MG-101, a cysteine protease inhibitor identified through high-throughput screening, exhibits in vivo efficacy and synergy with remdesivir against SARS-CoV-2.

The rapid evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has compromised the efficacy of many authorized monoclonal antibody products. This highlights the need for alternative strategies, especially for vulnerable populations such as immunocompromised individuals. Here, we optimized angiotensin-converting enzyme 2 (ACE2)-Fc fusion proteins by combining three engineering steps: in silico mutagenesis of the S protein binding interface to increase affinity, insertion of a flexible linker to improve protein stability and S protein accessibility, and generation of a tetrameric molecule to maximize avidity. Neutralizing activity was tested against a large panel of pre-Omicron and Omicron pseudoviruses and authentic viruses, including JN.1 and KP.2 variants. Optimized ACE2-Fc molecules demonstrated potent neutralizing activity, in the picomolar range, against all SARS-CoV-2 variants. Our molecules displayed similar potency but better resilience when compared to the monoclonal antibody Sipavibart. These findings support ACE2-Fc proteins as robust candidates for next-generation interventions against infection by an evolving SARS-CoV-2.

Targeting emerging viruses with phage display-driven engineered antibodies: Bridging molecular design and clinical application.

SARS-CoV-2 fusion-peptide-directed antibodies are elicited by natural infection and can mediate broad sarbecovirus neutralization.

Decoding emerging viral sepsis: Molecular crosstalk, dysregulation, and precision strategies.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection causes not only acute respiratory illness but also dysregulated immune responses, including autoimmunity and hypersensitivity reactions, which can worsen outcomes. SARS-CoV-2 infection, known publicly as COVID-19 disease, has presented a complex clinical landscape ranging from asymptomatic infection to SARS and multi-organ failure. Beyond direct viral damage, the pathogenesis of COVID-19 is heavily driven by immune dysregulation, which causes allergic-type reactions. Nutritional status and immunonutrition further modulate these processes and play a critical role. Vitamins C and D are essential for immune competence, with vitamin C serving as an antioxidant that supports barrier integrity and leukocyte function. In contrast, vitamin D regulates innate and adaptive responses. The intake of essential nutrients could be a strategic approach to bolster the innate and adaptive immune systems, aiming to prevent infection and mitigate disease severity. Saliva and oral health are increasingly recognized as central to COVID-19 immunopathology, both as diagnostic media and as immunological barriers. This review synthesizes recent findings on autoimmune phenomena, hypersensitivity reactions, immunonutrition, and oral health in SARS-CoV-2 infection, highlighting mechanisms and clinical implications.

Analysis of Ibuzatrelvir's Activity Against SARS-CoV-2 Circulating Variants and In Vitro Resistance Mutations.

Reported cases of acute liver injury with autoimmune features post-COVID-19 vaccination raise questions about whether this represents vaccine-triggered autoimmune hepatitis (AIH) or self-limiting drug-induced autoimmune-like hepatitis (DI-ALH). We report follow-up data to determine if the disease course is self-limiting or immunosuppression-dependent. Members of the International AIH Group and the European Reference Network on Hepatological Diseases who contributed cases to our original cohort provide follow-up data at 6 months, 12 months, and at last follow-up. Sixty-two patients (median age 56 years, 35 female) were included (median follow-up: 22.8 months). Fifty-eight (93%) received steroids ± azathioprine/mycophenolate. Four died of non-liver-related causes. Transaminases normalization rates were 71, 92, and 90% at 6 months, 12 months, and last follow-up, respectively. Twenty-four had a DI-ALH-like course, with ALT normalization and no relapse with or without (n = 4) a short (<9 months) immunosuppressive treatment. Nineteen had an AIH-like course, with relapse after discontinuation (n = 11) or persistent ALT elevation despite treatment (n = 8). Nineteen were unclassified. Risk factors for AIH-like progression included a higher revised AIH score, advanced fibrosis, and severe interface hepatitis. Most cases resemble DI-ALH, which we propose naming severe acute respiratory syndrome coronavirus 2 vaccine-associated liver injury, but a significant subset requires long-term immunosuppression, resembling classical AIH.

