothelial damage","neuroinflammation"],"therapeuticTargets":null,"symptoms":["cardiovascular"],"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9349051/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/35970046/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-35049500","title":"What triggers inflammation in COVID-19?","authors":["Sawa Tomohiro","Akaike Takaaki"],"doi":"10.7554/eLife.76231","pmid":"35049500","pmcid":"PMC8776248","publicationDate":"2022-01-20","journal":"eLife","abstract":"The spike protein of SARS-CoV-2 triggers macrophages and epithelial cells to produce excess levels of pro-inflammatory molecules, which can do more harm than good.","categories":["mechanisms"],"tags":[],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["The spike protein of SARS-CoV-2 triggers macrophages and epithelial cells to produce excess levels of pro-inflammatory molecules, which can do more harm than good."],"persistenceDuration":null,"mechanisms":["inflammation"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8776248/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/35049500/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-36423056","title":"Plant-Produced S1 Subunit Protein of SARS-CoV-2 Elicits Immunogenic Responses in Mice.","authors":["Panapitakkul Chalisa","Khorattanakulchai Narach","Rattanapisit Kaewta","Srisangsung Theerakarn","Shanmugaraj Balamurugan","Buranapraditkun Supranee","Ketloy Chutitorn","Prompetchara Eakachai"],"doi":"10.3390/vaccines10111961","pmid":"36423056","pmcid":"PMC9695278","publicationDate":"2022-01-18","journal":"Vaccines","abstract":"$a2","categories":["mechanisms"],"tags":["vaccine","s1-subunit"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["SARS-CoV-2 is responsible for the ongoing COVID-19 pandemic.","The virus spreads rapidly with a high transmission rate among humans, and hence virus management has been challenging owing to finding specific therapies or vaccinations.","Hence, an effective, low-cost vaccine is urgently required."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9695278/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/36423056/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-35216011","title":"Structural Bases of Zoonotic and Zooanthroponotic Transmission of SARS-CoV-2.","authors":["Clayton Emily","Ackerley Jacob","Aelmans Marianne","Ali Noor","Ashcroft Zoe","Ashton Clara","Barker Robert","Budryte Vakare"],"doi":"10.3390/v14020418","pmid":"35216011","pmcid":"PMC8875863","publicationDate":"2022-01-17","journal":"Viruses","abstract":"The emergence of multiple variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) highlights the importance of possible animal-to-human (zoonotic) and human-to-animal (zooanthroponotic) transmission and potential spread within animal species. A range of animal species have been verified for SARS-CoV-2 susceptibility, either in vitro or in vivo. However, the molecular bases of such a broad host spectrum for the SARS-CoV-2 remains elusive. Here, we structurally and genetically analysed the interaction between the spike protein, with a particular focus on receptor binding domains (RBDs), of SARS-CoV-2 and its receptor angiotensin-converting enzyme 2 (ACE2) for all conceivably susceptible groups of animals to gauge the structural bases of the SARS-CoV-2 host spectrum. We describe our findings in the context of existing animal infection-based models to provide a foundation on the possible virus persistence in animals and their implications in the future eradication of COVID-19.","categories":["persistence","mechanisms"],"tags":[],"studyType":"preclinical","spikeSource":["infection"],"keyFindings":["The emergence of multiple variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) highlights the importance of possible animal-to-human (zoonotic) and human-to-animal (zooanthroponotic) transmission and potential spread within animal species.","A range of animal species have been verified for SARS-CoV-2 susceptibility, either in vitro or in vivo.","However, the molecular bases of such a broad host spectrum for the SARS-CoV-2 remains elusive."],"persistenceDuration":null,"mechanisms":["ACE2 binding"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8875863/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/35216011/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-35329986","title":"Hypersensitivity Myocarditis after COVID-19 mRNA Vaccination.","authors":["Frustaci Andrea","Verardo Romina","Galea Nicola","Lavalle Carlo","Bagnato Giulia","Scialla Rossella","Chimenti Cristina"],"doi":"10.3390/jcm11061660","pmid":"35329986","pmcid":"PMC8949349","publicationDate":"2022-01-16","journal":"Journal of clinical medicine","abstract":"$a3","categories":["persistence","therapeutics","symptoms"],"tags":["vaccine","mRNA","myocarditis"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["BACKGROUND: Myocarditis, even in a severe and lethal form, may occur after COVID-19 mRNA (BNT162b2) vaccination.","However, its pathway, morphomolecular characterization and treatment are still unknown.","METHODS: Routine hematochemical screening, ECG, Holter monitoring, 2D echocardiogram cardiac magnetic resonance (CMR) and invasive cardiac studies (cardiac catheterization, selective coronary angiography, left ventriculography and left ventricular endomyocardial biopsy) are reported from three patients (39F-pt1, 78M-pt2, 52M-pt3) with severe compromise of conduction tissue (junctional rhythm and syncope, pt1) or cardiac function compromise (LVEF ≤ 35%, pt2 and pt3) after COVID-19 mRNA (BNT162b2)."],"persistenceDuration":"Up to 3 days","mechanisms":null,"therapeuticTargets":null,"symptoms":["myocarditis"],"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8949349/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/35329986/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-35697917","title":"Intranasal immunization with a proteosome-adjuvanted SARS-CoV-2 spike protein-based vaccine is immunogenic and efficacious in mice and hamsters.","authors":["Stark Felicity C","Akache Bassel","Deschatelets Lise","Tran Anh","Stuible Matthew","Durocher Yves","McCluskie Michael J","Agbayani Gerard"],"doi":"10.1038/s41598-022-13819-5","pmid":"35697917","pmcid":"PMC9191540","publicationDate":"2022-01-13","journal":"Scientific reports","abstract":"$a4","categories":["persistence"],"tags":["vaccine"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["With the persistence of the SARS-CoV-2 pandemic and the emergence of novel variants, the development of novel vaccine formulations with enhanced immunogenicity profiles could help reduce disease burden in the future.","Intranasally delivered vaccines offer a new modality to prevent SARS-CoV-2 infections through the induction of protective immune responses at the mucosal surface where viral entry occurs.","Herein, we evaluated a novel protein subunit vaccine formulation containing a resistin-trimerized prefusion Spike antigen (SmT1v3) and a proteosome-based mucosal adjuvant (BDX301) formulated to enable intranasal immunization."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9191540/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/35697917/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-36040867","title":"SARS-CoV-2 variant spike and accessory gene mutations alter pathogenesis.","authors":["McGrath Marisa E","Xue Yong","Dillen Carly","Oldfield Lauren","Assad-Garcia N","Zaveri Jayshree","Singh Natasha","Baracco Lauren"],"doi":"10.1073/pnas.2204717119","pmid":"36040867","pmcid":"PMC9477415","publicationDate":"2022-01-13","journal":"Proceedings of the National Academy of Sciences of the United States of America","abstract":"$a5","categories":["persistence","mechanisms"],"tags":["vaccine"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["The ongoing COVID-19 pandemic is a major public health crisis.","Despite the development and deployment of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pandemic persists.","The continued spread of the virus is largely driven by the emergence of viral variants, which can evade the current vaccines through mutations in the spike protein."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9477415/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/36040867/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-36557705","title":"Impaired VEGF-A-Mediated Neurovascular Crosstalk Induced by SARS-CoV-2 Spike Protein: A Potential Hypothesis Explaining Long COVID-19 Symptoms and COVID-19 Vaccine Side Effects?","authors":["Talotta Rossella"],"doi":"10.3390/microorganisms10122452","pmid":"36557705","pmcid":"PMC9784975","publicationDate":"2022-01-12","journal":"Microorganisms","abstract":"$a6","categories":["persistence","mechanisms","symptoms"],"tags":["long-covid","vaccine","neuroinflammation"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["Long coronavirus disease-19 (COVID-19) is a newly discovered syndrome characterized by multiple organ manifestations that persist for weeks to months, following the recovery from acute disease.","Occasionally, neurological and cardiovascular side effects mimicking long COVID-19 have been reported in recipients of COVID-19 vaccines.","Hypothetically, the clinical similarity could be due to a shared pathogenic role of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike (S) protein produced by the virus or used for immunization."],"persistenceDuration":null,"mechanisms":["endothelial damage","neuroinflammation"],"therapeuticTargets":null,"symptoms":["cardiovascular"],"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9784975/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/36557705/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-35774232","title":"Experimental Model of Pulmonary Inflammation Induced by SARS-CoV-2 Spike Protein and Endotoxin.","authors":["Puthia Manoj","Tanner Lloyd","Petruk Ganna","Schmidtchen Artur"],"doi":"10.1021/acsptsci.1c00219","pmid":"35774232","pmcid":"PMC9239546","publicationDate":"2022-01-11","journal":"ACS pharmacology & translational science","abstract":"COVID-19 is characterized by a dysregulated and excessive inflammatory response and, in severe cases, acute respiratory distress syndrome. We have recently demonstrated a previously unknown high-affinity interaction between the SARS-CoV-2 spike (S) protein and bacterial lipopolysaccharide (LPS), leading to the boosting of inflammation. Here we present a mouse inflammation model employing the coadministration of aerosolized S protein together with LPS to the lungs. Using NF-κB-RE-Luc reporter and C57BL/6 mice followed by combinations of bioimaging, cytokine, chemokine, fluorescence-activated cell sorting, and histochemistry analyses, we show that the model yields severe pulmonary inflammation and a cytokine profile similar to that observed in COVID-19. Therefore, the model offers utility for analyses of the pathophysiological features of COVID-19 and the development of new treatments.","categories":["mechanisms","therapeutics"],"tags":[],"studyType":"mouse-model","spikeSource":["infection"],"keyFindings":["COVID-19 is characterized by a dysregulated and excessive inflammatory response and, in severe cases, acute respiratory distress syndrome.","We have recently demonstrated a previously unknown high-affinity interaction between the SARS-CoV-2 spike (S) protein and bacterial lipopolysaccharide (LPS), leading to the boosting of inflammation.","Here we present a mouse inflammation model employing the coadministration of aerosolized S protein together with LPS to the lungs."],"persistenceDuration":null,"mechanisms":["inflammation"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9239546/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/35774232/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-35133792","title":"Emerging Vaccine-Breakthrough SARS-CoV-2 Variants.","authors":["Wang Rui","Chen Jiahui","Hozumi Yuta","Yin Changchuan","Wei Guo-Wei"],"doi":"10.1021/acsinfecdis.1c00557","pmid":"35133792","pmcid":"PMC8848511","publicationDate":"2022-01-11","journal":"ACS infectious diseases","abstract":"$a7","categories":["mechanisms","therapeutics"],"tags":["vaccine"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["The surge of COVID-19 infections has been fueled by new SARS-CoV-2 variants, namely Alpha, Beta, Gamma, Delta, and so forth.","The molecular mechanism underlying such surge is elusive due to the existence of 28 554 unique mutations, including 4 653 non-degenerate mutations on the spike protein.","Understanding the molecular mechanism of SARS-CoV-2 transmission and evolution is a prerequisite to foresee the trend of emerging vaccine-breakthrough variants and the design of mutation-proof vaccines and monoclonal antibodies."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":["Monoclonal antibodies"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8848511/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/35133792/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-35736649","title":"SARS-CoV-2-Induced Pathology-Relevance to COVID-19 Pathophysiology.","authors":["Zinserling Vsevolod A","Semenova Natalia Yu","Bikmurzina Anastasia E","Kruglova Natalia M","Rybalchenko Oksana V","Markov Alexander G"],"doi":"10.3390/pathophysiology29020021","pmid":"35736649","pmcid":"PMC9229620","publicationDate":"2022-01-10","journal":"Pathophysiology : the official journal of the International Society for Pathophysiology","abstract":"$a8","categories":["persistence","mechanisms","symptoms"],"tags":[],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["In spite of intensive studies of different aspects of a new coronavirus infection, many issues still remain unclear.","In a screening analysis of histopathology in l200 lethal cases, authors succeeded in performing a wide spectrum of immune histochemical reactions (CD2, CD 3, CD 4, CD 5, CD 7, CD 8, CD14, CD 20, CD 31, CD 34, CD 56, CD 57, CD 68, CD 163, collagen 1,3, spike protein SARS-CoV-2, caspase-3, MLCM; ACE2 receptor, occludin, and claudin-1 and -3) and electron microscopy.","The results of the histological and IHC studies of deceased people with varying degrees of severity of coronavirus infection confirmed the ability of these pathogens to cause cytoproliferative changes, primarily in epithelial and endothelial cells."],"persistenceDuration":null,"mechanisms":["endothelial damage","autoimmunity","ACE2 binding"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9229620/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/35736649/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-35744711","title":"Advanced Molecular and Immunological Diagnostic Methods to Detect SARS-CoV-2 Infection.","authors":["Rotondo John Charles","Martini Fernanda","Maritati Martina","Caselli Elisabetta","Gallenga Carla Enrica","Guarino Matteo","De Giorgio Roberto","Mazziotta Chiara"],"doi":"10.3390/microorganisms10061193","pmid":"35744711","pmcid":"PMC9231257","publicationDate":"2022-01-10","journal":"Microorganisms","abstract":"$a9","categories":["persistence","symptoms"],"tags":["vaccine"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["COVID-19 emerged in late 2019 in China and quickly spread across the globe, causing over 521 million cases of infection and 6.26 million deaths to date.","After 2 years, numerous advances have been made.","First of all, the preventive vaccine, which has been implemented in record time, is effective in more than 95% of cases."],"persistenceDuration":"Up to 2 years","mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9231257/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/35744711/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-34218284","title":"Long-Term Persistence of Spike Protein Antibody and Predictive Modeling of Antibody Dynamics After Infection With Severe Acute Respiratory Syndrome Coronavirus 2.","authors":["Grandjean Louis","Saso Anja","Torres Ortiz Arturo","Lam Tanya","Hatcher James","Thistlethwayte Rosie","Harris Mark","Best Timothy"],"doi":"10.1093/cid/ciab607","pmid":"34218284","pmcid":"PMC8994590","publicationDate":"2022-01-09","journal":"Clinical infectious diseases : an official publication of the Infectious Diseases Society of America","abstract":"$aa","categories":["persistence","mechanisms","symptoms"],"tags":[],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["BACKGROUND: Antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been shown to neutralize the virus in vitro and prevent disease in animal challenge models on reexposure.","However, the current understanding of SARS-CoV-2 humoral dynamics and longevity is conflicting.","METHODS: The COVID-19 Staff Testing of Antibody Responses Study (Co-Stars) prospectively enrolled 3679 healthcare workers to comprehensively characterize the kinetics of SARS-CoV-2 spike protein (S), receptor-binding domain, and nucleoprotein (N) antibodies in parallel."],"persistenceDuration":"Up to 7 months","mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8994590/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/34218284/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-36555121","title":"SARS-CoV-2 Spike Protein Induces Hemagglutination: Implications for COVID-19 Morbidities and Therapeutics and for Vaccine Adverse Effects.","authors":["Boschi Celine","Scheim David E","Bancod Audrey","Militello Muriel","Bideau Marion Le","Colson Philippe","Fantini Jacques","Scola Bernard La"],"doi":"10.3390/ijms232415480","pmid":"36555121","pmcid":"PMC9779393","publicationDate":"2022-01-07","journal":"International journal of molecular sciences","abstract":"$ab","categories":["persistence","mechanisms","therapeutics"],"tags":["vaccine","mRNA"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["Experimental findings for SARS-CoV-2 related to the glycan biochemistry of coronaviruses indicate that attachments from spike protein to glycoconjugates on the surfaces of red blood cells (RBCs), other blood cells and endothelial cells are key to the infectivity and morbidity of COVID-19.","To provide further insight into these glycan attachments and their potential clinical relevance, the classic hemagglutination (HA) assay was applied using spike protein from the Wuhan, Alpha, Delta and Omicron B.1.1.529 lineages of SARS-CoV-2 mixed with human RBCs.","The electrostatic potential of the central region of spike protein from these four lineages was studied through molecular modeling simulations."],"persistenceDuration":null,"mechanisms":["endothelial damage"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9779393/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/36555121/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-34937699","title":"SARS-CoV-2 spreads through cell-to-cell transmission.","authors":["Zeng Cong","Evans John P","King Tiffany","Zheng Yi-Min","Oltz Eugene M","Whelan Sean P J","Saif Linda J","Peeples Mark E"],"doi":"10.1073/pnas.2111400119","pmid":"34937699","pmcid":"PMC8740724","publicationDate":"2022-01-04","journal":"Proceedings of the National Academy of Sciences of the United States of America","abstract":"$ac","categories":["mechanisms","therapeutics"],"tags":["vaccine"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible coronavirus responsible for the global COVID-19 pandemic.","Herein, we provide evidence that SARS-CoV-2 spreads through cell-cell contact in cultures, mediated by the spike glycoprotein.","SARS-CoV-2 spike is more efficient in facilitating cell-to-cell transmission than is SARS-CoV spike, which reflects, in part, their differential cell-cell fusion activity."