Altered spike dynamics drives immune evasion of SARS-CoV-2

Rapid viral escape from protective immunity has been an unwanted hallmark of the COVID-19 pandemic. This escape has been attributed to mutations in critical neutralizing antibody epitopes mainly in the receptor binding domain (RBD) of the viral spike glycoprotein. Here we show that this notion is incomplete. We found that several broadly neutralizing human antibodies isolated over the past years retain an almost undiminished capacity for inhibitory targeting of RBDs of recent highly immunoevasive SARS-CoV-2 strains. Likewise, human sera collected during the pre-Omicron era from persons immunized with original Wuhan-based vaccines were found to contain abundant neutralizing activity targeted against the RBDs of modern Omicron variants. However, this unexpected neutralization sensitivity was observed only when these RBDs were incorporated into a mismatched spike protein backbone, whereas the corresponding native Omicron spike proteins were highly resistant against the same panel of antibodies and human sera. We conclude that changes occurring outside of the RBD and leading to altered conformational dynamics of the spike protein have played a key part in the viral evolution enabling SARS-CoV-2 to escape from neutralizing antibodies that target highly conserved cryptic RBD epitopes.