Epitope-driven polyfunctional divergence of SARS-CoV-2 RBD antibodies.

SARS-CoV-2 antibodies targeting the receptor-binding domain (RBD) of the spike protein can potently neutralize infection and exert additional antiviral functions. Here, we characterize the functional profiles of human RBD-specific memory B cell antibodies elicited by ancestral SARS-CoV-2 infection. While SARS-CoV-2 neutralizing antibodies, mainly class 1 and 3 anti-RBD antibodies, often lose binding and neutralizing activity against Omicron variants, most non-neutralizers that bind conserved RBD epitopes remain broadly reactive. Despite their restricted cross-reactivity, neutralizing antibodies mediate Fc-effector functions including antibody-dependent cellular cytotoxicity, phagocytosis, and complement deposition. Most neutralizers also enhance binding of antibodies that target the SARS-CoV-2 spike fusion peptide via receptor-mimetic allostery. In contrast, broadly reactive non-neutralizers fail to trigger phagocytic or allosteric effects. Thus, viral escape primarily affects neutralizing, polyfunctional antibodies, whereas cross-reactive non-neutralizing antibodies, which exert limited antiviral effects, may apply minimal immune pressure.