Global outbreaks of human immunodeficiency virus (HIV) and respiratory viruses - severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza, accounted for ~50 million infections in 2024. Prenatal exposure to these viruses poses substantial risks to maternal and fetal health, yet the underlying immunological mechanisms remain incompletely understood. Despite differences in viral biology and transmission, mounting evidence reveals a convergent theme of maternal immune activation during pregnancy. Even without vertical transmission, virus-elicted maternal immune responses alter the maternal-fetal interface and gut microbiome, reshaping fetal immunity and birth outcomes. These immune perturbations increase susceptibility to infections, neurodevelopmental disorders, and immune-mediated diseases later in life. Here, we discuss viral immune evasion strategies that modulate maternal immunity and review current clinical and emerging therapeutic approaches aimed at mitigating long-term consequences in exposed children. Understanding how prenatal viral exposure shapes lifelong health is critical for developing targeted interventions and reducing postnatal disease burden.

Coronaviruses remain a challenge due to the limited or incomplete protection provided by existing vaccines, highlighting the need for improved antigen-based designs that can reduce mortality, block transmission, and provide long-lasting, broad-spectrum protection. In this study, we adapted artificial antibody strategies to display receptor-binding domains (RBDs) from representative human coronaviruses, utilizing an engineered human IgG1 framework modified at the Fab and Fc domains to support diverse antigen presentation and enhanced immunopotentiation. The results indicate that bivalent, tetravalent, and multivalent RBD constructs developed within this framework confer broad-spectrum immune protection against severe acute respiratory syndrome coronavirus 2 and other pathogenic coronaviruses. Moreover, Fc-mediated antigen delivery, primarily engaging the neonatal Fcγ receptor, enhances mucosal, cellular, and sustained immune responses. This underscores the versatility and practical utility of the modified IgG1 framework, based on artificial antibody strategies, for developing broad-spectrum mucosal vaccine antigens, representing promising vaccine candidates targeting human coronaviruses.

Background Neutralising antibodies and infection with the newest severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant NB.1 in Chinese Felis silvestris catus remains unclear. This study compared the capability of neutralising antibodies in serum against the NB.1 variant prevalent in 2025 with that of the JN.1 variant circulating in 2024 among ill Chinese Felis silvestris catus , and determined whether they could be infected with SARS-CoV-2 variants. Methods A total of 392 serum samples from ill cats were subjected to enzyme-linked immunosorbent assay (ELISA) to detect the concentration of total antibodies against the receptor-binding domain of SARS-CoV-2; 40 serum samples screened positive by ELISA were subjected to pseudovirus neutralisation test to detect the titres of neutralising antibodies against the JN.1 and NB.1 variants, and 132 throat swab samples from ill cats were screened using specific reverse transcription polymerase chain reaction. Results The geometric mean neutralising titres against the total, NB.1, and JN.1 Omicron variants were 9.51 (95% confidence interval: 7.34–12.3), 24.26 (18.84–31.23), and 48.79 (36.51–65.21) among 40 serum samples from ill cats, respectively. Therefore, neutralisation assays against JN.1 and NB.1 indicated 5.1- and 2.6-fold reductions in neutralising antibody titres, respectively, compared with the total antibody. Additionally, NB.1 showed a 2.91-fold reduction in neutralising antibody titres compared with JN.1. None of the throat swabs from the 132 ill cats were found to be infected with SARS-CoV-2 variants. Conclusions NB.1 showed increased immune escape capacity in serum compared with JN.1 among Chinese Felis silvestris catus , suggesting that researchers should include the NB.1 antigen in COVID-19 vaccine candidates.