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8740724/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/34937699/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-34983527","title":"Monoclonal antibodies for COVID-19 therapy and SARS-CoV-2 detection.","authors":["Hwang Yu-Chyi","Lu Ruei-Min","Su Shih-Chieh","Chiang Pao-Yin","Ko Shih-Han","Ke Feng-Yi","Liang Kang-Hao","Hsieh Tzung-Yang"],"doi":"10.1186/s12929-021-00784-w","pmid":"34983527","pmcid":"PMC8724751","publicationDate":"2022-01-04","journal":"Journal of biomedical science","abstract":"$ad","categories":["mechanisms","therapeutics"],"tags":["vaccine"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["The coronavirus disease 2019 (COVID-19) pandemic is an exceptional public health crisis that demands the timely creation of new therapeutics and viral detection.","Owing to their high specificity and reliability, monoclonal antibodies (mAbs) have emerged as powerful tools to treat and detect numerous diseases.","Hence, many researchers have begun to urgently develop Ab-based kits for the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Ab drugs for use as COVID-19 therapeutic agents."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":["Monoclonal antibodies"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8724751/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/34983527/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-35704748","title":"Potent human broadly SARS-CoV-2-neutralizing IgA and IgG antibodies effective against Omicron BA.1 and BA.2.","authors":["Planchais Cyril","Fernández Ignacio","Bruel Timothée","de Melo Guilherme Dias","Prot Matthieu","Beretta Maxime","Guardado-Calvo Pablo","Dufloo Jérémy"],"doi":"10.1084/jem.20220638","pmid":"35704748","pmcid":"PMC9206116","publicationDate":"2022-01-04","journal":"The Journal of experimental medicine","abstract":"$ae","categories":["persistence","mechanisms","therapeutics"],"tags":[],"studyType":"mouse-model","spikeSource":["infection"],"keyFindings":["Memory B-cell and antibody responses to the SARS-CoV-2 spike protein contribute to long-term immune protection against severe COVID-19, which can also be prevented by antibody-based interventions.","Here, wide SARS-CoV-2 immunoprofiling in Wuhan COVID-19 convalescents combining serological, cellular, and monoclonal antibody explorations revealed humoral immunity coordination.","Detailed characterization of a hundred SARS-CoV-2 spike memory B-cell monoclonal antibodies uncovered diversity in their repertoire and antiviral functions."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":["Monoclonal antibodies","Antivirals"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9206116/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/35704748/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-35180381","title":"Respiratory mucosal delivery of next-generation COVID-19 vaccine provides robust protection against both ancestral and variant strains of SARS-CoV-2.","authors":["Afkhami Sam","D'Agostino Michael R","Zhang Ali","Stacey Hannah D","Marzok Art","Kang Alisha","Singh Ramandeep","Bavananthasivam Jegarubee"],"doi":"10.1016/j.cell.2022.02.005","pmid":"35180381","pmcid":"PMC8825346","publicationDate":"2022-01-03","journal":"Cell","abstract":"$af","categories":["persistence"],"tags":["vaccine"],"studyType":"mouse-model","spikeSource":["both"],"keyFindings":["The emerging SARS-CoV-2 variants of concern (VOCs) threaten the effectiveness of current COVID-19 vaccines administered intramuscularly and designed to only target the spike protein.","There is a pressing need to develop next-generation vaccine strategies for broader and long-lasting protection.","Using adenoviral vectors (Ad) of human and chimpanzee origin, we evaluated Ad-vectored trivalent COVID-19 vaccines expressing spike-1, nucleocapsid, and RdRp antigens in murine models."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8825346/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/35180381/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-35214693","title":"SARS-CoV-2-Specific Vaccine Candidates; the Contribution of Structural Vaccinology.","authors":["Pack Su Min","Peters Peter J"],"doi":"10.3390/vaccines10020236","pmid":"35214693","pmcid":"PMC8877865","publicationDate":"2022-01-03","journal":"Vaccines","abstract":"SARS-CoV-2 vaccine production has taken us by storm. We aim to fill in the history of concepts and the work of pioneers and provide a framework of strategies employing structural vaccinology. Cryo-electron microscopy became crucial in providing three-dimensional (3D) structures and creating candidates eliciting T and B cell-mediated immunity. It also determined structural changes in the emerging mutants in order to design new constructs that can be easily, quickly and safely added to the vaccines. The full-length spike (S) protein, the S1 subunit and its receptor binding domain (RBD) of the virus are the best candidates. The vaccine development to cease this COVID-19 pandemic sets a milestone for the pan-coronavirus vaccine's designing and manufacturing. By employing structural vaccinology, we propose that the mRNA and the protein sequences of the currently approved vaccines should be modified rapidly to keep up with the more infectious new variants.","categories":["mechanisms"],"tags":["vaccine","s1-subunit","mRNA"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["SARS-CoV-2 vaccine production has taken us by storm.","We aim to fill in the history of concepts and the work of pioneers and provide a framework of strategies employing structural vaccinology.","Cryo-electron microscopy became crucial in providing three-dimensional (3D) structures and creating candidates eliciting T and B cell-mediated immunity."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8877865/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/35214693/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-35163638","title":"SARS-CoV-2-Specific Immune Response and the Pathogenesis of COVID-19.","authors":["Gusev Evgenii","Sarapultsev Alexey","Solomatina Liliya","Chereshnev Valeriy"],"doi":"10.3390/ijms23031716","pmid":"35163638","pmcid":"PMC8835786","publicationDate":"2022-01-02","journal":"International journal of molecular sciences","abstract":"$b0","categories":["persistence","mechanisms"],"tags":[],"studyType":"review","spikeSource":["infection"],"keyFindings":["The review aims to consolidate research findings on the molecular mechanisms and virulence and pathogenicity characteristics of coronavirus disease (COVID-19) causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and their relevance to four typical stages in the development of acute viral infection.","These four stages are invasion; primary blockade of antiviral innate immunity; engagement of the virus's protection mechanisms against the factors of adaptive immunity; and acute, long-term complications of COVID-19.","The invasion stage entails the recognition of the spike protein (S) of SARS-CoV-2 target cell receptors, namely, the main receptor (angiotensin-converting enzyme 2, ACE2), its coreceptors, and potential alternative receptors."],"persistenceDuration":null,"mechanisms":["inflammation","autoimmunity","ACE2 binding"],"therapeuticTargets":["Antivirals"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8835786/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/35163638/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-34997294","title":"Cutting Edge: Circulating Exosomes with COVID Spike Protein Are Immunogenic and Potentially Contribute to the Immune Response in COVID-19","authors":["Bansal S","Perincheri S","Rodgers R"],"doi":"10.4049/jimmunol.2100638","pmid":"34997294","publicationDate":"2022-01-01","journal":"Journal of Immunology","abstract":"Exosomal spike protein is immunogenic and may propagate inflammatory signaling.","summary":"Exosomes carrying spike can trigger immune responses; proposed mechanism for sustained inflammation.","categories":["mechanisms"],"tags":["exosomes","inflammation"],"studyType":"preclinical","spikeSource":["infection","both"],"keyFindings":["Exosomal spike is immunogenic","May contribute to sustained immune activation","Potential vector for systemic inflammatory signaling"],"mechanisms":["inflammation","exosomal signaling"],"pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/34997294/","reviewed":true,"lastUpdated":"2026-07-06"},{"id":"pmid-35677080","title":"SARS-CoV-2 Variant Spike and accessory gene mutations alter pathogenesis.","authors":["McGrath M E","Xue Y","Dillen C","Oldfield L","Assad-Garcia N","Zaveri J","Singh N","Baracco L"],"doi":"10.1101/2022.05.31.494211","pmid":"35677080","pmcid":"PMC9176647","publicationDate":"2022-01-01","journal":"bioRxiv : the preprint server for biology","abstract":"$b1","categories":["persistence","mechanisms"],"tags":["vaccine"],"studyType":"preclinical","spikeSource":["both"],"keyFindings":["UNLABELLED: The ongoing COVID-19 pandemic is a major public health crisis.","Despite the development and deployment of vaccines against SARS-CoV-2, the pandemic persists.","The continued spread of the virus is largely driven by the emergence of viral variants, which can evade the current vaccines through mutations in the Spike protein."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9176647/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/35677080/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-35168246","title":"Germinal centre-driven maturation of B cell response to mRNA vaccination.","authors":["Kim Wooseob","Zhou Julian Q","Horvath Stephen C","Schmitz Aaron J","Sturtz Alexandria J","Lei Tingting","Liu Zhuoming","Kalaidina Elizaveta"],"doi":"10.1038/s41586-022-04527-1","pmid":"35168246","pmcid":"PMC9204750","publicationDate":"2022-01-01","journal":"Nature","abstract":"$b2","categories":["persistence","mechanisms","therapeutics"],"tags":["vaccine","mRNA"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["Germinal centres (GC) are lymphoid structures in which B cells acquire affinity-enhancing somatic hypermutations (SHM), with surviving clones differentiating into memory B cells (MBCs) and long-lived bone marrow plasma cells1-5 (BMPCs).","SARS-CoV-2 mRNA vaccination induces a persistent GC response that lasts for at least six months in humans6-8.","The fate of responding GC B cells as well as the functional consequences of such persistence remain unknown."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":["Monoclonal antibodies"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9204750/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/35168246/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-34915155","title":"SARS-CoV-2 spike S1 subunit induces neuroinflammatory, microglial and behavioral sickness responses: Evidence of PAMP-like properties.","authors":["Frank Matthew G","Nguyen Kathy H","Ball Jayson B","Hopkins Shelby","Kelley Tel","Baratta Michael V","Fleshner Monika","Maier Steven F"],"doi":"10.1016/j.bbi.2021.12.007","pmid":"34915155","pmcid":"PMC8667429","publicationDate":"2022-01-01","journal":"Brain, behavior, and immunity","abstract":"$b3","categories":["persistence","mechanisms","therapeutics","symptoms"],"tags":["s1-subunit","neuroinflammation"],"studyType":"preclinical","spikeSource":["infection"],"keyFindings":["SARS-CoV-2 infection produces neuroinflammation as well as neurological, cognitive (i.e., brain fog), and neuropsychiatric symptoms (e.g., depression, anxiety), which can persist for an extended period (6 months) after resolution of the infection.","The neuroimmune mechanism(s) that produces SARS-CoV-2-induced neuroinflammation has not been characterized.","Proposed mechanisms include peripheral cytokine signaling to the brain and/or direct viral infection of the CNS."],"persistenceDuration":"Up to 6 months","mechanisms":["inflammation","neuroinflammation"],"therapeuticTargets":null,"symptoms":["brain fog","cognitive dysfunction"],"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8667429/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/34915155/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-35967905","title":"Adenovirus-vectored SARS-CoV-2 vaccine expressing S1-N fusion protein.","authors":["Khan Muhammad S","Kim Eun","McPherson Alex","Weisel Florian J","Huang Shaohua","Kenniston Thomas W","Percivalle Elena","Cassaniti Irene"],"doi":"10.1093/abt/tbac015","pmid":"35967905","pmcid":"PMC9372896","publicationDate":"2022-01-01","journal":"Antibody therapeutics","abstract":"$b4","categories":["mechanisms"],"tags":["vaccine","s1-subunit"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["Additional COVID-19 vaccines that are safe and immunogenic are needed for global vaccine equity.","Here, we developed a recombinant type 5 adenovirus vector encoding for the SARS-CoV-2 S1 subunit antigen and nucleocapsid as a fusion protein (Ad5.SARS-CoV-2-S1N).","A single subcutaneous immunization with Ad5.SARS-CoV-2-S1N induced a similar humoral response, along with a significantly higher S1-specific cellular response, as a recombinant type 5 adenovirus vector encoding for S1 alone (Ad5.SARS-CoV-2-S1)."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9372896/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/35967905/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-35314834","title":"Eicosanoid signalling blockade protects middle-aged mice from severe COVID-19.","authors":["Wong Lok-Yin Roy","Zheng Jian","Wilhelmsen Kevin","Li Kun","Ortiz Miguel E","Schnicker Nicholas J","Thurman Andrew","Pezzulo Alejandro A"],"doi":"10.1038/s41586-022-04630-3","pmid":"35314834","pmcid":"PMC9783543","publicationDate":"2022-01-01","journal":"Nature","abstract":"$b5","categories":["persistence","mechanisms","therapeutics"],"tags":["vaccine","mRNA"],"studyType":"mouse-model","spikeSource":["both"],"keyFindings":["Coronavirus disease 2019 (COVID-19) is especially severe in aged populations1.","Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are highly effective, but vaccine efficacy is partly compromised by the emergence of SARS-CoV-2 variants with enhanced transmissibility2.","The emergence of these variants emphasizes the need for further development of anti-SARS-CoV-2 therapies, especially for aged populations."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9783543/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/35314834/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-35397075","title":"Spike protein of SARS-CoV-2 variants: a brief review and practical implications.","authors":["Candido Kattlyn Laryssa","Eich Caio Ricardo","de Fariña Luciana Oliveira","Kadowaki Marina Kimiko","da Conceição Silva José Luis","Maller Alexandre","Simão Rita de Cássia Garcia"],"doi":"10.1007/s42770-022-00743-z","pmid":"35397075","pmcid":"PMC8994061","publicationDate":"2022-01-01","journal":"Brazilian journal of microbiology : [publication of the Brazilian Society for Microbiology]","abstract":"The scientific community has been alarmed by the possible immunological evasion, higher infectivity, and severity of disease caused by the newest variants of SARS-CoV-2. The spike protein has an important role in the cellular invasion of viruses and is the target of several vaccines and therapeutic resources, such as monoclonal antibodies. In addition, some of the most relevant mutations in the different variants are on the spike (S) protein gene sequence that leads to structural alterations in the predicted protein, thus causing concern about the protection mediated by vaccines against these new strains. The present review highlights the most recent knowledge about COVID-19 and vaccines, emphasizing the different spike protein structures of SARS-CoV-2 and updating the reader about the emerging viral variants and their classifications, the more common viral mutations described and their distribution in Brazil. It also compiles a table with the most recent knowledge about all of the Omicron spike mutations.","categories":["therapeutics"],"tags":["vaccine"],"studyType":"review","spikeSource":["both"],"keyFindings":["The scientific community has been alarmed by the possible immunological evasion, higher infectivity, and severity of disease caused by the newest variants of SARS-CoV-2.","The spike protein has an important role in the cellular invasion of viruses and is the target of several vaccines and therapeutic resources, such as monoclonal antibodies.","In addition, some of the most relevant mutations in the different variants are on the spike (S) protein gene sequence that leads to structural alterations in the predicted protein, thus causing concern about the protection mediated by vaccines against these new strains."