Structural and functional ramifications of antigenic drift in recent SARS-CoV-2 variants

Yuan, Meng; Huang, Deli; Lee, Chang-Chun D.; Wu, Nicholas C.; Jackson, Abigail M.; Zhu, Xueyong; Liu, Hejun; Peng, Linghang; van Gils, Marit J.; Sanders, Rogier W.; Burton, Dennis R.; Reincke, S. Momsen; Prüss, Harald; Kreye, Jakob; Nemazee, David; Ward, Andrew B.; Wilson, Ian A.

The protective efficacy of neutralizing antibodies (nAbs) elicited during natural infection with SARS-CoV-2 and by vaccination based on its spike protein has been compromised with emergence of the recent SARS-CoV-2 variants. Residues E484 and K417 in the receptor-binding site (RBS) are both mutated in lineages first described in South Africa (B.1.351) and Brazil (B.1.1.28.1). The nAbs isolated from SARS-CoV-2 patients are preferentially encoded by certain heavy-chain germline genes and the two most frequently elicited antibody families (IGHV3–53/3–66 and IGHV1–2) can each bind the RBS in two different binding modes. However, their binding and neutralization are abrogated by either the E484K or K417N mutation, whereas nAbs to the cross-reactive CR3022 and S309 sites are largely unaffected. This structural and functional analysis illustrates why mutations at E484 and K417 adversely affect major classes of nAbs to SARS-CoV-2 with consequences for next-generation COVID-19 vaccines.