Structural basis of a public antibody response to SARS-CoV-2

Molecular-level understanding of human neutralizing antibody responses to SARS-CoV-2 could accelerate vaccine design and facilitate drug discovery. We analyzed 294 SARS-CoV-2 antibodies and found that IGHV3–53 is the most frequently used IGHV gene for targeting the receptor binding domain (RBD) of the spike (S) protein. We determined crystal structures of two IGHV3–53 neutralizing antibodies +/− Fab CR3022 ranging from 2.33 to 3.11 Å resolution. The germline-encoded residues of IGHV3–53 dominate binding to the ACE2 binding site epitope with no overlap with the CR3022 epitope. Moreover, IGHV3–53 is used in combination with a very short CDR H3 and different light chains. Overall, IGHV3–53 represents a versatile public VH in neutralizing SARS-CoV-2 antibodies, where their specific germline features and minimal affinity maturation provide important insights for vaccine design and assessing outcomes.