Distinct evolution of SARS-CoV-2 Omicron XBB and BA.2.86 lineages combining increased fitness and antibody evasion.

The unceasing SARS-CoV-2 circulation in an immune population led to the continuous emergence of new viral sublineages. Here, we isolated and characterized XBF, XBB.1, XBB.1.5, XBB.1.9.1, XBB.1.16.1, EG.5.1.1, EG.5.1.3 and BA.2.86.1 variants, that represented >80% of circulating strains as of November 2023. These XBB subvariants carry few recurrent mutations in the spike, whereas BA.2.86.1 harbors >30 additional mutations. We compared their fitness in culture, sensitivity to antivirals and sera from vaccinees. These variants replicated in IGROV-1 and no longer in VeroE6 cells. They were not markedly fusogenic. BA.2.86.1 displayed the strongest binding to ACE2. They potently infected nasal epithelial cells, with EG.5.1.3 exhibiting the highest fitness. Nirmatrelvir, Remdesivir and Molnupiravir remained active, whereas Sotrovimab lost efficacy against BA.2.86.1. Neutralizing antibody (NAb) responses from vaccinees and BA.1/BA.2-infected individuals were 7 to 21-fold lower compared to BA.1, without major differences between variants. A breakthrough XBB infection enhanced NAb responses, particularly against XBB variants. Thus, while distinct, the evolution trajectory of these variants combines increased fitness and antibody evasion.