Kaposi’s Sarcoma-associated herpesvirus (KSHV) and Epstein–Barr virus (EBV) are oncogenic gammaherpesviruses with high prevalence in sub-Saharan Africa. Both viruses are typically acquired during childhood, establishing lifelong latency. While viral reactivation into the lytic cycle has been mainly studied in adult HIV-infected populations—and more recently in the context of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) co-infection—the dynamics of KSHV and EBV infection in children remain poorly understood. Here, we characterize pediatric patients (n = 175; median age 4.6 years; IQR 2.0–8.3) presenting with inflammatory conditions during the COVID-19 pandemic in South Africa (from July 2020 to February 2024). Including a healthy, non-inflammatory control group, we found widespread exposure to SARS-CoV-2 (70.9% seropositivity), with 72.6% of the children being seropositive for EBV and 19.4% for KSHV. There were no significant differences in seroprevalence between children with inflammatory conditions and healthy controls for any of these viruses, although SARS-CoV-2 antibody titers were significantly higher in the inflammatory group, while EBV immune responses were lower in children presenting with inflammation. Among the KSHV-seropositive children, no active viremia was detected (as determined by the absence of viral DNA in the peripheral blood). In contrast, 34.4% of EBV-seropositive children had detectable EBV viral load, with a modestly higher proportion in the inflammatory group. However, EBV viral load levels were comparable between children diagnosed with Multisystem Inflammatory Syndrome in Children (MIS-C), Kawasaki Disease (KD), and other inflammatory conditions. Logistic regression analyses revealed that increasing age was significantly associated with higher risk of SARS-CoV-2 and EBV seropositivity, but not KSHV. Notably, the risk of EBV DNA detection in the peripheral blood decreased with age. In summary, this study suggests effective immunological control of gammaherpesvirus infections in HIV-negative paediatric patients, even in the presence of inflammatory conditions that might otherwise trigger viral reactivation.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection results in dysregulated inflammatory and coagulation pathways that drive immunothrombosis and contribute to adverse clinical outcomes. While individual cytokines and endothelial biomarkers have been associated with disease severity and mortality, the prognostic relevance of combined inflammatory and endothelial signatures remains incompletely characterised. To identify inflammatory cytokines and markers of endothelial activation associated with mortality in patients with severe COVID-19 requiring supplemental oxygen. This retrospective observational study included 73 consecutive adults admitted to a dedicated supplemental oxygen unit with severe COVID-19. Plasma concentrations of IL-1α, IL-1β, IL-6, IL-8, IL-10, TNF-α, von Willebrand factor (VWF) antigen and propeptide, ADAMTS13 antigen and activity, and ADAMTS13 autoantibodies were measured on admission using ELISA-based assays. Associations with mortality were assessed using non-parametric analyses, age-adjusted logistic regression, multivariable logistic regression, and receiver operating characteristic (ROC) curve analysis. Increasing age was independently associated with mortality. After adjustment for age, higher IL-1α concentrations were associated with increased odds of death, whereas a higher IL-6/IL-10 ratio was independently protective. In multivariable models, including non-ratio variables, ADAMTS13 autoantibody levels remained independently associated with mortality. In ratio-based multivariable analysis, both the ADAMTS13 activity/autoantibody ratio and the IL-6/IL-10 ratio were independently protective, while age was no longer significant. IL-10 and ADAMTS13 autoantibodies demonstrated moderate discriminative performance for mortality prediction (AUC ~0.70). A combined biomarker model incorporating IL-1α, IL-8, IL-10, and ADAMTS13 autoantibodies yielded very high predicted mortality probabilities. Our findings highlight IL-1α and ADAMTS13 autoantibodies as independent predictors of mortality in severe COVID-19, reflecting the interplay between inflammatory and endothelial pathways. Biomarker ratios capturing immune and endothelial balance—particularly the ADAMTS13 activity/autoantibody ratio—may enhance risk stratification and support integrated prognostic models.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to cause significant morbidity and mortality despite the end of its pandemic phase. The emergence of highly mutated SARS-CoV-2 variants of concern highlights the requirement of broad-spectrum antiviral countermeasures which possess both prophylactic and therapeutic efficacies. Here, we obtain a macrocyclic peptide, 6L3-3P11K, that effectively inhibits a wide range of SARS-CoV-2 variants and subvariants. Structural studies show that 6L3-3P11K forms homotrimers that lock the spike protein (S) trimer into a "closed" conformation by engaging a conserved non-receptor binding motif (non-RBM) of S. This interaction disrupts the binding between S and ACE2 receptor. Structure-guided modifications result in a thermostable and trypsin-resistant macrocyclic peptide, 6L3-1F3P11hR, that exhibits prophylactic and therapeutic effects against SARS-CoV-2 infection in a male hACE2 transgenic mouse model after intranasal administration. Our results provide a drug candidate for the control and prevention of COVID-19 and may stimulate further research on macrocyclic broad-spectrum anti-coronavirus drug development.