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":["Monoclonal antibodies"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8994061/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/35397075/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-36072173","title":"Neurological Complications of COVID-19: A Review of the Literature.","authors":["Dale Lucy"],"doi":"10.7759/cureus.27633","pmid":"36072173","pmcid":"PMC9438291","publicationDate":"2022-01-01","journal":"Cureus","abstract":"Coronavirus disease 2019 (COVID-19) has caused the most unprecedented health crisis since the 1918 H1N1 pandemic. Whilst COVID-19 is traditionally considered to be a respiratory disease, it is important to understand that this virus has the potential to disseminate throughout the body causing multi-organ failure. Both peripheral and central neurological systems have been shown to be greatly affected. This review aims to look at the available literature published on COVID-19 and summarize the main neurological complications seen so far.","categories":["mechanisms"],"tags":["neuroinflammation"],"studyType":"review","spikeSource":["infection"],"keyFindings":["Coronavirus disease 2019 (COVID-19) has caused the most unprecedented health crisis since the 1918 H1N1 pandemic.","Whilst COVID-19 is traditionally considered to be a respiratory disease, it is important to understand that this virus has the potential to disseminate throughout the body causing multi-organ failure.","Both peripheral and central neurological systems have been shown to be greatly affected."],"persistenceDuration":null,"mechanisms":["neuroinflammation"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9438291/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/36072173/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-35372556","title":"A Spike Protein-Based Subunit SARS-CoV-2 Vaccine for Pets: Safety, Immunogenicity, and Protective Efficacy in Juvenile Cats.","authors":["Tabynov Kairat","Orynbassar Madiana","Yelchibayeva Leila","Turebekov Nurkeldi","Yerubayev Toktassyn","Matikhan Nurali","Yespolov Tlektes","Petrovsky Nikolai"],"doi":"10.3389/fvets.2022.815978","pmid":"35372556","pmcid":"PMC8967242","publicationDate":"2022-01-01","journal":"Frontiers in veterinary science","abstract":"$b6","categories":["persistence","therapeutics"],"tags":["vaccine"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["Whereas, multiple vaccine types have been developed to curb the spread of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) among humans, there are very few vaccines being developed for animals including pets.","To combat the threat of human-to-animal, animal-to-animal, and animal-to-human transmission and the generation of new virus variants, we developed a subunit SARS-CoV-2 vaccine which is based on the recombinant spike protein extracellular domain expressed in insect cells and then formulated with appropriate adjuvants.","Sixteen 8-12-week-old outbred female and male kittens (n = 4 per group) were randomly assigned into four treatment groups: spike protein alone; spike plus ESSAI oil-in-water (O/W) 1849102 adjuvant; spike plus aluminum hydroxide adjuvant; and a PBS control."],"persistenceDuration":"Up to 2 weeks","mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8967242/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/35372556/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-35320941","title":"SARS-CoV-2 Spike Protein 1 Activates Microvascular Endothelial Cells and Complement System Leading to Platelet Aggregation.","authors":["Perico Luca","Morigi Marina","Galbusera Miriam","Pezzotta Anna","Gastoldi Sara","Imberti Barbara","Perna Annalisa","Ruggenenti Piero"],"doi":"10.3389/fimmu.2022.827146","pmid":"35320941","pmcid":"PMC8936079","publicationDate":"2022-01-01","journal":"Frontiers in immunology","abstract":"$b7","categories":["mechanisms"],"tags":[],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["Microvascular thrombosis is associated with multiorgan failure and mortality in coronavirus disease 2019 (COVID-19).","Although thrombotic complications may be ascribed to the ability of SARS-CoV-2 to infect and replicate in endothelial cells, it has been poorly investigated whether, in the complexity of viral infection in the human host, specific viral elements alone can induce endothelial damage.","Detection of circulating spike protein in the sera of severe COVID-19 patients was evaluated by ELISA."],"persistenceDuration":null,"mechanisms":["endothelial damage","complement activation","ACE2 binding"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8936079/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/35320941/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-35773398","title":"Neutralization mechanism of a human antibody with pan-coronavirus reactivity including SARS-CoV-2.","authors":["Sun Xiaoyu","Yi Chunyan","Zhu Yuanfei","Ding Longfei","Xia Shuai","Chen Xingchen","Liu Mu","Gu Chenjian"],"doi":"10.1038/s41564-022-01155-3","pmid":"35773398","pmcid":"7095418","publicationDate":"2022-01-01","journal":"Nature microbiology","abstract":"$b8","categories":["mechanisms","therapeutics"],"tags":["vaccine"],"studyType":"mouse-model","spikeSource":["both"],"keyFindings":["Frequent outbreaks of coronaviruses underscore the need for antivirals and vaccines that can counter a broad range of coronavirus types.","We isolated a human antibody named 76E1 from a COVID-19 convalescent patient, and report that it has broad-range neutralizing activity against multiple α- and β-coronaviruses, including the SARS-CoV-2 variants.","76E1 also binds its epitope in peptides from γ- and δ-coronaviruses."],"persistenceDuration":null,"mechanisms":["ACE2 binding"],"therapeuticTargets":["Antivirals"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/7095418/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/35773398/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-35405186","title":"Placental pathology from COVID-19-recovered (nonacute) patients.","authors":["Boyraz Baris","James Kaitlyn","Hornick Jason L","Roberts Drucilla J"],"doi":"10.1016/j.humpath.2022.04.005","pmid":"35405186","pmcid":"PMC8993452","publicationDate":"2022-01-01","journal":"Human pathology","abstract":"$b9","categories":["persistence"],"tags":[],"studyType":"review","spikeSource":["infection"],"keyFindings":["Placental pathology can identify characteristic features of specific infectious pathogens.","The histopathology of acute SARS-CoV-2 placental infection and exposure without infection has been well described.","However, whether the characteristic placental pathology persists after the acute phase of the infection is less clear."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8993452/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/35405186/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-34994337","title":"Monoclonal Antibodies and their Target Specificity Against SARS-CoV-2 Infections: Perspectives and Challenges.","authors":["Bakkari Mohammed A","Moni Sivakumar Sivagurunathan","Sultan Muhammad Hadi","Madkhali Osama A"],"doi":"10.2174/1872208316666220106110014","pmid":"34994337","pmcid":null,"publicationDate":"2022-01-01","journal":"Recent patents on biotechnology","abstract":"$ba","categories":["mechanisms","therapeutics"],"tags":[],"studyType":"review","spikeSource":["infection"],"keyFindings":["The world continues to be in the midst of a distressing pandemic of coronavirus disease 2019 (COVID-19) infection caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a novel virus with multiple antigenic systems.","The virus enters via nasopharynx, oral and infects cells by the expression of the spike protein, and enters the lungs using the angiotensin-converting enzyme-2 receptor.","The spectrum of specific immune responses to SARS-CoV-2 virus infection is increasingly challenging as frequent mutations have been reported and their antigen specificity varies accordingly."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":["Monoclonal antibodies"],"symptoms":null,"pdfUrl":null,"pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/34994337/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-36260961","title":"The Omicron variant of concern: Diversification and convergent evolution in spike protein, and escape from anti-Spike monoclonal antibodies.","authors":["Focosi Daniele","McConnell Scott","Casadevall Arturo"],"doi":"10.1016/j.drup.2022.100882","pmid":"36260961","pmcid":"PMC9528072","publicationDate":"2022-01-01","journal":"Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy","abstract":"WHO-defined SARS-CoV-2 variants of concern (VOC) drive therapeutics and vaccine development. The Omicron VOC is dominating the arena since November 2021, but the number of its sublineages is growing in complexity. Omicron represent a galaxy with a myriad of stars that suddenly rise and expand before collapsing into apparent extinction when a more fit sublineage appears. This has already happened with BA.1, BA.2, and BA.4/5 and is happening with BA.2.75. We review here the current PANGO phylogeny, focusing on sublineages with Spike mutations, and show how frequently xxxxxxxx convergent evolution has occurred in these sublineages. We finally summarize how Omicron evolution has progressively defeated the anti-Spike monoclonal antibodies authorized so far, leaving clinicians to again fall back on COVID19 convalescent plasma from vaccinated donors as the only antibody-based therapy available.","categories":["therapeutics"],"tags":["vaccine"],"studyType":"review","spikeSource":["both"],"keyFindings":["WHO-defined SARS-CoV-2 variants of concern (VOC) drive therapeutics and vaccine development.","The Omicron VOC is dominating the arena since November 2021, but the number of its sublineages is growing in complexity.","Omicron represent a galaxy with a myriad of stars that suddenly rise and expand before collapsing into apparent extinction when a more fit sublineage appears."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":["Monoclonal antibodies"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9528072/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/36260961/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-35392091","title":"The S1 Subunit of the SARS-CoV-2 Spike Protein Activates Human Monocytes to Produce Cytokines Linked to COVID-19: Relevance to Galectin-3.","authors":["Schroeder John T","Bieneman Anja P"],"doi":"10.3389/fimmu.2022.831763","pmid":"35392091","pmcid":"PMC8982143","publicationDate":"2022-01-01","journal":"Frontiers in immunology","abstract":"$bb","categories":["persistence","mechanisms","therapeutics"],"tags":["vaccine","s1-subunit"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), rapidly evolved into a pandemic -the likes of which has not been experienced in 100 years.","While novel vaccines show great efficacy, and therapeutics continue to be developed, the persistence of disease, with the concomitant threat of emergent variants, continues to impose massive health and socioeconomic issues worldwide.","Studies show that in susceptible individuals, SARS-CoV-2 infection can rapidly progress toward lung injury and acute respiratory distress syndrome (ARDS), with evidence for an underlying dysregulated innate immune response or cytokine release syndrome (CRS)."],"persistenceDuration":"Up to 100 years","mechanisms":["ACE2 binding"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8982143/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/35392091/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-35289434","title":"Advances in the Omicron variant development.","authors":["Vitiello Antonio","Ferrara Francesco","Auti Amogh M","Di Domenico Marina","Boccellino Mariarosaria"],"doi":"10.1111/joim.13478","pmid":"35289434","pmcid":"PMC9115048","publicationDate":"2022-01-01","journal":"Journal of internal medicine","abstract":"$bc","categories":["mechanisms","therapeutics"],"tags":["vaccine"],"studyType":"review","spikeSource":["both"],"keyFindings":["Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 has spread worldwide, leading the World Health Organization (WHO) to declare a pandemic, on 11 March 2020.","Variants of concern have appeared at regular intervals-Alpha, Beta, Gamma, Delta, and now Omicron.","Omicron variant, first identified in Botswana in November 2021, is rapidly becoming the dominant circulating variant."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":["Monoclonal antibodies","Antivirals"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9115048/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/35289434/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-35803289","title":"Monoclonal antibody therapies against SARS-CoV-2.","authors":["Focosi Daniele","McConnell Scott","Casadevall Arturo","Cappello Emiliano","Valdiserra Giulia","Tuccori Marco"],"doi":"10.1016/S1473-3099(22)00311-5","pmid":"35803289","pmcid":"PMC9255948","publicationDate":"2022-01-01","journal":"The Lancet. Infectious diseases","abstract":"Monoclonal antibodies (mAbs) targeting the spike protein of SARS-CoV-2 have been widely used in the ongoing COVID-19 pandemic. In this paper, we review the properties of mAbs and their effect as therapeutics in the pandemic, including structural classification, outcomes in clinical trials that led to the authorisation of mAbs, and baseline and treatment-emergent immune escape. We show how the omicron (B.1.1.529) variant of concern has reset treatment strategies so far, discuss future developments that could lead to improved outcomes, and report the intrinsic limitations of using mAbs as therapeutic agents.","categories":["therapeutics"],"tags":[],"studyType":"review","spikeSource":["infection"],"keyFindings":["Monoclonal antibodies (mAbs) targeting the spike protein of SARS-CoV-2 have been widely used in the ongoing COVID-19 pandemic.","In this paper, we review the properties of mAbs and their effect as therapeutics in the pandemic, including structural classification, outcomes in clinical trials that led to the authorisation of mAbs, and baseline and treatment-emergent immune escape.","We show how the omicron (B.1.1.529) variant of concern has reset treatment strategies so far, discuss future developments that could lead to improved outcomes, and report the intrinsic limitations of using mAbs as therapeutic agents."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":["Monoclonal antibodies"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9255948/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/35803289/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-35028901","title":"Could SARS-CoV-2 Spike Protein Be Responsible for Long-COVID Syndrome?","authors":["Theoharides Theoharis C"],"doi":"10.1007/s12035-021-02696-0","pmid":"35028901","pmcid":"PMC8757925","publicationDate":"2022-01-01","journal":"Molecular neurobiology","abstract":"$bd","categories":["persistence","mechanisms","symptoms"],"tags":["vaccine","mRNA","neuroinflammation"],"studyType":"mouse-model","spikeSource":["both"],"keyFindings":["SARS-CoV-2 infects cells via its spike protein binding to its surface receptor on target cells and results in acute symptoms involving especially the lungs known as COVID-19.","However, increasing evidence indicates that many patients develop a chronic condition characterized by fatigue and neuropsychiatric symptoms, termed long-COVID.","Most of the vaccines produced so far for COVID-19 direct mammalian cells via either mRNA or an adenovirus vector to express the spike protein, or administer recombinant spike protein, which is recognized by the immune system leading to the production of neutralizing antibodies."],"persistenceDuration":null,"mechanisms":["inflammation","neuroinflammation","autoimmunity"],"therapeuticTargets":null,"symptoms":["fatigue"],"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8757925/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/35028901/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-35446889","title":"Long-term persistence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein-specific and neutralizing antibodies in recovered COVID-19 patients.","authors":["Chansaenroj Jira","Yorsaeng Ritthideach","Puenpa Jiratchaya","Wanlapakorn Nasamon","Chirathaworn Chintana","Sudhinaraset Natthinee","Sripramote Manit","Chalongviriyalert Piti"],"doi":"10.1371/journal.pone.0267102","pmid":"35446889","pmcid":"PMC9022880","publicationDate":"2022-01-01","journal":"PloS one","abstract":"$be","categories":["persistence","mechanisms","symptoms"],"tags":["vaccine"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["Understanding antibody responses after natural severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can guide the coronavirus disease 2019 (COVID-19) vaccine schedule, especially in resource-limited settings.","This study aimed to assess the dynamics of SARS-CoV-2 antibodies, including anti-spike protein 1 (S1) immunoglobulin (Ig)G, anti-receptor-binding domain (RBD) total Ig, anti-S1 IgA, and neutralizing antibody against wild-type SARS-CoV-2 over time in a cohort of patients who were previously infected with the wild-type SARS-CoV-2.","Between March and May 2020, 531 individuals with virologically confirmed cases of wild-type SARS-CoV-2 infection were enrolled in our immunological study."],"persistenceDuration":"Up to 12 months","mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9022880/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/35446889/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-34811761","title":"Emerging