Comparative analysis of replication and immune evasion among SARS-CoV-2 subvariants BA.2.86, JN.1, KP.2, and KP.3

The study advances our understanding of the roles of immune evasion and replication fitness in driving the evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from the BA.2.86 sublineage to its descendants (JN.1, KP.2, and KP.3). Through head-to-head comparisons of the replication fitness of recombinant SARS-CoV-2 strains containing spike sequences from BA.2.86 and its descendants in primary human airway epithelium cells, alongside assessments of their neutralization sensitivity to human sera, we revealed how recurrent mutations R346T, L455S, F456L, and Q493E in the receptor-binding domain (RBD) fine-tune immune evasion and viral replication fitness, underscoring the critical need for updated countermeasures to combat newly emerged SARS-CoV-2 variants. Additionally, our analysis showed that the L455S and Q493E mutations in the RBD can influence spike cleavage, offering new insights into SARS-CoV-2 spike biology.