Prior SARS-CoV-2 infection affects adaptive immune responses to Omicron BA.4/BA.5 mRNA boosterWachter, Xu, Shi
et alJ Allergy Clin Immunol (2025)
Abstract: Bivalent coronavirus disease 2019 (COVID) mRNA vaccines encoding Wuhan-1 and Omicron BA.4/BA.5 spike proteins (S) can prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but the quality of adaptive immune responses and the importance of hybrid immunity are not well documented.Adaptive immune responses to the bivalent vaccine were studied in 40 healthy participants with (COVID+) or without (COVID-) history of SARS-CoV-2 infection.We analyzed anti-nucleocapsid protein and anti-S IgG titers and surrogate virus neutralization capacity against variants of concern and assessed SARS-CoV-2-specific B- and T-cell responses by high-dimensional spectral flow cytometry, intracellular cytokine staining assay on stimulation with SARS-CoV-2 peptides, and TRB and IGH repertoire analysis.The COVID+ group had higher anti-S IgG levels before and after boost and higher neutralization activity against BA.4/BA.5 than the COVID- group. Spike antibody levels positively correlated with neutralizing activity against Omicron variants of concern in all participants. For variants of concern, lowest neutralization capacity was against XBB.1.5. At baseline, the proportion of S1+RBD+ B cells was higher in COVID+ than in COVID- subjects, but an increase of these cells after boost was detected only in the COVID- group. Consistent with natural infection, COVID+ subjects had a higher frequency of IgA+CXCR3+S1+RBD+ B cells at baseline than COVID- subjects. CD4+ memory T-cell responses and breath of class II epitope SARS-CoV-2-specific clonotypes were increased after boost only in COVID- participants.The bivalent vaccine induces robust adaptive immune responses against the Omicron variant. Prior SARS-CoV-2 infection provides increased protection, but optimal timing of booster administration after natural infection should be defined to maximize benefits.Published by Elsevier Inc.
Induction of the Inflammasome by the SARS-CoV-2 Accessory Protein ORF9b, Abrogated by Small-Molecule ORF9b Homodimerization InhibitorsZodda, Pons, DeMoya-Valenzuela
et alJ Med Virol (2025) 97 (2), e70145
Abstract: Viral accessory proteins play critical roles in viral escape from host innate immune responses and in viral inflammatory pathogenesis. Here we show that the SARS-CoV-2 accessory protein, ORF9b, but not other SARS-CoV-2 accessory proteins (ORF3a, ORF3b, ORF6, ORF7, ORF8, ORF9c, and ORF10), strongly activates inflammasome-dependent caspase-1 in A549 lung carcinoma cells and THP-1 monocyte-macrophage cells. Exposure to lipopolysaccharide (LPS) and ATP additively enhanced the activation of caspase-1 by ORF9b, suggesting that ORF9b and LPS follow parallel pathways in the activation of the inflammasome and caspase-1. Following rational in silico approaches, we have designed small molecules capable of inhibiting the homodimerization of ORF9b, which experimentally inhibited ORF9b-ORF9b homotypic interactions, caused mitochondrial eviction of ORF9b, inhibited ORF9b-induced activation of caspase-1 in A549 and THP-1 cells, cytokine release in THP-1 cells, and restored type I interferon (IFN-I) signaling suppressed by ORF9b in both cell models. These small molecules are first-in-class compounds targeting a viral accessory protein critical for viral-induced exacerbated inflammation and escape from innate immune responses, with the potential of mitigating the severe immunopathogenic damage induced by highly pathogenic coronaviruses and restoring antiviral innate immune responses curtailed by viral infection.© 2025 Wiley Periodicals LLC.
A comprehensive review of current insights into the virulence factors of SARS-CoV-2Wang, Xia, Gao
J Virol (2025) 99 (2), e0204924
Abstract: The evolution of SARS-CoV-2 pathogenicity has been a major focus of attention. However, the determinants of pathogenicity are still unclear. Various hypotheses have attempted to elucidate the mechanisms underlying the evolution of viral pathogenicity, but a definitive conclusion has yet to be reached. Here, we review the potential impact of all proteins in SARS-CoV-2 on the viral pathogenic process and analyze the effects of their mutations on pathogenicity evolution. We aim to summarize which virus-encoded proteins are crucial in influencing viral pathogenicity, defined as disease severity following infection. Mutations in these key proteins, which are the virulence factors in SARS-CoV-2, may be the driving forces behind the evolution of viral pathogenicity. Mutations in the S protein can impact viral entry and fusogenicity. Mutations in proteins such as NSP2, NSP5, NSP14, and ORF7a can alter the virus's ability to suppress host protein synthesis and innate immunity. Mutations in NSP3, NSP4, NSP6, N protein, NSP5, and NSP12 may alter viral replication efficiency. The combined effects of mutations in the S protein and NSP6 can significantly reduce viral replication. In addition, various viral proteins, including ORF3a, ORF8, NSP4, Spike protein, N protein, and E protein, directly participate in the inflammatory process. Mutations in these proteins can modulate the levels of inflammation following infection. Collectively, these viral protein mutations can influence SARS-CoV-2 pathogenicity by impacting viral immune evasion, replication capacity, and the level of inflammation mediated by infection. In conclusion, the evolution of SARS-CoV-2 pathogenicity is likely determined by multiple virulence factors.
Identification of patient demographic, clinical, and SARS-CoV-2 genomic factors associated with severe COVID-19 using supervised machine learning: a retrospective multicenter studyNirmalarajah, Aftanas, Barati
et alBMC Infect Dis (2025) 25 (1), 132
Abstract: Drivers of COVID-19 severity are multifactorial and include multidimensional and potentially interacting factors encompassing viral determinants and host-related factors (i.e., demographics, pre-existing conditions and/or genetics), thus complicating the prediction of clinical outcomes for different severe acute respiratory syndrome coronavirus (SARS-CoV-2) variants. Although millions of SARS-CoV-2 genomes have been publicly shared in global databases, linkages with detailed clinical data are scarce. Therefore, we aimed to establish a COVID-19 patient dataset with linked clinical and viral genomic data to then examine associations between SARS-CoV-2 genomic signatures and clinical disease phenotypes.A cohort of adult patients with laboratory confirmed SARS-CoV-2 from 11 participating healthcare institutions in the Greater Toronto Area (GTA) were recruited from March 2020 to April 2022. Supervised machine learning (ML) models were developed to predict hospitalization using SARS-CoV-2 lineage-specific genomic signatures, patient demographics, symptoms, and pre-existing comorbidities. The relative importance of these features was then evaluated.Complete clinical data and viral whole genome level information were obtained from 617 patients, 50.4% of whom were hospitalized. Notably, inpatients were older with a mean age of 66.67 years (SD ± 17.64 years), whereas outpatients had a mean age of 44.89 years (SD ± 16.00 years). SHapley Additive exPlanations (SHAP) analyses revealed that underlying vascular disease, underlying pulmonary disease, and fever were the most significant clinical features associated with hospitalization. In models built on the amino acid sequences of functional regions including spike, nucleocapsid, ORF3a, and ORF8 proteins, variants preceding the emergence of variants of concern (VOCs) or pre-VOC variants, were associated with hospitalization.Viral genomic features have limited utility in predicting hospitalization across SARS-CoV-2 diversity. Combining clinical and viral genomic datasets provides perspective on patient specific and virus-related factors that impact COVID-19 disease severity. Overall, clinical features had greater discriminatory power than viral genomic features in predicting hospitalization.© 2025. The Author(s).
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