SARS-CoV-2 variants can potentially break set epidemiological barriers in COVID-19.","authors":["Kumar Ashutosh","Parashar Rakesh","Kumar Sujeet","Faiq Muneeb A","Kumari Chiman","Kulandhasamy Maheswari","Narayan Ravi K","Jha Rakesh K"],"doi":"10.1002/jmv.27467","pmid":"34811761","pmcid":"PMC9011477","publicationDate":"2022-01-01","journal":"Journal of medical virology","abstract":"$bf","categories":["persistence","mechanisms"],"tags":["vaccine"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["Young age, female sex, absence of comorbidities, and prior infection or vaccination are known epidemiological barriers for contracting the new infection and/or increased disease severity.","Demographic trends from the recent coronavirus disease 2019 waves, which are believed to be driven by newer severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, indicate that the aforementioned epidemiological barriers are being breached and a larger number of younger and healthy individuals are developing severe disease.","The new SARS-CoV-2 variants have key mutations that can induce significant changes in the virus-host interactions."],"persistenceDuration":null,"mechanisms":["inflammation","ACE2 binding"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9011477/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/34811761/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-35598822","title":"Native, engineered and de novo designed ligands targeting the SARS-CoV-2 spike protein.","authors":["Costa Carlos F S","Barbosa Arménio J M","Dias Ana Margarida G C","Roque Ana Cecília A"],"doi":"10.1016/j.biotechadv.2022.107986","pmid":"35598822","pmcid":"PMC9119173","publicationDate":"2022-01-01","journal":"Biotechnology advances","abstract":"$c0","categories":["mechanisms","therapeutics"],"tags":["vaccine"],"studyType":"review","spikeSource":["both"],"keyFindings":["The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the deadly coronavirus disease 2019 (Covid-19) and is a concerning hazard to public health.","This virus infects cells by establishing a contact between its spike protein (S-protein) and host human angiotensin-converting enzyme 2 (hACE2) receptor, subsequently initiating viral fusion.","The inhibition of the interaction between the S-protein and hACE2 has immediately drawn attention amongst the scientific community, and the S-protein was considered the prime target to design vaccines and to develop affinity ligands for diagnostics and therapy."],"persistenceDuration":null,"mechanisms":["ACE2 binding"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9119173/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/35598822/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-36376393","title":"Safety and immunogenicity of a prefusion non-stabilized spike protein mRNA COVID-19 vaccine: a phase I trial.","authors":["Gatechompol Sivaporn","Kittanamongkolchai Wonngarm","Ketloy Chutitorn","Prompetchara Eakchai","Thitithanyanont Arunee","Jongkaewwattana Anan","Buranapraditkun Supranee","Alameh Mohamad-Gabriel"],"doi":"10.1038/s41564-022-01271-0","pmid":"36376393","pmcid":"8386155","publicationDate":"2022-01-01","journal":"Nature microbiology","abstract":"$c1","categories":["persistence","symptoms"],"tags":["vaccine","mRNA"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["Effective mRNA SARS-CoV-2 vaccines are available but need to be stored in freezers, limiting their use to countries that have appropriate storage capacity.","ChulaCov19 is a prefusion non-stabilized SARS-CoV-2 spike-protein-encoding, nucleoside-modified mRNA, lipid nanoparticle encapsulated vaccine that we report to be stable when stored at 2-8 °C for up to 3 months.","Here we report safety and immunogenicity data from a phase I open-label, dose escalation, first-in-human trial of the ChulaCov19 vaccine (NCT04566276)."],"persistenceDuration":"Up to 3 months","mechanisms":null,"therapeuticTargets":null,"symptoms":["fatigue"],"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/8386155/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/36376393/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-37193049","title":"Emerging SARS-CoV-2 variants: Why, how, and what's next?","authors":["Chen Yu","Liu Qianyun","Zhou Li","Zhou You","Yan Huan","Lan Ke"],"doi":"10.1016/j.cellin.2022.100029","pmid":"37193049","pmcid":"PMC9057926","publicationDate":"2022-01-01","journal":"Cell insight","abstract":"The emergence of the SARS-CoV-2 Omicron variant poses a striking threat to human society. More than 30 mutations in the Spike protein of the Omicron variant severely compromised the protective immunity elicited by either vaccination or prior infection. The persistent viral evolutionary trajectory generates Omicron-associated lineages, such as BA.1 and BA.2. Moreover, the virus recombination upon Delta and Omicron co-infections has been reported lately, although the impact remains to be assessed. This minireview summarizes the characteristics, evolution and mutation control, and immune evasion mechanisms of SARS-CoV-2 variants, which will be helpful for the in-depth understanding of the SARS-CoV-2 variants and policy-making related to COVID-19 pandemic control.","categories":["persistence","mechanisms"],"tags":["vaccine"],"studyType":"review","spikeSource":["both"],"keyFindings":["The emergence of the SARS-CoV-2 Omicron variant poses a striking threat to human society.","More than 30 mutations in the Spike protein of the Omicron variant severely compromised the protective immunity elicited by either vaccination or prior infection.","The persistent viral evolutionary trajectory generates Omicron-associated lineages, such as BA.1 and BA.2."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9057926/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/37193049/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-35356515","title":"Understanding the Role of SARS-CoV-2 ORF3a in Viral Pathogenesis and COVID-19.","authors":["Zhang Jiantao","Ejikemeuwa Amara","Gerzanich Volodymyr","Nasr Mohamed","Tang Qiyi","Simard J Marc","Zhao Richard Y"],"doi":"10.3389/fmicb.2022.854567","pmid":"35356515","pmcid":"PMC8959714","publicationDate":"2022-01-01","journal":"Frontiers in microbiology","abstract":"$c2","categories":["persistence","mechanisms"],"tags":[],"studyType":"review","spikeSource":["infection"],"keyFindings":["The ongoing SARS-CoV-2 pandemic has shocked the world due to its persistence, COVID-19-related morbidity and mortality, and the high mutability of the virus.","One of the major concerns is the emergence of new viral variants that may increase viral transmission and disease severity.","In addition to mutations of spike protein, mutations of viral proteins that affect virulence, such as ORF3a, also must be considered."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8959714/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/35356515/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-35287384","title":"PQQ Supplementation and SARS-CoV-2 Spike Protein-Induced Heart Inflammation.","authors":["Boretti Alberto"],"doi":"10.1177/1934578X221080929","pmid":"35287384","pmcid":"PMC8905048","publicationDate":"2022-01-01","journal":"Natural product communications","abstract":"SARS-CoV-2 spike protein-induced heart inflammation may originate from either COVID-19 infection or the administration of COVID-19 mRNA vaccines. As pyrroloquinoline quinone (PQQ) is a scavenger of free radicals, redox cofactor, and antioxidant which supports cognitive and mitochondrial functions, supplementation with PQQ could have a positive effect to reduce heart inflammation after COVID-19 mRNA vaccines. However, there is no evidence yet for this opportunity in the literature. Cellular and animal model results are missing. Similarly, no clinical trials have been conducted. While it is recommended to measure the levels of the cardiac biomarkers before and after COVID-19 vaccination, no recommendation can be made about supplementation with PQQ, which, however, we note has no contraindication.","categories":["mechanisms"],"tags":["vaccine","mRNA"],"studyType":"mouse-model","spikeSource":["both"],"keyFindings":["SARS-CoV-2 spike protein-induced heart inflammation may originate from either COVID-19 infection or the administration of COVID-19 mRNA vaccines.","As pyrroloquinoline quinone (PQQ) is a scavenger of free radicals, redox cofactor, and antioxidant which supports cognitive and mitochondrial functions, supplementation with PQQ could have a positive effect to reduce heart inflammation after COVID-19 mRNA vaccines.","However, there is no evidence yet for this opportunity in the literature."],"persistenceDuration":null,"mechanisms":["inflammation"],"therapeuticTargets":null,"symptoms":["cognitive dysfunction"],"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8905048/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/35287384/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-35143839","title":"The spike protein of SARS-CoV-2 induces endothelial inflammation through integrin α5β1 and NF-κB signaling.","authors":["Robles Juan Pablo","Zamora Magdalena","Adan-Castro Elva","Siqueiros-Marquez Lourdes","Martinez de la Escalera Gonzalo","Clapp Carmen"],"doi":"10.1016/j.jbc.2022.101695","pmid":"35143839","pmcid":"PMC8820157","publicationDate":"2022-01-01","journal":"The Journal of biological chemistry","abstract":"$c3","categories":["persistence","mechanisms"],"tags":[],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["Vascular endothelial cells (ECs) form a critical interface between blood and tissues that maintains whole-body homeostasis.","In COVID-19, disruption of the EC barrier results in edema, vascular inflammation, and coagulation, hallmarks of this severe disease.","However, the mechanisms by which ECs are dysregulated in COVID-19 are unclear."],"persistenceDuration":null,"mechanisms":["inflammation","endothelial damage","ACE2 binding"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8820157/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/35143839/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-36238082","title":"SARS-CoV-2, long COVID, prion disease and neurodegeneration.","authors":["Zhao Yuhai","Jaber Vivian R","Lukiw Walter J"],"doi":"10.3389/fnins.2022.1002770","pmid":"36238082","pmcid":"PMC9551214","publicationDate":"2022-01-01","journal":"Frontiers in neuroscience","abstract":"","categories":["symptoms"],"tags":["long-covid","neuroinflammation"],"studyType":"clinical","spikeSource":["infection"],"keyFindings":[],"persistenceDuration":null,"mechanisms":["neuroinflammation"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9551214/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/36238082/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-35090164","title":"Memory B cell repertoire from triple vaccinees against diverse SARS-CoV-2 variants.","authors":["Wang Kang","Jia Zijing","Bao Linilin","Wang Lei","Cao Lei","Chi Hang","Hu Yaling","Li Qianqian"],"doi":"10.1038/s41586-022-04466-x","pmid":"35090164","pmcid":"PMC8967717","publicationDate":"2022-01-01","journal":"Nature","abstract":"$c4","categories":["mechanisms","therapeutics"],"tags":["vaccine"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["Omicron (B.1.1.529), the most heavily mutated SARS-CoV-2 variant so far, is highly resistant to neutralizing antibodies, raising concerns about the effectiveness of antibody therapies and vaccines1,2.","Here we examined whether sera from individuals who received two or three doses of inactivated SARS-CoV-2 vaccine could neutralize authentic Omicron.","The seroconversion rates of neutralizing antibodies were 3.3% (2 out of 60) and 95% (57 out of 60) for individuals who had received 2 and 3 doses of vaccine, respectively."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":["Monoclonal antibodies"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8967717/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/35090164/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-36374180","title":"ICTV Virus Taxonomy Profile:","authors":["Liu Ying","Dyall-Smith Mike","Oksanen Hanna M"],"doi":"10.1099/jgv.0.001793","pmid":"36374180","pmcid":"PMC12642806","publicationDate":"2022-01-01","journal":"The Journal of general virology","abstract":"Members of the family Pleolipoviridae are pseudo-spherical and pleomorphic archaeal viruses composed of a membrane vesicle, which encloses a DNA genome. The genome is either circular ssDNA or dsDNA, or linear dsDNA molecules of approximately 7 to 17 kilonucleotides or kbp. Typically, virions contain a single type of transmembrane spike protein at the envelope and a single type of membrane protein, which is embedded in the envelope and located in the internal side of the membrane. All viruses infect extremely halophilic archaea in the class Halobacteria (phylum Euryarchaeota). Pleolipoviruses have a narrow host range and a persistent, non-lytic life cycle. Some viruses are temperate and can integrate into the host chromosome. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the family Pleolipoviridae, which is available at ictv.global/report/pleolipoviridae.","categories":["persistence"],"tags":[],"studyType":"clinical","spikeSource":["unspecified"],"keyFindings":["Members of the family Pleolipoviridae are pseudo-spherical and pleomorphic archaeal viruses composed of a membrane vesicle, which encloses a DNA genome.","The genome is either circular ssDNA or dsDNA, or linear dsDNA molecules of approximately 7 to 17 kilonucleotides or kbp.","Typically, virions contain a single type of transmembrane spike protein at the envelope and a single type of membrane protein, which is embedded in the envelope and located in the internal side of the membrane."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12642806/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/36374180/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-34965032","title":"Kinetics and persistence of anti-SARS-CoV-2 neutralisation and antibodies after BNT162b2 vaccination in a Swiss cohort.","authors":["Šošić Lara","Paolucci Marta","Duda Agathe","Hasler Fabio","Walton Senta M","Kündig Thomas M","Johansen Pål"],"doi":"10.1002/iid3.583","pmid":"34965032","pmcid":"PMC8926495","publicationDate":"2022-01-01","journal":"Immunity, inflammation and disease","abstract":"$c5","categories":["persistence"],"tags":["vaccine"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["INTRODUCTION: Since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), substantial effort has been made to gain knowledge about the immunity elicited by infection or vaccination.","METHODS: We studied the kinetics of antibodies and virus neutralisation induced by vaccination with BNT162b2 in a Swiss cohort of SARS-CoV-2 naïve (n = 40) and convalescent (n = 9) persons.","Blood sera were analysed in a live virus neutralisation assay and specific IgG and IgA levels were measured by enzyme-linked immunoassay and analysed by descriptive statistics."],"persistenceDuration":"Up to 4 weeks","mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8926495/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/34965032/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-34710552","title":"Unravelling the molecular interactions between the SARS-CoV-2 RBD spike protein and various specific monoclonal antibodies.","authors":["Martí Didac","Alsina Marc","Alemán Carlos","Bertran Oscar","Turon Pau","Torras Juan"],"doi":"10.1016/j.biochi.2021.10.013","pmid":"34710552","pmcid":"PMC8545699","publicationDate":"2022-01-01","journal":"Biochimie","abstract":"$c6","categories":["mechanisms","therapeutics"],"tags":["vaccine"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["Vaccination against SARS-CoV-2 just started in most of the countries.","However, the development of specific vaccines against SARS-CoV-2 is not the only approach to control the virus and monoclonal antibodies (mAbs) start to merit special attention as a therapeutic option to treat COVID-19 disease.","Here, the main conformations and interactions between the receptor-binding domain (RBD) of spike glycoprotein of SARS-CoV-2 (S protein) with two mAbs (CR3022 and S309) and the ACE2 cell receptor are studied as the main representatives of three different epitopes on the RBD of S protein."],"persistenceDuration":null,"mechanisms":["ACE2 binding"],"therapeuticTargets":["Monoclonal antibodies"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8545699/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/34710552/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-35966177","title":"Nature of viruses and pandemics: Coronaviruses.","authors":["Enjuanes Luis","Sola Isabel","Zúñiga Sonia","Honrubia José M","Bello-Pérez Melissa","Sanz-Bravo Alejandro","González-Miranda Ezequiel","Hurtado-Tamayo Jesús"],"doi":"10.1016/j.crimmu.2022.08.003","pmid":"35966177","pmcid":"PMC9359481","publicationDate":"2022-01-01","journal":"Current research in immunology","abstract":"$c7","categories":["persistence","mechanisms"],"tags":["vaccine","mRNA"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["Coronaviruses (CoVs) have the largest genome among RNA viruses and store large amounts of information without genome integration as they replicate in the cell cytoplasm.","The replication of the virus is a continuous process, whereas the transcription of the subgenomic mRNAs is a discontinuous one, involving a template switch, which resembles a high frequency recombination mechanism that may favor virus genome variability.","The origin of the three deadly human CoVs SARS-CoV, MERS-CoV and SARS-CoV-2 are zoonotic events."