SARS-CoV-2 infection or vaccination produces
neutralizing antibody responses that contribute to better clinical outcomes. The receptor binding domain (RBD) and the N-terminal domain (NTD) of the spike trimer (S) constitute the two major neutralizing targets for the antibody system.
Neutralizing antibodies targeting the RBD bind to several different sites on this domain. In contrast, most
neutralizing antibodies to NTD characterized to date bind to a single supersite, however these
antibodies were obtained by methods that were not NTD specific. Here we use NTD specific probes to focus on anti-NTD memory B cells in a cohort of pre-omicron infected individuals some of which were also vaccinated. Of 275 NTD binding
antibodies tested 103 neutralized at least one of three tested strains: Wuhan-Hu-1, Gamma, or PMS20, a synthetic variant which is extensively mutated in the NTD supersite. Among the 43
neutralizing antibodies that were further characterized, we found 6 complementation groups based on competition binding experiments. 58% targeted
epitopes outside the NTD supersite, and 58% neutralized either Gamma or Omicron, but only 14% were broad neutralizers. Three of the broad neutralizers were characterized structurally. C1520 and C1791 recognize
epitopes on opposite faces of the NTD with a distinct binding pose relative to previously described
antibodies allowing for greater potency and cross-reactivity with 7 different variants including Beta, Delta, Gamma and Omicron. Antibody C1717 represents a previously uncharacterized class of NTD-directed
antibodies that recognizes the viral membrane proximal side of the NTD and SD2 domain, leading to cross-neutralization of Beta, Gamma and Omicron. We conclude
SARS-CoV-2 infection and/or Wuhan-Hu-1
mRNA vaccination produces a diverse collection of memory B cells that produce anti-NTD
antibodies some of which can neutralize variants of concern. Rapid recruitment of these cells into the antibody secreting plasma cell compartment upon
re-infection likely contributes to the relatively benign course of subsequent
infections with SARS-CoV-2 variants including omicron.