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  ABSTRACT With the SARS-CoV-2 Omicron XBB.1.9 subvariants circulating worldwide, two XBB.1.9 variants, EG.5.1 and HK.3 , spread rapidly and became dominant in mid-2023. However, the spike features, pathogenicity, and transmissibility of HK.3 are largely unknown. Here, we performed multiscale investigations to reveal the virological features of XBB.1.9 subvariants , including the newly emerging HK.3 . HK.3 revealed high replication efficiency and enhanced TMPRSS2 utilization in vitro. The HK.3 spike exhibited enhanced processing, although its infectivity, fusogenicity, and human ACE2 (hACE2) binding affinity were comparable to those of the EG.5 and XBB.1 spikes. All XBB.1.9.1, EG.5.1, and HK.3 strains demonstrated efficient transmission in hamsters , although XBB.1.9.1 exhibited stronger fitness in the upper airways . XBB.1.9.1, EG.5.1, and HK.3 exhibited greater pathogenicity than BA.2 in H11-K18-hACE2 hamsters. Our studies provide insights into the newly emerging pathogens EG.5.1...

  Abstract The emergence of the SARS-CoV-2 JN.1 lineage in late 2023 marked a major shift in viral evolution . By January 2024, it had displaced XBB variants to become the dominant strain worldwide. JN.1 and its descendants are antigenically distinct from earlier Omicron subvariants , with approximately 30 additional spike mutations compared to XBB-derived viruses. The combination of these features alongside growing evidence of considerable immune evasion prompted the FDA to recommend that vaccine formulations be updated to target JN.1 rather than XBB.1.5. The continued dominance of JN.1-derived variants necessitates the characterization of viral infection in established animal models to inform vaccine efficacy and elucidate host–pathogen interactions driving disease outcomes. In this study, transgenic mice expressing human ACE2 were infected with SARS-CoV-2 subvariants JN.1, KP.2, and EG.5.1 to compare the pathogenicity of JN.1-lineage and XBB-lineage SARS-CoV-2 viruses. Infection...

Highlights •  This study evaluated differences in SARS-CoV-2 variant severity from 2020-2023 •  SARS-CoV-2 whole-genome sequencing from 6,916 respiratory swabs was performed •  Four conserved kmer sequences associated with severity were identified •  Infections from the Delta variant had highest likelihood of severe infection •  Omicron BA.4/5 variant was more severe than BA.1 in children, vice-versa in adults Abstract We performed virus whole-genome sequencing of 6,916 upper respiratory swabs from adults and children from March 2020 through May 2023 and collected clinical metadata to assess differences in SARS-CoV-2 variant severity and symptomatology. Multivariable logistic regression showed a severity peak with Delta , which had the highest likelihood of severe infection. In children , another peak was observed with BA.4/BA.5 , which was associated with more severe infection than both prior ( BA.1 ) and later ( BQ.1, BF.7, and XBB ) Omicron variants . In cont...

ABSTRACT The evolution of the antibody response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is impacted by the nature and number of antigenic exposures . First-generation coronavirus disease 2019 (COVID-19) vaccines encoded an ancestral spike protein . Updated bivalent vaccines and breakthrough infections have shaped the intricate diversity of the polyclonal antibody response and specificity of individual antibody clones. We and others previously showed that bivalent vaccines containing the ancestral and Omicron (BA.5) spikes induce high levels of cross-reactive antibodies but undetectable BA.5-specific antibodies in serum. Here, we assessed sera collected before as well as 1 and 3 months following administration of an updated XBB.1.5 monovalent vaccine to individuals with diverse infection and vaccination histories. Vaccination increased neutralization against recent variants of concern , including HV.1, JN.1 , and the vaccine-homologous XBB.1.5. Antibody bindi...

Abstract The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly evolved over short timescales, leading to the emergence of more transmissible variants such as Alpha and Delta.  The arrival of the Omicron variant marked a major shift, introducing numerous extra mutations in the spike gene compared with earlier variants. These evolutionary changes have raised concerns regarding their potential impact on immune evasion, disease severity and the effectiveness of vaccines and treatments. In this epidemiological study, we identified two distinct patterns in the protective effect of natural infection against reinfection in the Omicron versus pre-Omicron eras. Before Omicron, natural infection provided strong and durable protection against reinfection, with minimal waning over time. However, during the Omicron era, protection was robust only for those recently infected , declining rapidly over time and diminishing within a year. These results demonstrate that SARS-CoV...

Abstract As new SARS-CoV-2 variants continue to emerge , it is important to evaluate the potency of antiviral drugs to support their continued use. Remdesivir (RDV; VEKLURY®) an approved antiviral treatment for COVID-19, and obeldesivir (ODV) are inhibitors of the SARS-CoV-2 RNA-dependent RNA polymerase Nsp12. Here we show these two compounds retain antiviral activity against the Omicron variants BA.2.86, BF.7, BQ.1, CH.1.1, EG.1.2, EG.5.1, EG.5.1.4, FL.22, HK.3, HV.1, JN.1, JN.1.7, JN.1.18, KP.2, KP.3, LB.1, XBB.1.5, XBB.1.5.72, XBB.1.16, XBB.2.3.2, XBC.1.6, and XBF when compared with reference strains. Genomic analysis identified 29 Nsp12 polymorphisms in these and previous Omicron variants. Phenotypic analysis of these polymorphisms confirmed no impact on the antiviral activity of RDV or ODV and suggests Omicron variants containing these Nsp12 polymorphisms remain susceptible to both compounds. These data support the continued use of RDV in the context of circulating SARS-CoV-2 vari...

Abstract White-tailed deer (Odocoileus virginianus) have high value for research, conservation, agriculture, and recreation and might be key SARS-CoV-2 reservoirs . In November 2023, we sampled 15 female deer in a captive facility in Texas, USA . All deer had neutralizing antibodies to SARS-CoV-2 ; respiratory swab samples from 11 deer were SARS-CoV-2–positive by quantitative reverse transcription PCR, and 1 deer also had a positive rectal swab sample . Six of the 11 respiratory swab samples yielded infectious virus; replication kinetics of most samples displayed lower growth 24–48 hours postinfection in vitro than Omicron lineages isolated from humans in Texas in the same period. Virus growth was similar between groups by 72 hours, suggesting no strong attenuation of deer-derived virus. All deer viruses clustered in XBB Omicron clade and demonstrated more mutations than expected compared with contemporaneous viruses in humans, suggesting that crossing the species barrier was accompani...