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9359481/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/35966177/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-35728038","title":"Nucleocapsid mutations in SARS-CoV-2 augment replication and pathogenesis.","authors":["Johnson Bryan A","Zhou Yiyang","Lokugamage Kumari G","Vu Michelle N","Bopp Nathen","Crocquet-Valdes Patricia A","Kalveram Birte","Schindewolf Craig"],"doi":"10.1371/journal.ppat.1010627","pmid":"35728038","pmcid":"PMC9275689","publicationDate":"2022-01-01","journal":"PLoS pathogens","abstract":"$c8","categories":["mechanisms"],"tags":[],"studyType":"preclinical","spikeSource":["infection"],"keyFindings":["While SARS-CoV-2 continues to adapt for human infection and transmission, genetic variation outside of the spike gene remains largely unexplored.","This study investigates a highly variable region at residues 203-205 in the SARS-CoV-2 nucleocapsid protein.","Recreating a mutation found in the alpha and omicron variants in an early pandemic (WA-1) background, we find that the R203K+G204R mutation is sufficient to enhance replication, fitness, and pathogenesis of SARS-CoV-2."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9275689/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/35728038/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-35687563","title":"Factors associated with anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein antibody titer and neutralizing activity among healthcare workers following vaccination with the BNT162b2 vaccine.","authors":["Kobashi Yurie","Shimazu Yuzo","Kawamura Takeshi","Nishikawa Yoshitaka","Omata Fumiya","Kaneko Yudai","Kodama Tatsuhiko","Tsubokura Masaharu"],"doi":"10.1371/journal.pone.0269917","pmid":"35687563","pmcid":"PMC9187057","publicationDate":"2022-01-01","journal":"PloS one","abstract":"$c9","categories":["persistence"],"tags":["vaccine"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["The purpose of this study was to identify factors associated with the increase in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S1) protein and neutralizing antibody titer following SARS-CoV-2 vaccination.","This observational study was conducted among healthcare workers working for a private hospital group in Fukushima Prefecture, Japan.","Two blood samples were obtained from each participant."],"persistenceDuration":"Up to 6 weeks","mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9187057/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/35687563/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-35584583","title":"ACE2, B","authors":["Zhang Yuanyuan","Yan Renhong","Zhou Qiang"],"doi":"10.1016/j.sbi.2022.102388","pmid":"35584583","pmcid":"PMC9108414","publicationDate":"2022-01-01","journal":"Current opinion in structural biology","abstract":"$ca","categories":["mechanisms","therapeutics","symptoms"],"tags":["vaccine"],"studyType":"review","spikeSource":["both"],"keyFindings":["The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged as a public health crisis and led to tremendous economic devastation.","The spike protein (S) of SARS-CoV-2 hijacks the angiotensin converting enzyme 2 (ACE2) as a receptor for virus entry, representing the initial step of viral infection.","S is one of the major targets for development of the antiviral drugs, antibodies, and vaccines."],"persistenceDuration":null,"mechanisms":["ACE2 binding"],"therapeuticTargets":["Antivirals"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9108414/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/35584583/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-34988889","title":"Neutralizing antibody: a savior in the Covid-19 disease.","authors":["Gupta Sneh Lata","Jaiswal Rishi Kumar"],"doi":"10.1007/s11033-021-07020-6","pmid":"34988889","pmcid":"PMC8731133","publicationDate":"2022-01-01","journal":"Molecular biology reports","abstract":"$cb","categories":["mechanisms","therapeutics"],"tags":["vaccine"],"studyType":"review","spikeSource":["both"],"keyFindings":["Coronavirus outbreak was declared a pandemic by World Health Organization (WHO) in March 2020.","The pandemic has led to a devastating loss of life.","It has shown us how infectious diseases can cause human existence at stake, and community health is important."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":["Monoclonal antibodies"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8731133/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/34988889/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-35104837","title":"Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity.","authors":["Meng Bo","Abdullahi Adam","Ferreira Isabella A T M","Goonawardane Niluka","Saito Akatsuki","Kimura Izumi","Yamasoba Daichi","Gerber Pehuén Pereyra"],"doi":"10.1038/s41586-022-04474-x","pmid":"35104837","pmcid":"PMC8942856","publicationDate":"2022-01-01","journal":"Nature","abstract":"$cc","categories":["mechanisms","therapeutics"],"tags":["vaccine","mRNA"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["The SARS-CoV-2 Omicron BA.1 variant emerged in 20211 and has multiple mutations in its spike protein2.","Here we show that the spike protein of Omicron has a higher affinity for ACE2 compared with Delta, and a marked change in its antigenicity increases Omicron's evasion of therapeutic monoclonal and vaccine-elicited polyclonal neutralizing antibodies after two doses.","mRNA vaccination as a third vaccine dose rescues and broadens neutralization."],"persistenceDuration":null,"mechanisms":["ACE2 binding"],"therapeuticTargets":["Monoclonal antibodies","Antivirals"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8942856/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/35104837/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-34089662","title":"SARS-CoV-2 spike protein S1 induces fibrin(ogen) resistant to fibrinolysis: implications for microclot formation in COVID-19","authors":["Grobbelaar LM","Venter C","Pretorius E"],"doi":"10.1101/2021.03.05.434100","pmid":"34089662","publicationDate":"2021-05-13","journal":"bioRxiv / Bioscience Reports","abstract":"Spike S1 subunit interacts with fibrinogen producing amyloidogenic fibrin resistant to breakdown.","summary":"Key fibrin-spike interaction paper: S1 may promote microclots resistant to fibrinolysis — relevant to long COVID pathophysiology hypotheses.","categories":["mechanisms","symptoms"],"tags":["fibrin","s1-subunit","microclots","long-covid"],"studyType":"preclinical","spikeSource":["recombinant","infection"],"keyFindings":["S1 induces fibrin resistant to fibrinolysis","Amyloidogenic fibrin formation demonstrated","Proposed link to microclot pathology in PASC"],"mechanisms":["fibrin/clotting","endothelial damage"],"symptoms":["fatigue","dyspnea"],"pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/34089662/","reviewed":true,"lastUpdated":"2026-07-06"},{"id":"pmid-32730589","title":"Persistent minimal sequences of SARS-CoV-2.","authors":["Pratas Diogo","Silva Jorge M"],"doi":"10.1093/bioinformatics/btaa686","pmid":"32730589","pmcid":"PMC7559010","publicationDate":"2021-01-29","journal":"Bioinformatics (Oxford, England)","abstract":"$cd","categories":["persistence","mechanisms","therapeutics"],"tags":[],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["MOTIVATION: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused more than 14 million cases and more than half million deaths.","Given the absence of implemented therapies, new analysis, diagnosis and therapeutics are of great importance.","RESULTS: Analysis of SARS-CoV-2 genomes from the current outbreak reveals the presence of short persistent DNA/RNA sequences that are absent from the human genome and transcriptome (PmRAWs)."],"persistenceDuration":null,"mechanisms":["ACE2 binding"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559010/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/32730589/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-33671076","title":"TMPRSS11D and TMPRSS13 Activate the SARS-CoV-2 Spike Protein.","authors":["Kishimoto Mai","Uemura Kentaro","Sanaki Takao","Sato Akihiko","Hall William W","Kariwa Hiroaki","Orba Yasuko","Sawa Hirofumi"],"doi":"10.3390/v13030384","pmid":"33671076","pmcid":"PMC8001073","publicationDate":"2021-01-28","journal":"Viruses","abstract":"Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) utilizes host proteases, including a plasma membrane-associated transmembrane protease, serine 2 (TMPRSS2) to cleave and activate the virus spike protein to facilitate cellular entry. Although TMPRSS2 is a well-characterized type II transmembrane serine protease (TTSP), the role of other TTSPs on the replication of SARS-CoV-2 remains to be elucidated. Here, we have screened 12 TTSPs using human angiotensin-converting enzyme 2-expressing HEK293T (293T-ACE2) cells and Vero E6 cells and demonstrated that exogenous expression of TMPRSS11D and TMPRSS13 enhanced cellular uptake and subsequent replication of SARS-CoV-2. In addition, SARS-CoV-1 and SARS-CoV-2 share the same TTSPs in the viral entry process. Our study demonstrates the impact of host TTSPs on infection of SARS-CoV-2, which may have implications for cell and tissue tropism, for pathogenicity, and potentially for vaccine development.","categories":["persistence"],"tags":["vaccine"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) utilizes host proteases, including a plasma membrane-associated transmembrane protease, serine 2 (TMPRSS2) to cleave and activate the virus spike protein to facilitate cellular entry.","Although TMPRSS2 is a well-characterized type II transmembrane serine protease (TTSP), the role of other TTSPs on the replication of SARS-CoV-2 remains to be elucidated.","Here, we have screened 12 TTSPs using human angiotensin-converting enzyme 2-expressing HEK293T (293T-ACE2) cells and Vero E6 cells and demonstrated that exogenous expression of TMPRSS11D and TMPRSS13 enhanced cellular uptake and subsequent replication of SARS-CoV-2."],"persistenceDuration":null,"mechanisms":["ACE2 binding"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001073/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/33671076/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-33608565","title":"Flexibility and mobility of SARS-CoV-2-related protein structures.","authors":["Römer Rudolf A","Römer Navodya S","Wallis A Katrine"],"doi":"10.1038/s41598-021-82849-2","pmid":"33608565","pmcid":"PMC7896093","publicationDate":"2021-01-19","journal":"Scientific reports","abstract":"$ce","categories":["mechanisms"],"tags":["vaccine","s1-subunit"],"studyType":"preclinical","spikeSource":["both"],"keyFindings":["The worldwide CoVid-19 pandemic has led to an unprecedented push across the whole of the scientific community to develop a potent antiviral drug and vaccine as soon as possible.","Existing academic, governmental and industrial institutions and companies have engaged in large-scale screening of existing drugs, in vitro, in vivo and in silico.","Here, we are using in silico modelling of possible SARS-CoV-2 drug targets, as deposited on the Protein Databank (PDB), and ascertain their dynamics, flexibility and rigidity."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":["Antivirals"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896093/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/33608565/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-34103349","title":"Senolytics reduce coronavirus-related mortality in old mice.","authors":["Camell Christina D","Yousefzadeh Matthew J","Zhu Yi","Prata Larissa G P Langhi","Huggins Matthew A","Pierson Mark","Zhang Lei","O'Kelly Ryan D"],"doi":"10.1126/science.abe4832","pmid":"34103349","pmcid":"PMC8607935","publicationDate":"2021-01-16","journal":"Science (New York, N.Y.)","abstract":"$cf","categories":["mechanisms"],"tags":[],"studyType":"mouse-model","spikeSource":["infection"],"keyFindings":["The COVID-19 pandemic has revealed the pronounced vulnerability of the elderly and chronically ill to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced morbidity and mortality.","Cellular senescence contributes to inflammation, multiple chronic diseases, and age-related dysfunction, but effects on responses to viral infection are unclear.","Here, we demonstrate that senescent cells (SnCs) become hyper-inflammatory in response to pathogen-associated molecular patterns (PAMPs), including SARS-CoV-2 spike protein-1, increasing expression of viral entry proteins and reducing antiviral gene expression in non-SnCs through a paracrine mechanism."],"persistenceDuration":null,"mechanisms":["inflammation"],"therapeuticTargets":["Antivirals"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8607935/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/34103349/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-34782609","title":"The glycosylation in SARS-CoV-2 and its receptor ACE2.","authors":["Gong Yanqiu","Qin Suideng","Dai Lunzhi","Tian Zhixin"],"doi":"10.1038/s41392-021-00809-8","pmid":"34782609","pmcid":"PMC8591162","publicationDate":"2021-01-15","journal":"Signal transduction and targeted therapy","abstract":"Coronavirus disease 2019 (COVID-19), a highly infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected more than 235 million individuals and led to more than 4.8 million deaths worldwide as of October 5 2021. Cryo-electron microscopy and topology show that the SARS-CoV-2 genome encodes lots of highly glycosylated proteins, such as spike (S), envelope (E), membrane (M), and ORF3a proteins, which are responsible for host recognition, penetration, binding, recycling and pathogenesis. Here we reviewed the detections, substrates, biological functions of the glycosylation in SARS-CoV-2 proteins as well as the human receptor ACE2, and also summarized the approved and undergoing SARS-CoV-2 therapeutics associated with glycosylation. This review may not only broad the understanding of viral glycobiology, but also provide key clues for the development of new preventive and therapeutic methodologies against SARS-CoV-2 and its variants.","categories":["mechanisms","therapeutics"],"tags":[],"studyType":"review","spikeSource":["infection"],"keyFindings":["Coronavirus disease 2019 (COVID-19), a highly infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected more than 235 million individuals and led to more than 4.8 million deaths worldwide as of October 5 2021.","Cryo-electron microscopy and topology show that the SARS-CoV-2 genome encodes lots of highly glycosylated proteins, such as spike (S), envelope (E), membrane (M), and ORF3a proteins, which are responsible for host recognition, penetration, binding, recycling and pathogenesis.","Here we reviewed the detections, substrates, biological functions of the glycosylation in SARS-CoV-2 proteins as well as the human receptor ACE2, and also summarized the approved and undergoing SARS-CoV-2 therapeutics associated with glycosylation."],"persistenceDuration":null,"mechanisms":["ACE2 binding"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8591162/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/34782609/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-33217246","title":"Tissue-Specific Immunopathology in Fatal COVID-19.","authors":["Dorward David A","Russell Clark D","Um In Hwa","Elshani Mustafa","Armstrong Stuart D","Penrice-Randal Rebekah","Millar Tracey","Lerpiniere Chris E B"],"doi":"10.1164/rccm.202008-3265OC","pmid":"33217246","pmcid":"PMC7874430","publicationDate":"2021-01-15","journal":"American journal of respiratory and critical care medicine","abstract":"$d0","categories":["persistence","mechanisms","therapeutics"],"tags":[],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["Rationale: In life-threatening coronavirus disease (COVID-19), corticosteroids reduce mortality, suggesting that immune responses have a causal role in death.","Whether this deleterious inflammation is primarily a direct reaction to the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or an independent immunopathologic process is unknown.Objectives: To determine SARS-CoV-2 organotropism and organ-specific inflammatory responses and the relationships among viral presence, inflammation, and organ injury.Methods: Tissue was acquired from 11 detailed postmortem examinations.","SARS-CoV-2 organotropism was mapped by using multiplex PCR and sequencing, with cellular resolution achieved by in situ viral S (spike) protein detection."],"persistenceDuration":null,"mechanisms":["inflammation","endothelial damage"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874430/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/33217246/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-34685735","title":"Quantifying Renin-Angiotensin-System Alterations in COVID-19.","authors":["Pucci Fabrizio","Annoni Filippo","Dos Santos Robson Augusto Souza","Taccone Fabio Silvio","Rooman Marianne"],"doi":"10.3390/cells10102755","pmid":"34685735","pmcid":"PMC8535134","publicationDate":"2021-01-14","journal":"Cells","abstract":"$d1","categories":["persistence","mechanisms"],"tags":[],"studyType":"meta-analysis","spikeSource":["infection"],"keyFindings":["The renin-angiotensin system (RAS) plays a pivotal role in a wide series of physiological processes, among which inflammation and blood pressure regulation.","One of its key components, the angiotensin-converting enzyme 2, has been identified as the entry point of the SARS-CoV-2 virus into the host cells, and therefore a lot of research has been devoted to study RAS dysregulation in COVID-19.","Here we discuss the alterations of the regulatory RAS axes due to SARS-CoV-2 infection on the basis of a series of recent clinical investigations and experimental analyzes quantifying, e.g., the levels and activity of RAS components."],"persistenceDuration":null,"mechanisms":["inflammation"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8535134/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/34685735/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-34902063","title":"Host Manipulation Mechanisms of SARS-CoV-2.","authors":["Massey Steven E"],"doi":"10.1007/s10441-021-09425-z","pmid":"34902063","pmcid":"PMC8667538","publicationDate":"2021-01-13","journal":"Acta