Enhanced evasion of neutralizing antibody response by Omicron XBB.1.5, CH.1.1, and CA.3.1 variants

Omicron subvariants continuingly challenge current vaccination strategies. Here, we demonstrate nearly complete escape of the XBB.1.5, CH.1.1, and CA.3.1 variants from neutralizing antibodies stimulated by three doses of mRNA vaccine or by BA.4/5 wave infection, but neutralization is rescued by a BA.5-containing bivalent booster. CH.1.1 and CA.3.1 show strong immune escape from monoclonal antibody S309. Additionally, XBB.1.5, CH.1.1, and CA.3.1 spike proteins exhibit increased fusogenicity and enhanced processing compared with BA.2. Homology modeling reveals the key roles of G252V and F486P in the neutralization resistance of XBB.1.5, with F486P also enhancing receptor binding. Further, K444T/M and L452R in CH.1.1 and CA.3.1 likely drive escape from class II neutralizing antibodies, whereas R346T and G339H mutations could confer the strong neutralization resistance of these two subvariants to S309-like antibodies. Overall, our results support the need for administration of the bivalent mRNA vaccine and continued surveillance of Omicron subvariants. [Display omitted] •Bivalent booster induces 2- to 8-fold higher nAb titer than monovalent against XBB and XBB.1.5•CH.1.1 and CA.3.1 exhibit nearly complete escape of neutralization from bivalent booster•XBB.1.5, CH.1.1, and CA.3.1 show increased fusogenicity compared with BA.2•Homology modeling shows impacts of F486P mutation present in XBB.1.5 on ACE2 binding Qu et al. show that bivalent booster recipients, compared with monovalent recipients, exhibit higher nAb titers against Omicron subvariants XBB, XBB.1, and XBB.1.5. The CH.1.1 and CA.3.1 variants show more substantial neutralization escape than the XBB variants. Further, structural modeling reveals that the F486P mutation in XBB.1.5 enhances ACE2 binding.