Most analyses of the antibody responses induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have focused on antibodies cloned from memory B cells. This approach has led researchers to conclude that neutralizing antibodies (nAbs) primarily target the receptor-binding domain (RBD) of the virus's spike protein. Voss et al. took a different approach, using proteomic deconvolution of the serum immunoglobulin G antibody repertoire from four COVID-19 convalescent patients. They found that the nAb response was largely directed against epitopes such as the N-terminal domain (NTD), which lie outside the RBD. Several of these nAbs were shared among donors and targeted an NTD epitope that is frequently mutated by variants of concern.
Science , abg5268, this issue p. [1108][1]
The molecular composition and binding epitopes of the immunoglobulin G (IgG) antibodies that circulate in blood plasma after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are unknown. Proteomic deconvolution of the IgG repertoire to the spike glycoprotein in convalescent subjects revealed that the response is directed predominantly (>80%) against epitopes residing outside the receptor binding domain (RBD). In one subject, just four IgG lineages accounted for 93.5% of the response, including an amino (N)-terminal domain (NTD)–directed antibody that was protective against lethal viral challenge. Genetic, structural, and functional characterization of a multidonor class of “public” antibodies revealed an NTD epitope that is recurrently mutated among emerging SARS-CoV-2 variants of concern. These data show that “public” NTD-directed and other non-RBD plasma antibodies are prevalent and have implications for SARS-CoV-2 protection and antibody escape.