biotheoretica","abstract":"$d2","categories":["mechanisms"],"tags":["s1-subunit","neuroinflammation"],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["Viruses are the simplest of pathogens, but possess sophisticated molecular mechanisms to manipulate host behavior, frequently utilizing molecular mimicry.","Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been shown to bind to the host receptor neuropilin-1 in order to gain entry into the cell.","To do this, the virus utilizes its spike protein polybasic cleavage site (PCS), which mimics the CendR motif of neuropilin-1's endogenous ligands."],"persistenceDuration":null,"mechanisms":["neuroinflammation","ACE2 binding"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8667538/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/34902063/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-33574281","title":"A genome-wide CRISPR screen identifies host factors that regulate SARS-CoV-2 entry.","authors":["Zhu Yunkai","Feng Fei","Hu Gaowei","Wang Yuyan","Yu Yin","Zhu Yuanfei","Xu Wei","Cai Xia"],"doi":"10.1038/s41467-021-21213-4","pmid":"33574281","pmcid":"PMC7878750","publicationDate":"2021-01-11","journal":"Nature communications","abstract":"The global spread of SARS-CoV-2 is posing major public health challenges. One feature of SARS-CoV-2 spike protein is the insertion of multi-basic residues at the S1/S2 subunit cleavage site. Here, we find that the virus with intact spike (Sfull) preferentially enters cells via fusion at the plasma membrane, whereas a clone (Sdel) with deletion disrupting the multi-basic S1/S2 site utilizes an endosomal entry pathway. Using Sdel as model, we perform a genome-wide CRISPR screen and identify several endosomal entry-specific regulators. Experimental validation of hits from the CRISPR screen shows that host factors regulating the surface expression of angiotensin-converting enzyme 2 (ACE2) affect entry of Sfull virus. Animal-to-animal transmission with the Sdel virus is reduced compared to Sfull in the hamster model. These findings highlight the critical role of the S1/S2 boundary of SARS-CoV-2 spike protein in modulating virus entry and transmission and provide insights into entry of coronaviruses.","categories":["mechanisms"],"tags":[],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["The global spread of SARS-CoV-2 is posing major public health challenges.","One feature of SARS-CoV-2 spike protein is the insertion of multi-basic residues at the S1/S2 subunit cleavage site.","Here, we find that the virus with intact spike (Sfull) preferentially enters cells via fusion at the plasma membrane, whereas a clone (Sdel) with deletion disrupting the multi-basic S1/S2 site utilizes an endosomal entry pathway."],"persistenceDuration":null,"mechanisms":["ACE2 binding"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878750/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/33574281/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-34160250","title":"SARS-CoV-2 Spike Protein Induces Paracrine Senescence and Leukocyte Adhesion in Endothelial Cells.","authors":["Meyer Keith","Patra Tapas","Vijayamahantesh","Ray Ranjit"],"doi":"10.1128/JVI.00794-21","pmid":"34160250","pmcid":"PMC8354225","publicationDate":"2021-01-10","journal":"Journal of virology","abstract":"$d3","categories":["mechanisms","therapeutics"],"tags":[],"studyType":"preclinical","spikeSource":["infection"],"keyFindings":["Increased mortality in COVID-19 cases is often associated with microvascular complications.","We have recently shown that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein promotes an inflammatory cytokine interleukin 6 (IL-6)/IL-6R-induced trans signaling response and alarmin secretion.","Virus-infected or spike-transfected human epithelial cells exhibited an increase in senescence, with a release of senescence-associated secretory phenotype (SASP)-related inflammatory molecules."],"persistenceDuration":null,"mechanisms":["endothelial damage"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8354225/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/34160250/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-33461210","title":"Evolution of antibody immunity to SARS-CoV-2.","authors":["Gaebler Christian","Wang Zijun","Lorenzi Julio C C","Muecksch Frauke","Finkin Shlomo","Tokuyama Minami","Cho Alice","Jankovic Mila"],"doi":"10.1038/s41586-021-03207-w","pmid":"33461210","pmcid":"PMC8221082","publicationDate":"2021-01-01","journal":"Nature","abstract":"$d4","categories":["persistence","mechanisms","symptoms"],"tags":[],"studyType":"mouse-model","spikeSource":["infection"],"keyFindings":["Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected 78 million individuals and is responsible for over 1.7 million deaths to date.","Infection is associated with the development of variable levels of antibodies with neutralizing activity, which can protect against infection in animal models1,2.","Antibody levels decrease with time, but, to our knowledge, the nature and quality of the memory B cells that would be required to produce antibodies upon reinfection has not been examined."],"persistenceDuration":"Up to 2 months","mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221082/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/33461210/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-34687279","title":"Rapid Detection and Inhibition of SARS-CoV-2-Spike Mutation-Mediated Microthrombosis.","authors":["Satta Sandro","Lai Angela","Cavallero Susana","Williamson Cayden","Chen Justin","Blázquez-Medela Ana M","Roustaei Mehrdad","Dillon Barbara J"],"doi":"10.1002/advs.202103266","pmid":"34687279","pmcid":"PMC8646611","publicationDate":"2021-01-01","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","abstract":"$d5","categories":["persistence","mechanisms"],"tags":["vaccine"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["Activation of endothelial cells following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is thought to be the primary driver for the increasingly recognized thrombotic complications in coronavirus disease 2019 patients, potentially due to the SARS-CoV-2 Spike protein binding to the human angiotensin-converting enzyme 2 (hACE2).","Vaccination therapies use the same Spike sequence or protein to boost host immune response as a protective mechanism against SARS-CoV-2 infection.","As a result, cases of thrombotic events are reported following vaccination."],"persistenceDuration":null,"mechanisms":["endothelial damage","ACE2 binding"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8646611/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/34687279/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-33545711","title":"SARS-CoV-2 evolution during treatment of chronic infection.","authors":["Kemp Steven A","Collier Dami A","Datir Rawlings P","Ferreira Isabella A T M","Gayed Salma","Jahun Aminu","Hosmillo Myra","Rees-Spear Chloe"],"doi":"10.1038/s41586-021-03291-y","pmid":"33545711","pmcid":"PMC7610568","publicationDate":"2021-01-01","journal":"Nature","abstract":"$d6","categories":["therapeutics"],"tags":[],"studyType":"preclinical","spikeSource":["infection"],"keyFindings":["The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for virus infection through the engagement of the human ACE2 protein1 and is a major antibody target.","Here we show that chronic infection with SARS-CoV-2 leads to viral evolution and reduced sensitivity to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma, by generating whole-genome ultra-deep sequences for 23 time points that span 101 days and using in vitro techniques to characterize the mutations revealed by sequencing.","There was little change in the overall structure of the viral population after two courses of remdesivir during the first 57 days."],"persistenceDuration":"Up to 101 days","mechanisms":["ACE2 binding"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610568/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/33545711/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-34522180","title":"Possible mechanisms of cholesterol elevation aggravating COVID-19.","authors":["Tang Yan","Hu Longtai","Liu Yi","Zhou Bangyi","Qin Xiaohuan","Ye Jujian","Shen Maoze","Wu Zhijian"],"doi":"10.7150/ijms.62021","pmid":"34522180","pmcid":"PMC8436106","publicationDate":"2021-01-01","journal":"International journal of medical sciences","abstract":"$d7","categories":["persistence","mechanisms","therapeutics"],"tags":["vaccine"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["Importance: Despite the availability of a vaccine against the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), humans will have to live with this virus and the after-effects of the coronavirus disease 2019 (COVID-19) infection for a long time.","Cholesterol plays an important role in the infection and prognosis of SARS-CoV-2, and the study of its mechanism is of great significance not only for the treatment of COVID-19 but also for research on generic antiviral drugs.","Observations: Cholesterol promotes the development of atherosclerosis by activating NLR family pyrin domain containing 3 (NLRP3), and the resulting inflammatory environment indirectly contributes to COVID-19 infection and subsequent deterioration."],"persistenceDuration":null,"mechanisms":["ACE2 binding"],"therapeuticTargets":["Antivirals"],"symptoms":["cardiovascular"],"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8436106/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/34522180/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-33827113","title":"Drugs that inhibit TMEM16 proteins block SARS-CoV-2 spike-induced syncytia.","authors":["Braga Luca","Ali Hashim","Secco Ilaria","Chiavacci Elena","Neves Guilherme","Goldhill Daniel","Penn Rebecca","Jimenez-Guardeño Jose M"],"doi":"10.1038/s41586-021-03491-6","pmid":"33827113","pmcid":"PMC7611055","publicationDate":"2021-01-01","journal":"Nature","abstract":"$d8","categories":["mechanisms"],"tags":[],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["COVID-19 is a disease with unique characteristics that include lung thrombosis1, frequent diarrhoea2, abnormal activation of the inflammatory response3 and rapid deterioration of lung function consistent with alveolar oedema4.","The pathological substrate for these findings remains unknown.","Here we show that the lungs of patients with COVID-19 contain infected pneumocytes with abnormal morphology and frequent multinucleation."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611055/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/33827113/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-33587268","title":"Making sense of spike D614G in SARS-CoV-2 transmission.","authors":["Shi Aria C","Xie Xuping"],"doi":"10.1007/s11427-020-1893-9","pmid":"33587268","pmcid":"PMC7882856","publicationDate":"2021-01-01","journal":"Science China. Life sciences","abstract":"$d9","categories":["persistence","mechanisms","therapeutics"],"tags":["vaccine"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of the current coronavirus disease 2019 (COVID-19) pandemic, has evolved to adapt to human host and transmission over the past 12 months.","One prominent adaptive mutation is the asparagine-to-glycine substitution at amino acid position 614 in the viral spike protein (D614G), which has become dominant in the currently circulating virus strains.","Since spike protein determines host ranges, tissue tropism, and pathogenesis through binding to the cellular receptor of angiotensin converting enzyme 2 (ACE2), the D614G mutation is hypothesized to enhance viral fitness in human host, leading to increased transmission during the global pandemic."],"persistenceDuration":"Up to 12 months","mechanisms":["ACE2 binding"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882856/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/33587268/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-33737214","title":"Structural and molecular perspectives of SARS-CoV-2.","authors":["Kumar Swatantra","Saxena Shailendra K"],"doi":"10.1016/j.ymeth.2021.03.007","pmid":"33737214","pmcid":"PMC7959701","publicationDate":"2021-01-01","journal":"Methods (San Diego, Calif.)","abstract":"$da","categories":["mechanisms","therapeutics"],"tags":[],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["Recent emergence of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transpired into pandemic coronavirus disease 2019 (COVID-19).","SARS-CoV-2 has been rapidly transmitted across the globe within a short period of time, with more than 106 million cases and 2.3 million deaths.","The continuous rise in worldwide cases of COVID-19, transmission dynamics of SARS-CoV-2 including re-infections and enormous case-fatality rates emphasizes the urgent need of potential preventive and therapeutic measures."],"persistenceDuration":null,"mechanisms":["ACE2 binding"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959701/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/33737214/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-33432128","title":"Super(antigen) target for SARS-CoV-2.","authors":["Brown Matthew","Bhardwaj Nina"],"doi":"10.1038/s41577-021-00502-5","pmid":"33432128","pmcid":"PMC7798007","publicationDate":"2021-01-01","journal":"Nature reviews. Immunology","abstract":"This preprint further characterizes a superantigen motif identified in SARS-CoV-2 spike protein and evaluates a monoclonal antibody targeting this region that can neutralize live virus.","categories":["therapeutics"],"tags":[],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["This preprint further characterizes a superantigen motif identified in SARS-CoV-2 spike protein and evaluates a monoclonal antibody targeting this region that can neutralize live virus."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":["Monoclonal antibodies"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7798007/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/33432128/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-34100279","title":"Be aware of SARS-CoV-2 spike protein: There is more than meets the eye.","authors":["Theoharides T C","Conti P"],"doi":"10.23812/THEO_EDIT_3_21","pmid":"34100279","pmcid":null,"publicationDate":"2021-01-01","journal":"Journal of biological regulators and homeostatic agents","abstract":"$db","categories":["persistence","mechanisms"],"tags":["vaccine","mRNA"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["The COVID-19 pandemic necessitated the rapid production of vaccines aimed at the production of neutralizing antibodies against the COVID-19 spike protein required for the corona virus binding to target cells.","The best well-known vaccines have utilized either mRNA or an adenovirus vector to direct human cells to produce the spike protein against which the body produces mostly neutralizing antibodies.","However, recent reports have raised some skepticism as to the biologic actions of the spike protein and the types of antibodies produced."],"persistenceDuration":null,"mechanisms":["endothelial damage"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":null,"pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/34100279/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-34497376","title":"Neutralizing antibodies for the prevention and treatment of COVID-19.","authors":["Du Lanying","Yang Yang","Zhang Xiujuan"],"doi":"10.1038/s41423-021-00752-2","pmid":"34497376","pmcid":"PMC8424621","publicationDate":"2021-01-01","journal":"Cellular & molecular immunology","abstract":"$dc","categories":["mechanisms","therapeutics"],"tags":["s1-subunit"],"studyType":"review","spikeSource":["infection"],"keyFindings":["Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) initiates the infection process by binding to the viral cellular receptor angiotensin-converting enzyme 2 through the receptor-binding domain (RBD) in the S1 subunit of the viral spike (S) protein.","This event is followed by virus-cell membrane fusion mediated by the S2 subunit, which allows virus entry into the host cell.","Therefore, the SARS-CoV-2 S protein is a key therapeutic target, and prevention and treatment of coronavirus disease 2019 (COVID-19) have focused on the development of neutralizing monoclonal antibodies (nAbs) that target this protein."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":["Monoclonal antibodies"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424621/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/34497376/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-34305894","title":"The Spike of SARS-CoV-2: Uniqueness and Applications.","authors":["Kumavath Ranjith","Barh Debmalya","Andrade Bruno Silva","Imchen Madangchanok","Aburjaile Flavia Figueira","Ch Athira","Rodrigues Diego Lucas Neres","Tiwari Sandeep"],"doi":"10.3389/fimmu.2021.663912","pmid":"34305894","pmcid":"PMC8297464","publicationDate":"2021-01-01","journal":"Frontiers in immunology","abstract":"$dd","categories":["mechanisms"],"tags":["vaccine"],"studyType":"meta-analysis","spikeSource":["both"],"keyFindings":["The Spike (S) protein of the SARS-CoV-2 virus is critical for its ability to attach and fuse into the host cells, leading to infection, and transmission.","In this review, we have initially performed a meta-analysis of keywords associated with the S protein to frame the outline of important research findings and directions related to it.","Based on this outline, we have reviewed the structure, uniqueness, and origin of the S protein of SARS-CoV-2."