Prevalent, protective, and convergent IgG recognition of SARS-CoV-2 non-RBD spike epitopes in COVID-19 convalescent plasma

The molecular composition and binding epitopes of the immunoglobulin G (IgG) antibodies that circulate in blood plasma following SARS-CoV-2 infection are unknown. Proteomic deconvolution of the IgG repertoire (Ig-Seq) to the spike ectodomain (S-ECD) in four convalescent study subjects revealed that the plasma response is oligoclonal and directed predominantly to S-ECD epitopes that lie outside the receptor-binding domain (RBD). This includes antibodies against the N-terminal domain (NTD) that can equal or exceed RBD-directed antibodies in relative abundance and virus-neutralizing potency. Just four IgG lineages (one anti-S2, two anti-NTD and one anti-RBD) accounted for 93.5 percent of the repertoire in one subject, and only the anti-NTD antibody was sufficient for protection from lethal viral challenge. We identified protective plasma anti-NTD antibodies in three of the four subjects analyzed and discovered a shared class of genetically conserved antibodies that use the unique IgG heavy-chain variable region 1-24 (IGHV1-24). Structural analysis revealed that their binding engages an NTD epitope that is crippled by mutations found in two novel variants which have recently emerged from the United Kingdom and South Africa. Together with reports of germline IGHV1-24 antibodies isolated by B cell cloning, our data reveal a class of shared and protective IgG antibodies that are readily elicited and recurrently observed in convalescent plasmas and underscore the role of NTD-directed antibodies in protection against SARS-CoV-2.