Antibodies targeting a quaternary site on SARS-CoV-2 spike glycoprotein prevent viral receptor engagement by conformational locking.

SARS-CoV-2 continues to evolve, with many variants evading clinically authorized antibodies. To isolate monoclonal antibodies (mAbs) with broadly neutralizing capacities against the virus, we screened serum samples from convalescing COVID-19 patients. We isolated two mAbs, 12-16 and 12-19, which neutralized all SARS-CoV-2 variants tested, including the XBB subvariants, and prevented infection in hamsters challenged with Omicron BA.1 intranasally. Structurally, both antibodies targeted a conserved quaternary epitope located at the interface between the N-terminal domain and subdomain 1, uncovering a site of vulnerability on SARS-CoV-2 spike. These antibodies prevented viral receptor engagement by locking the receptor-binding domain (RBD) of spike in the down conformation, revealing a mechanism of virus neutralization for non-RBD antibodies. Deep mutational scanning showed that SARS-CoV-2 could mutate to escape 12-19, but such mutations are rarely found in circulating viruses. Antibodies 12-16 and 12-19 hold promise as prophylactic agents for immunocompromised persons who do not respond robustly to COVID-19 vaccines. [Display omitted] • Isolated bnAbs 12-16 and 12-19 from a SARS-CoV-2 recovered/vaccinated individual • These mAbs target a conserved quaternary epitope at the interface between NTD-SD1 • The mAbs neutralize all current SARS-CoV-2 VOCs by locking RBD in down conformation • 12-19 escape mutations are rarely found in circulating SARS-CoV-2 viruses Current variants of SARS-CoV-2 can evade clinically authorized antibodies. Liu et al. demonstrate that two monoclonal antibodies isolated from convalescing COVID-19 patients neutralize all current SARS-CoV-2 variants of concern via interaction with a mechanism that locks the RBD in the down conformation. Mutations in the epitope targeted by these mAbs are rarely found in circulating SARS-CoV-2 viruses, suggesting clinical applicability. [ABSTRACT FROM AUTHOR]