Virological characterization of SARS-CoV-2 BA.2.86 variants by assessing antiviral susceptibility, in vivo infectivity and replicative fitness

In late 2023, the BA.2.86 and EG.5.1 SARS-CoV-2 variants co-circulated globally, raising concerns about enhanced immune evasion and altered replicative capacity. In this study, we assessed their virological characteristics using live viruses. We evaluated sensitivity to therapeutic monoclonal antibodies and antivirals targeting NSP5 and NSP12, and performed direct competition assays. BA.2.86 displayed a complete loss of neutralization by Sotrovimab, consistent with the presence of the K356T escape mutation, whereas EG.5.1 retained similar susceptibility to its XBB ancestor. Both variants remained sensitive to antiviral compounds, with no evidence of resistance-linked mutations. In vivo, BA.2.86 showed reduced replication in hamster lungs (3–4 log10 reduction) and a moderate reduction in the upper respiratory airways, compared to an ancestral reference strain (B.1 D614G). Direct in vitro competition, in primary nasal cells, further confirmed the reduced fitness of BA.2.86 relative to EG.5.1. Altogether, these results underscore the limited replicative potential of BA.2.86 despite immune escape and emphasize the value of assessing emerging SARS-CoV-2 variants using native viruses.