SARS-COV-2 Omicron variants conformationally escape a rare quaternary antibody binding mode

Understanding how SARS-CoV-2 mutations affect the dynamics of antibody-antigen interactions is crucial to the development of broadly protective antibodies and vaccines. Here we report the discovery and characterization of a potent neutralizing antibody (N3-1) identified from a COVID-19 patient during the first disease wave. Cryo-EM revealed a quaternary binding mode that enables direct interactions with all three receptor-binding domains of the spike protein trimer, resulting in extraordinary avidity and potent neutralization of all major variants of concern until the emergence of Omicron. Structure-based rational design of N3-1 mutants improved binding to all Omicron variants but only partially restored neutralization of the conformationally distinct Omicron BA.1. This study provides new insights into immune evasion through changes in spike protein dynamics and highlights considerations for future conformationally biased multivalent vaccine designs.