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.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of COVID-19, has affected millions of people worldwide and significantly impacted public health. The detection of viral RNA in the feces of infected individuals prompted several countries to adopt wastewater-based epidemiology (WBE) as a tool to monitor SARS-CoV-2 circulation within communities. However, most surveillance studies have focused on large urban centers. This study aimed to analyze the presence and persistence of SARS-CoV-2 in wastewater from two small Brazilian towns with low socioeconomic indicators, limited sewage coverage, and low population density, located in northern Minas Gerais. Wastewater samples were collected biweekly over 12 months, between 2023 and 2024, from three sampling points in Salinas and one in Rubelita. Viral RNA was concentrated using electronegative membranes, and SARS-CoV-2 detection was performed using real-time quantitative polymerase chain reaction. SARS-CoV-2 RNA was detected at all sampling points, with a high frequency of positive samples observed in May, June, October, November 2023, and January 2024. Notably, viral RNA was detected even after the World Health Organization declared the end of the global health emergency on May 5, 2023, and in the absence of officially reported human cases. These findings underscore the value of wastewater surveillance as a tool for monitoring SARS-CoV-2, particularly in areas with limited clinical testing capacity. The study highlights the potential of WBE to detect ongoing viral transmission across diverse urban and socioeconomic contexts, including regions with case underreporting and challenges in mass testing, thereby supporting public health preparedness and response.

Palmitoylation is a reversible post‐translational modification that enhances protein hydrophobicity and regulates cellular functions such as trafficking and signaling. In humans, this modification is catalyzed by 23 DHHC enzymes, but the mechanisms by which they recognize their substrates remain unclear. The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) spike protein undergoes palmitoylation primarily by DHHC20 with subsequent modification by DHHC9 at 10 cytoplasmic tail (CT) cysteines, a modification crucial for membrane fusion and viral entry. Using AlphaFold2 modeling and site‐directed mutagenesis, we identified three key components critical for efficient spike palmitoylation: (i) Lys1211 at the ectodomain–transmembrane domain (TMD) interface, likely facilitating electrostatic interactions with DHHC20's acidic residues; (ii) a stable trimeric TMD helix, where mutations at the trimer interface impair palmitoylation, in contrast to changes in outward‐facing residues; and (iii) a conserved hydrophilic motif in the CT, located between acylated cysteine clusters, likely promoting optimal substrate positioning near DHHC20's catalytic site. Co‐immunoprecipitation assays revealed that mutations in these residues disrupt spike‐DHHC20 interactions, while leaving spike–DHHC9 binding unchanged, suggesting that they affect enzyme‐substrate complex formation. Fusion assays revealed nuanced effects; while palmitoylation generally correlated positively with membrane fusion, certain exceptions highlighted the complex relationship between these processes. Mutations in the CT markedly reduce total spike palmitoylation but only modestly affect cell–cell fusion. Some substitutions in the TMD impair fusion with little change in overall acylation. Our findings elucidate the structural and biophysical determinants of spike palmitoylation and its distinct roles in membrane fusion, offering insights into SARS‐CoV‐2 pathogenesis and potential antiviral targets.