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8297464/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/34305894/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-34667599","title":"Endothelial dysfunction and COVID-19 (Review).","authors":["Daher Jalil"],"doi":"10.3892/br.2021.1478","pmid":"34667599","pmcid":"PMC8517756","publicationDate":"2021-01-01","journal":"Biomedical reports","abstract":"$de","categories":["persistence","mechanisms","therapeutics","symptoms"],"tags":[],"studyType":"review","spikeSource":["both"],"keyFindings":["It is hypothesized that several comorbidities increase the severity of COVID-19 symptoms.","Cardiovascular disease including hypertension was shown to play a critical role in the severity of COVID-19 infection by affecting the survival of patients with COVID-19.","Hypertension and the renin-angiotensin-aldosterone system are involved in increasing vascular inflammation and endothelial dysfunction (ED), and both processes are instrumental in COVID-19."],"persistenceDuration":null,"mechanisms":["inflammation","endothelial damage","ACE2 binding"],"therapeuticTargets":["Monoclonal antibodies"],"symptoms":["cardiovascular"],"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8517756/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/34667599/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-34595467","title":"Passive Immunity Should and Will Work for COVID-19 for Some Patients.","authors":["Cimolai Nevio"],"doi":"10.2991/chi.k.210328.001","pmid":"34595467","pmcid":"PMC8432400","publicationDate":"2021-01-01","journal":"Clinical hematology international","abstract":"$df","categories":["persistence","mechanisms","therapeutics"],"tags":["vaccine"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["In the absence of effective antiviral chemotherapy and still in the context of emerging vaccines for severe acute respiratory syndrome-CoV-2 infections, passive immunotherapy remains a key treatment and possible prevention strategy.","What might initially be conceived as a simplified donor-recipient process, the intricacies of donor plasma, IV immunoglobulins, and monoclonal antibody modality applications are becoming more apparent.","Key targets of such treatment have largely focused on virus neutralization and the specific viral components of the attachment Spike protein and its constituents (e.g., receptor binding domain, N-terminal domain)."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":["Monoclonal antibodies","Antivirals"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432400/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/34595467/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-34339040","title":"SARS-CoV-2 spike protein: pathogenesis, vaccines, and potential therapies.","authors":["Almehdi Ahmed M","Khoder Ghalia","Alchakee Aminah S","Alsayyid Azizeh T","Sarg Nadin H","Soliman Sameh S M"],"doi":"10.1007/s15010-021-01677-8","pmid":"34339040","pmcid":"PMC8326314","publicationDate":"2021-01-01","journal":"Infection","abstract":"$e0","categories":["mechanisms","therapeutics"],"tags":["vaccine"],"studyType":"review","spikeSource":["both"],"keyFindings":["PURPOSE: COVID-19 pandemic has emerged as a result of infection by the deadly pathogenic severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), causing enormous threats to humans.","Coronaviruses are distinguished by a clove-like spike (S) protein, which plays a key role in viral pathogenesis, evolutions, and transmission.","The objectives of this study are to investigate the distinctive structural features of SARS-CoV-2 S protein, its essential role in pathogenesis, and its use in the development of potential therapies and vaccines."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8326314/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/34339040/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-34371003","title":"Potential therapeutic approaches for the early entry of SARS-CoV-2 by interrupting the interaction between the spike protein on SARS-CoV-2 and angiotensin-converting enzyme 2 (ACE2).","authors":["Xiang Yusen","Wang Mengge","Chen Hongzhuan","Chen Lili"],"doi":"10.1016/j.bcp.2021.114724","pmid":"34371003","pmcid":"PMC8349388","publicationDate":"2021-01-01","journal":"Biochemical pharmacology","abstract":"$e1","categories":["mechanisms","therapeutics"],"tags":["vaccine"],"studyType":"review","spikeSource":["both"],"keyFindings":["The COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has quickly spread around the globe.","At present, there is no precise and effective treatment for the patients with COVID-19, so rapid development of drugs is urgently needed in order to contain the highly infectious disease.","The virus spike protein (S protein) can recognize the angiotensin-converting enzyme 2 (ACE2) receptor on the host cell membrane and undergo a series of conformational changes, protease cleavage and membrane fusion to complete the virus entry, so S protein is an important target for vaccine and drug development."],"persistenceDuration":null,"mechanisms":["ACE2 binding"],"therapeuticTargets":["Antivirals"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8349388/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/34371003/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-34023935","title":"Glycosylation is a key in SARS-CoV-2 infection.","authors":["Reis Celso A","Tauber Rudolf","Blanchard Véronique"],"doi":"10.1007/s00109-021-02092-0","pmid":"34023935","pmcid":"PMC8140746","publicationDate":"2021-01-01","journal":"Journal of molecular medicine (Berlin, Germany)","abstract":"$e2","categories":["mechanisms","therapeutics"],"tags":["vaccine"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["SARS-CoV-2 causes the respiratory syndrome COVID-19 and is responsible for the current pandemic.","The S protein of SARS-CoV-2-mediating virus binding to target cells and subsequent viral uptake is extensively glycosylated.","Here we focus on how glycosylation of both SARS-CoV-2 and target cells crucially impacts SARS-CoV-2 infection at different levels: (1) virus binding and entry to host cells, with glycosaminoglycans of host cells acting as a necessary co-factor for SARS-CoV-2 infection by interacting with the receptor-binding domain of the SARS-CoV-2 spike glycoprotein, (2) innate and adaptive immune response where glycosylation plays both a protective role and contributes to immune evasion by masking of viral polypeptide epitopes and may add to the cytokine cascade via non-fucosylated IgG, and (3) therapy and vaccination where a monoclonal antibody-neutralizing SARS-CoV-2 was shown to interact also with a distinct glycan epitope on the SARS-CoV-2 spike protein."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":["Monoclonal antibodies"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140746/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/34023935/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-34570010","title":"Antibody therapy for COVID-19.","authors":["Hammarström Lennart","Marcotte Harold","Piralla Antonio","Baldanti Fausto","Pan-Hammarström Qiang"],"doi":"10.1097/ACI.0000000000000787","pmid":"34570010","pmcid":"PMC8577309","publicationDate":"2021-01-01","journal":"Current opinion in allergy and clinical immunology","abstract":"PURPOSE OF REVIEW: To provide an update of the current state of antibody therapy for Severe Acute Respiratory Syndrome Coronavirus 2 infection that has progressed immensely in a very short time period. RECENT FINDINGS: Limited clinical effect of classical passive immunotherapy (plasma therapy, hyperimmune immunoglobulin [IgG] preparations) whereas monoclonal antibody therapy, if initiated early in the disease process, shows promising results. SUMMARY: Although antibody therapy still remains to be fully explored in patients with COVID-19, a combination of IgG monoclonal antibodies against the receptor-binding domain of the spike protein currently appears to provide the best form of antibody therapy, Immunoglobulin A dimers and Immunoglobulin M pentamers also show promising preliminary therapeutic results.","categories":["mechanisms","therapeutics"],"tags":[],"studyType":"review","spikeSource":["infection"],"keyFindings":["PURPOSE OF REVIEW: To provide an update of the current state of antibody therapy for Severe Acute Respiratory Syndrome Coronavirus 2 infection that has progressed immensely in a very short time period.","RECENT FINDINGS: Limited clinical effect of classical passive immunotherapy (plasma therapy, hyperimmune immunoglobulin [IgG] preparations) whereas monoclonal antibody therapy, if initiated early in the disease process, shows promising results.","SUMMARY: Although antibody therapy still remains to be fully explored in patients with COVID-19, a combination of IgG monoclonal antibodies against the receptor-binding domain of the spike protein currently appears to provide the best form of antibody therapy, Immunoglobulin A dimers and Immunoglobulin M pentamers also show promising preliminary therapeutic results."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":["Monoclonal antibodies"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8577309/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/34570010/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-33904269","title":"Monoclonal antibody therapy in COVID-19.","authors":["Conti P","Pregliasco F E","Calvisi V","Caraffa Al","Gallenga C E","Kritas S K","Ronconi G"],"doi":"10.23812/Conti_Edit_35_2_1","pmid":"33904269","pmcid":null,"publicationDate":"2021-01-01","journal":"Journal of biological regulators and homeostatic agents","abstract":"$e3","categories":["mechanisms","therapeutics","symptoms"],"tags":["vaccine","fibrin"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["Acute severe respiratory syndrome coronavirus-2 (SARS-CoV-2) infection causes coronavirus disease-2019 (COVID-19) which is associated with inflammation, thrombosis edema, hemorrhage, intra-alveolar fibrin deposition, and vascular and pulmonary damage.","In COVID-19, the coronavirus activates macrophages by inducing the generation of pro-inflammatory cytokines [interleukin (IL)-1, IL-6, IL-18 and TNF] that can damage endothelial cells, activate platelets and neutrophils to produce thromboxane A2 (TxA2), and mediate thrombus generation.","In severe cases, all these phenomena can lead to patient death."],"persistenceDuration":null,"mechanisms":["inflammation","endothelial damage","fibrin/clotting"],"therapeuticTargets":["Monoclonal antibodies"],"symptoms":["fatigue","cardiovascular"],"pdfUrl":null,"pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/33904269/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-34284707","title":"COVID-19: Myths and Reality.","authors":["Kordyukova Larisa V","Shanko Andrey V"],"doi":"10.1134/S0006297921070026","pmid":"34284707","pmcid":"PMC8265000","publicationDate":"2021-01-01","journal":"Biochemistry. Biokhimiia","abstract":"$e4","categories":["mechanisms","therapeutics"],"tags":["vaccine"],"studyType":"review","spikeSource":["both"],"keyFindings":["COVID-19, a new human respiratory disease that has killed nearly 3 million people in a year since the start of the pandemic, is a global public health challenge.","Its infectious agent, SARS-CoV-2, differs from other coronaviruses in a number of structural features that make this virus more pathogenic and transmissible.","In this review, we discuss some important characteristics of the main SARS-CoV-2 surface antigen, the spike (S) protein, such as (i) ability of the receptor-binding domain (RBD) to switch between the \"standing-up\" position (open pre-fusion conformation) for receptor binding and the \"lying-down\" position (closed pre-fusion conformation) for immune system evasion; (ii) advantage of a high binding affinity of the RBD open conformation to the human angiotensin-converting enzyme 2 (ACE2) receptor for efficient cell entry; and (iii) S protein preliminary activation by the intracellular furin-like proteases for facilitation of the virus spreading across different cell types."],"persistenceDuration":null,"mechanisms":["ACE2 binding"],"therapeuticTargets":["Antivirals"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265000/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/34284707/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-34100011","title":"SARS-CoV-2 Spreads through Cell-to-Cell Transmission.","authors":["Zeng Cong","Evans John P","King Tiffany","Zheng Yi-Min","Oltz Eugene M","Whelan Sean P J","Saif Linda","Peeples Mark E"],"doi":"10.1101/2021.06.01.446579","pmid":"34100011","pmcid":"PMC8183005","publicationDate":"2021-01-01","journal":"bioRxiv : the preprint server for biology","abstract":"$e5","categories":["mechanisms","therapeutics"],"tags":["vaccine"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible coronavirus responsible for the global COVID-19 pandemic.","Herein we provide evidence that SARS-CoV-2 spreads through cell-cell contact in cultures, mediated by the spike glycoprotein.","SARS-CoV-2 spike is more efficient in facilitating cell-to-cell transmission than SARS-CoV spike, which reflects, in part, their differential cell-cell fusion activity."],"persistenceDuration":null,"mechanisms":["ACE2 binding"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183005/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/34100011/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-34789872","title":"Independent infections of porcine deltacoronavirus among Haitian children.","authors":["Lednicky John A","Tagliamonte Massimiliano S","White Sarah K","Elbadry Maha A","Alam Md Mahbubul","Stephenson Caroline J","Bonny Tania S","Loeb Julia C"],"doi":"10.1038/s41586-021-04111-z","pmid":"34789872","pmcid":"PMC8636265","publicationDate":"2021-01-01","journal":"Nature","abstract":"$e6","categories":["mechanisms"],"tags":["s1-subunit"],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["Coronaviruses have caused three major epidemics since 2003, including the ongoing SARS-CoV-2 pandemic.","In each case, the emergence of coronavirus in our species has been associated with zoonotic transmissions from animal reservoirs1,2, underscoring how prone such pathogens are to spill over and adapt to new species.","Among the four recognized genera of the family Coronaviridae, human infections reported so far have been limited to alphacoronaviruses and betacoronaviruses3-5."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8636265/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/34789872/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-35341224","title":"Spike Glycoprotein Is Central to Coronavirus Pathogenesis-Parallel Between m-CoV and SARS-CoV-2.","authors":["Saadi Fareeha","Pal Debnath","Sarma Jayasri Das"],"doi":"10.1177/09727531211023755","pmid":"35341224","pmcid":"PMC8948335","publicationDate":"2021-01-01","journal":"Annals of neurosciences","abstract":"$e7","categories":["mechanisms","therapeutics"],"tags":[],"studyType":"review","spikeSource":["infection"],"keyFindings":["BACKGROUND: Coronaviruses (CoVs) are single-stranded, polyadenylated, enveloped RNA of positive polarity with a unique potential to alter host tropism.","This has been exceptionally demonstrated by the emergence of deadly virus outbreaks of the past: Severe Acute Respiratory Syndrome (SARS-CoV) in 2003 and Middle East Respiratory Syndrome (MERS-CoV) in 2012.","SUMMARY: The 2019 outbreak by the new cross-species transmission of SARS-CoV-2 has put the world on alert."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":["Antivirals"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8948335/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/35341224/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-34307449","title":"Structural Basis of Glycan Recognition of Rotavirus.","authors":["Sun Xiaoman","Li Dandi","Duan Zhaojun"],"doi":"10.3389/fmolb.2021.658029","pmid":"34307449","pmcid":"PMC8296142","publicationDate":"2021-01-01","journal":"Frontiers in molecular biosciences","abstract":"$e8","categories":["persistence","mechanisms"],"tags":["vaccine"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["Rotavirus (RV) is an important pathogen causing acute gastroenteritis in young humans and animals.","Attachment to the host receptor is a crucial step for the virus infection.","The recent advances in illustrating the interactions between RV and glycans promoted our understanding of the host range and epidemiology of RVs."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8296142/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/34307449/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-32941780","title":"Therapeutic antibodies and fusion inhibitors targeting the spike protein of SARS-CoV-2.","authors":["Jiang Shibo","Zhang Xiujuan","Du Lanying"],"doi":"10.1080/14728222.2020.1820482","pmid":"32941780","pmcid":"PMC7544964","publicationDate":"2021-01-01","journal":"Expert opinion on therapeutic targets","abstract":"","categories":["therapeutics"],"tags":[],"studyType":"clinical","spikeSource":["infection"],"keyFindings":[],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544964/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/32941780/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-32473127","title":"Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals.","authors":["Grifoni Alba","Weiskopf Daniela","Ramirez Sydney I","Mateus Jose","Dan Jennifer M","Moderbacher Carolyn Rydyznski","Rawlings Stephen A","Sutherland Aaron"],"doi":"10.1016/j.cell.2020.05.015","pmid":"32473127","pmcid":"PMC7237901","publicationDate":"2020-01-25","journal":"Cell","abstract":"Understanding adaptive immunity to SARS-CoV-2 is important for vaccine development, interpreting coronavirus disease 2019 (COVID-19) pathogenesis, and calibration of pandemic control measures. Using HLA class I and II predicted peptide \"megapools,\" circulating SARS-CoV-2-specific CD8+ and CD4+ T cells were identified in ∼70% and 100% of COVID-19 convalescent patients, respectively. CD4+ T cell responses to spike, the main target of most vaccine efforts, were robust and correlated with the magnitude of the anti-SARS-CoV-2 IgG and IgA titers. The M, spike, and N proteins each accounted for 11%-27% of the total CD4+ response, with additional responses commonly targeting nsp3, nsp4, ORF3a, and ORF8, among others. For CD8+ T cells, spike and M were recognized, with at least eight SARS-CoV-2 ORFs targeted. Importantly, we detected SARS-CoV-2-reactive CD4+ T cells in ∼40%-60% of unexposed individuals, suggesting cross-reactive T cell recognition between circulating \"common cold\" coronaviruses and SARS-CoV-2.","categories":["persistence","mechanisms"],"tags":["vaccine"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["Understanding adaptive immunity to SARS-CoV-2 is important for vaccine development, interpreting coronavirus disease 2019 (COVID-19) pathogenesis, and calibration of pandemic control measures.","Using HLA class I and II predicted peptide \"megapools,\" circulating SARS-CoV-2-specific CD8+ and CD4+ T cells were identified in ∼70% and 100% of COVID-19 convalescent patients, respectively.","CD4+ T cell responses to spike, the main target of most vaccine efforts, were robust and correlated with the magnitude of the anti-SARS-CoV-2 IgG and IgA titers."