Antibodies that neutralize all current SARS-CoV-2 variants of concern by conformational locking

SARS-CoV-2 continues to evolve and evade most existing neutralizing antibodies, including all clinically authorized antibodies. We have isolated and characterized two human monoclonal antibodies, 12-16 and 12-19, which exhibited neutralizing activities against all SARS-CoV-2 variants tested, including BQ.1.1 and XBB.1.5. They also blocked infection in hamsters challenged with Omicron BA.1 intranasally. Structural analyses revealed both antibodies targeted a conserved quaternary epitope located at the interface between the N-terminal domain and subdomain 1, revealing a previously unrecognized site of vulnerability on SARS-CoV-2 spike. These antibodies prevent viral receptor engagement by locking the receptor-binding domain of spike in the down conformation, revealing a novel mechanism of virus neutralization for non-RBD antibodies. Deep mutational scanning showed that SARS-CoV-2 could mutate to escape 12-19, but the responsible 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. ### Competing Interest Statement L.L., S.I., M.S.N., J.Y., Y.H., and D.D.H. are inventors on a provisional patent application for the new antibodies described in this manuscript, titled "Isolation, characterization, and sequences of potent and broadly neutralizing monoclonal antibodies against SARS-CoV-2 and its variants as well as related coronaviruses" (63/271,627). D.D.H. is a co-founder of TaiMed Biologics and RenBio, a consultant to WuXi Biologics, Brii Biosciences, Apexigen, and Veru Inc., and a board director for Vicarious Surgical. J.D.B. consults for Apriorio Bio, Invivyd, Aerium Therapeutics, and the Vaccine Company. J.D.B. and B.D. are inventors on Fred Hutch licensed patents related to deep mutational scanning of viral proteins. All other authors declare no competing interests.