The host genetics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have previously been studied based on cases from the earlier waves of the pandemic in 2020 and 2021, identifying 51 genomic loci associated with infection and/or severity. SARS-CoV-2 has shown rapid sequence evolution, increasing transmissibility, particularly for Omicron variants, which raises the question of whether this affected the host genetic factors. We performed a genome-wide association study of SARS-CoV-2 infection with Omicron variants, including more than 150,000 cases from four cohorts. We identified 13 genome-wide significant loci, of which only five were previously described as associated with SARS-CoV-2 infection. The strongest signal was a single nucleotide polymorphism in an intron of ST6GAL1, a gene affecting immune development and function, connected to three other associated loci (harboring MUC1, MUC5AC and MUC16) through O-glycan biosynthesis. Our study provides robust evidence for individual genetic variation related to glycosylation, translating into susceptibility to SARS-CoV-2 infections with Omicron variants.

Since its first detection in 2019, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has infected approximately 778million people and claimed 7.1million lives globally. A deeper understanding of the biology of SARS-CoV-2 was instrumental in facilitating the development of protective vaccines and new therapeutics, as well as evaluating the impact of drug re-purposing to limit the pandemic. To date, approximately 13.64billion vaccine doses have been administered; with approximately 67% of the global population having completed their primary series of COVID-19 vaccinations. The FDA has authorised the use of several repurposed drugs to combat the disease and while these developments have been instrumental in curbing the pandemic, the approved therapies have shown poor efficacy in cases of severe disease. Furthermore, several vaccine candidates received FDA approval following clinical trials where they proved to be both safe and efficacious. These vaccines were sanctioned for emergency roll-out to the global population, conferring herd immunity and reducing both infections and related mortalities. However, these vaccines are not without flaws and are limited by short term immune responses and poor efficacy against emerging variants, which has resulted in slip-through infections. Hence, efforts to develop potent drugs and vaccines are continuing. In these efforts, physiologically relevant models of SARS-CoV-2 infection are critical. This review describes available SARS-CoV-2 particle mimics, their contribution to COVID-19 research and the development of new vaccines and therapies.

ABSTRACT Since its emergence in late 2019, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has continuously threatened human health through constantly arising variants with iterative immune escape abilities. While SARS-CoV-2 variants have been recently classified into six serotypes based on cross-reactive antibody responses, T cell response features against these serotypes remain largely unknown. We evaluated SARS-CoV-2 spike-specific T cell responses among convalescents infected by three different strains (prototype, BA.5.2/BF.7, and XBB/EG.5.1) against SARS-CoV-2 prototype and 15 subvariants covering all six serotypes. Generally, cross-reactive T cells could recognize variants within the same serotype, but they also mounted weaker responses to variants from subsequent serotypes. Serotype I (prototype) convalescents showed lower T cell responses against Omicron variants (Serotype II to IV), with cross-reactive T cell gaps between different serotype strains, i.e. Serotype II > III > IV. Serotype IV (BA.5.2/BF.7) convalescents exhibited weaker T cell responses to Serotype V (XBB/XBB.1.5/XBB.1.16/EG.5.1) strains and even lower responses to Serotype VI (BA.2.86/JN.1) strains. Similarly, Serotype V (XBB) convalescents showed significantly weaker cross-T cell responses to the Serotype VI (BA.2.86) strains than to the Serotype V strains. We also identified key serotype-signature mutations in T cell epitope hotspot regions that could attenuate CD8+ and/or CD4+ T cell recognition, potentially underlying SARS-CoV-2 serotype-associated T cell immune evasion mechanisms. Our findings reveal the pivotal role of population T cell immune barrier against emerging SARS-CoV-2 variants in a serotype-associated pattern and provide insights into the T cell-oriented universal vaccine development for coronaviruses.