Structural basis for broad neutralization of human antibody against Omicron sublineages and evasion by XBB variant

The continuous emergence of SARS-CoV-2 variants, particularly the newly circulating Omicron XBB subvariants, has led to a significant reduction in the neutralizing potency and breadth of Antibodies. In this study, we report a SARS-CoV-2 human neutralizing antibody, 1G11, which potently and broadly neutralizes diverse variants, including Omicron subvariants BA.4/5 and BF.7, but is evaded by the recently emerged BQ.1.1 and XBBs. Cryo-electron microscopy structure analysis of the 1G11 in complex with the BA.4/5 spike trimer reveals that 1G11, a Class 3 nAb, recognizes an epitope similar to those of S309 and LY-CoV1404. Structurally, the mutations K444T and V445P in BQ.1.1 and XBB subvariants are found to disrupt the interface between 1G11 and the spike protein, resulting in antibody evasion. 1G11 is further demonstrated to mediate neutralization through multiple mechanisms, including receptor binding blockage, interspike cross-linking, Fc-mediated ADCC and ADCP. Collectively, these findings provide insights into a better understanding of neutralizing antibody evasion and highlight the potential for broad neutralization by structure-based modification of available Antibodies. IMPORTANCE The ongoing COVID-19 pandemic has been characterized by the emergence of new SARS-CoV-2 variants including the highly transmissible Omicron XBB sublineages, which have shown significant resistance to neutralizing Antibodies (nAbs). This resistance has led to decreased vaccine effectiveness and therefore result in breakthrough infections and reinfections, which continuously threaten public health. To date, almost all available therapeutic nAbs, including those authorized under Emergency Use Authorization nAbs that were previously clinically useful against early strains, have recently been found to be ineffective against newly emerging variants. In this study, we provide a comprehensive structural basis about how the Class 3 nAbs, including 1G11 in this study and noted LY-CoV1404, are evaded by the newly emerged SARS-CoV-2 variants.

SARS-CoV-2; broad neutralization; cryo-EM; immune evasion; neutralizing antibody.