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237901/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/32473127/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-33208819","title":"Serological follow-up of SARS-CoV-2 asymptomatic subjects.","authors":["Milani Gregorio Paolo","Dioni Laura","Favero Chiara","Cantone Laura","Macchi Chiara","Delbue Serena","Bonzini Matteo","Montomoli Emanuele"],"doi":"10.1038/s41598-020-77125-8","pmid":"33208819","pmcid":"PMC7674414","publicationDate":"2020-01-18","journal":"Scientific reports","abstract":"$e9","categories":["persistence","symptoms"],"tags":[],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["SARS-CoV-2 symptoms are non-specific and can range from asymptomatic presentation to severe pneumonia.","Asymptomatic subjects carrying SARS-CoV-2 often remain undiagnosed and it is still debated whether they develop immunoglobulins (Ig) and how long they persist.","The aim of this study was to investigate the development and persistence of antibodies against SARS-CoV-2 in asymptomatic subjects infected by the virus."],"persistenceDuration":"Up to 8 weeks","mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674414/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/33208819/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-34041482","title":"Targeting the SARS-CoV-2-spike protein: from antibodies to miniproteins and peptides.","authors":["Pomplun Sebastian"],"doi":"10.1039/d0md00385a","pmid":"34041482","pmcid":"PMC8128053","publicationDate":"2020-01-17","journal":"RSC medicinal chemistry","abstract":"Coronavirus disease-19, caused by the novel β-coronavirus SARS-CoV-2, has created a global pandemic unseen in a century. Rapid worldwide efforts have enabled the characterization of the virus and its pathogenic mechanism. An early key finding is that SARS-CoV-2 uses spike proteins, the virus' most exposed structures, to bind to human ACE2 receptors and initiate cell invasion. Competitive targeting of the spike protein is a promising strategy to neutralize virus infectivity. This review article summarizes the discovery, binding modes and eventual applications of several classes of (bio)molecules targeting the spike protein: antibodies, nanobodies, soluble ACE2 variants, miniproteins, peptides and small molecules.","categories":["mechanisms"],"tags":[],"studyType":"review","spikeSource":["infection"],"keyFindings":["Coronavirus disease-19, caused by the novel β-coronavirus SARS-CoV-2, has created a global pandemic unseen in a century.","Rapid worldwide efforts have enabled the characterization of the virus and its pathogenic mechanism.","An early key finding is that SARS-CoV-2 uses spike proteins, the virus' most exposed structures, to bind to human ACE2 receptors and initiate cell invasion."],"persistenceDuration":null,"mechanisms":["ACE2 binding"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128053/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/34041482/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-32846196","title":"Prospect of SARS-CoV-2 spike protein: Potential role in vaccine and therapeutic development.","authors":["Samrat Subodh Kumar","Tharappel Anil M","Li Zhong","Li Hongmin"],"doi":"10.1016/j.virusres.2020.198141","pmid":"32846196","pmcid":"PMC7443330","publicationDate":"2020-01-15","journal":"Virus research","abstract":"$ea","categories":["mechanisms","therapeutics"],"tags":["vaccine"],"studyType":"review","spikeSource":["both"],"keyFindings":["The recent outbreak of the betacoronavirus SARS-CoV-2 has become a significant concern to public health care worldwide.","As of August 19, 2020, more than 22,140,472 people are infected, and over 781,135 people have died due to this deadly virus.","In the USA alone, over 5,482,602 people are currently infected, and more than 171,823 people have died."],"persistenceDuration":null,"mechanisms":["ACE2 binding"],"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443330/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/32846196/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-33159009","title":"Preexisting and de novo humoral immunity to SARS-CoV-2 in humans.","authors":["Ng Kevin W","Faulkner Nikhil","Cornish Georgina H","Rosa Annachiara","Harvey Ruth","Hussain Saira","Ulferts Rachel","Earl Christopher"],"doi":"10.1126/science.abe1107","pmid":"33159009","pmcid":"PMC7857411","publicationDate":"2020-01-11","journal":"Science (New York, N.Y.)","abstract":"Zoonotic introduction of novel coronaviruses may encounter preexisting immunity in humans. Using diverse assays for antibodies recognizing SARS-CoV-2 proteins, we detected preexisting humoral immunity. SARS-CoV-2 spike glycoprotein (S)-reactive antibodies were detectable using a flow cytometry-based method in SARS-CoV-2-uninfected individuals and were particularly prevalent in children and adolescents. They were predominantly of the immunoglobulin G (IgG) class and targeted the S2 subunit. By contrast, SARS-CoV-2 infection induced higher titers of SARS-CoV-2 S-reactive IgG antibodies targeting both the S1 and S2 subunits, and concomitant IgM and IgA antibodies, lasting throughout the observation period. SARS-CoV-2-uninfected donor sera exhibited specific neutralizing activity against SARS-CoV-2 and SARS-CoV-2 S pseudotypes. Distinguishing preexisting and de novo immunity will be critical for our understanding of susceptibility to and the natural course of SARS-CoV-2 infection.","categories":["persistence"],"tags":[],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["Zoonotic introduction of novel coronaviruses may encounter preexisting immunity in humans.","Using diverse assays for antibodies recognizing SARS-CoV-2 proteins, we detected preexisting humoral immunity.","SARS-CoV-2 spike glycoprotein (S)-reactive antibodies were detectable using a flow cytometry-based method in SARS-CoV-2-uninfected individuals and were particularly prevalent in children and adolescents."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857411/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/33159009/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-33161277","title":"COVID-19 update: The race to therapeutic development.","authors":["Twomey Julianne D","Luo Shen","Dean Alexis Q","Bozza William P","Nalli Ancy","Zhang Baolin"],"doi":"10.1016/j.drup.2020.100733","pmid":"33161277","pmcid":"PMC7584885","publicationDate":"2020-01-01","journal":"Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy","abstract":"$eb","categories":["mechanisms","therapeutics"],"tags":["vaccine"],"studyType":"review","spikeSource":["both"],"keyFindings":["The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), represents an unprecedented challenge to global public health.","At the time of this review, COVID-19 has been diagnosed in over 40 million cases and associated with 1.1 million deaths worldwide.","Current management strategies for COVID-19 are largely supportive, and while there are more than 2000 interventional clinical trials registered with the U.S."],"persistenceDuration":null,"mechanisms":["ACE2 binding"],"therapeuticTargets":["Antivirals"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584885/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/33161277/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-32768882","title":"Targeting SARS-CoV2 Spike Protein Receptor Binding Domain by Therapeutic Antibodies.","authors":["Hussain Arif","Hasan Anwarul","Nejadi Babadaei Mohammad Mahdi","Bloukh Samir Haj","Chowdhury Muhammad E H","Sharifi Majid","Haghighat Setareh","Falahati Mojtaba"],"doi":"10.1016/j.biopha.2020.110559","pmid":"32768882","pmcid":"PMC7395593","publicationDate":"2020-01-01","journal":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","abstract":"$ec","categories":["mechanisms","therapeutics"],"tags":["vaccine"],"studyType":"review","spikeSource":["vaccine-derived"],"keyFindings":["As the number of people infected with the newly identified 2019 novel coronavirus (SARS-CoV2) is continuously increasing every day, development of potential therapeutic platforms is vital.","Based on the comparatively high similarity of receptor-binding domain (RBD) in SARS-CoV2 and SARS-CoV, it seems crucial to assay the cross-reactivity of anti-SARS-CoV monoclonal antibodies (mAbs) with SARS-CoV2 spike (S)-protein.","Indeed, developing mAbs targeting SARS-CoV2 S-protein RBD could show novel applications for rapid and sensitive development of potential epitope-specific vaccines (ESV)."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":["Monoclonal antibodies"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395593/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/32768882/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-32407507","title":"Genomic Epidemiology, Evolution, and Transmission Dynamics of Porcine Deltacoronavirus.","authors":["He Wan-Ting","Ji Xiang","He Wei","Dellicour Simon","Wang Shilei","Li Gairu","Zhang Letian","Gilbert Marius"],"doi":"10.1093/molbev/msaa117","pmid":"32407507","pmcid":"PMC7454817","publicationDate":"2020-01-01","journal":"Molecular biology and evolution","abstract":"$ed","categories":["mechanisms"],"tags":["s1-subunit"],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has shown once again that coronavirus (CoV) in animals are potential sources for epidemics in humans.","Porcine deltacoronavirus (PDCoV) is an emerging enteropathogen of swine with a worldwide distribution.","Here, we implemented and described an approach to analyze the epidemiology of PDCoV following its emergence in the pig population."],"persistenceDuration":"Up to 15 years","mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454817/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/32407507/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-32231345","title":"Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion.","authors":["Xia Shuai","Liu Meiqin","Wang Chao","Xu Wei","Lan Qiaoshuai","Feng Siliang","Qi Feifei","Bao Linlin"],"doi":"10.1038/s41422-020-0305-x","pmid":"32231345","pmcid":"PMC7104723","publicationDate":"2020-01-01","journal":"Cell research","abstract":"$ee","categories":["mechanisms","therapeutics"],"tags":[],"studyType":"clinical","spikeSource":["infection"],"keyFindings":["The recent outbreak of coronavirus disease (COVID-19) caused by SARS-CoV-2 infection in Wuhan, China has posed a serious threat to global public health.","To develop specific anti-coronavirus therapeutics and prophylactics, the molecular mechanism that underlies viral infection must first be defined.","Therefore, we herein established a SARS-CoV-2 spike (S) protein-mediated cell-cell fusion assay and found that SARS-CoV-2 showed a superior plasma membrane fusion capacity compared to that of SARS-CoV."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104723/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/32231345/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-29125455","title":"ICTV Virus Taxonomy Profile: Pleolipoviridae.","authors":["Bamford Dennis H","Pietilä Maija K","Roine Elina","Atanasova Nina S","Dienstbier Ana","Oksanen Hanna M","Ictv Report Consortium"],"doi":"10.1099/jgv.0.000972","pmid":"29125455","pmcid":"PMC5882103","publicationDate":"2017-01-01","journal":"The Journal of general virology","abstract":"Members of the family Pleolipoviridae (termed pleolipoviruses) are pseudo-spherical and pleomorphic archaeal viruses. The enveloped virion is a simple membrane vesicle, which encloses different types of DNA genomes of approximately 7-16 kbp (or kilonucleotides). Typically, virions contain a single type of transmembrane (spike) protein at the envelope and a single type of membrane protein, which is embedded in the envelope and located in the internal side of the membrane. All viruses infect extremely halophilic archaea in the class Halobacteria (phylum Euryarchaeota). Pleolipoviruses have a narrow host range and a persistent, non-lytic life cycle. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the taxonomy of the Pleolipoviridae which is available at www.ictv.global/report/pleolipoviridae.","categories":["persistence"],"tags":[],"studyType":"clinical","spikeSource":["unspecified"],"keyFindings":["Members of the family Pleolipoviridae (termed pleolipoviruses) are pseudo-spherical and pleomorphic archaeal viruses.","The enveloped virion is a simple membrane vesicle, which encloses different types of DNA genomes of approximately 7-16 kbp (or kilonucleotides).","Typically, virions contain a single type of transmembrane (spike) protein at the envelope and a single type of membrane protein, which is embedded in the envelope and located in the internal side of the membrane."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882103/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/29125455/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-27936982","title":"MERS-CoV spike protein: a key target for antivirals.","authors":["Du Lanying","Yang Yang","Zhou Yusen","Lu Lu","Li Fang","Jiang Shibo"],"doi":"10.1080/14728222.2017.1271415","pmid":"27936982","pmcid":"PMC5457961","publicationDate":"2017-01-01","journal":"Expert opinion on therapeutic targets","abstract":"$ef","categories":["mechanisms","therapeutics"],"tags":[],"studyType":"review","spikeSource":["infection"],"keyFindings":["The continual Middle East respiratory syndrome (MERS) threat highlights the importance of developing effective antiviral therapeutics to prevent and treat MERS coronavirus (MERS-CoV) infection.","A surface spike (S) protein guides MERS-CoV entry into host cells by binding to cellular receptor dipeptidyl peptidase-4 (DPP4), followed by fusion between virus and host cell membranes.","MERS-CoV S protein represents a key target for developing therapeutics to block viral entry and inhibit membrane fusion."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":["Monoclonal antibodies","Antivirals"],"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5457961/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/27936982/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-28090561","title":"Diversity in Rotavirus-Host Glycan Interactions: A \"Sweet\" Spectrum.","authors":["Ramani Sasirekha","Hu Liya","Venkataram Prasad B V","Estes Mary K"],"doi":"10.1016/j.jcmgh.2016.03.002","pmid":"28090561","pmcid":"PMC5042371","publicationDate":"2016-01-01","journal":"Cellular and molecular gastroenterology and hepatology","abstract":"$f0","categories":["persistence","mechanisms"],"tags":["vaccine"],"studyType":"clinical","spikeSource":["both"],"keyFindings":["Interaction with cellular glycans is a critical initial step in the pathogenesis of many infectious agents.","Technological advances in glycobiology have expanded the repertoire of studies delineating host glycan-pathogen interactions.","For rotavirus, the VP8* domain of the outer capsid spike protein VP4 is known to interact with cellular glycans."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5042371/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/28090561/","reviewed":false,"lastUpdated":"2026-07-06"},{"id":"pmid-27712624","title":"Feline Coronaviruses: Pathogenesis of Feline Infectious Peritonitis.","authors":["Tekes G","Thiel H-J"],"doi":"10.1016/bs.aivir.2016.08.002","pmid":"27712624","pmcid":"PMC7112361","publicationDate":"2016-01-01","journal":"Advances in virus research","abstract":"$f1","categories":["persistence","mechanisms"],"tags":[],"studyType":"review","spikeSource":["both"],"keyFindings":["Feline infectious peritonitis (FIP) belongs to the few animal virus diseases in which, in the course of a generally harmless persistent infection, a virus acquires a small number of mutations that fundamentally change its pathogenicity, invariably resulting in a fatal outcome.","The causative agent of this deadly disease, feline infectious peritonitis virus (FIPV), arises from feline enteric coronavirus (FECV).","The review summarizes our current knowledge of the genome and proteome of feline coronaviruses (FCoVs), focusing on the viral surface (spike) protein S and the five accessory proteins."],"persistenceDuration":null,"mechanisms":null,"therapeuticTargets":null,"symptoms":null,"pdfUrl":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7112361/pdf/","pubmedUrl":"https://pubmed.ncbi.nlm.nih.gov/27712624/","reviewed":false,"lastUpdated":"2026-07-06"}]}]}]]}]
19:["$","section",null,{"id":"limitations","children":[["$","h2",null,{"className":"text-2xl font-semibold text-foreground","children":"Limitations & uncertainty"}],["$","p",null,{"className":"mt-3 leading-relaxed","children":"Heterogeneous cohorts, assay variability, selection bias toward symptomatic patients, and small autopsy series limit generalizability. Persistence does not equal pathogenicity. Causality between spike detection and clinical symptoms remains unproven in randomized studies."}]]}]
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