Defining the mechanism of cross-reactivity for a SARS-CoV-2 Beta-elicited antibody toward omicron sub-lineages

Despite the continual emergence of SARS-CoV-2 variants and increasing diversity within the receptor binding domain (RBD), some antibody responses that are directed to conserved regions can display cross-reactivity against variants. We previously isolated an RBD-directed monoclonal antibody (084-7D) from a Beta-infected donor that neutralized Beta and emerging Omicron variants. Here, we solved a high-resolution crystal structure of the 084-7D Fab in complex with the Beta RBD. These data revealed an epitope overlapping both the ACE2 binding site and those of other class 1 antibodies. Furthermore, the epitope includes highly conserved residues, Q409, D420, and Y489, that are present in recent Omicron variants. The N417 residue that emerged with Beta and has since persisted is tolerated within the epitope of 084-7D, explaining the preferential neutralization of contemporaneous N417-containing variants. These structural data defined the mechanism for cross-reactivity of a Beta-elicited neutralizing antibody, potentially informing the design of future broadly reactive SARS-CoV-2 therapeutics.