Structural insights into human monoclonal antibodies with pan-coronavirus reactivity

Abstract Human monoclonal antibodies from convalescent individuals that target the SARS-CoV-2 spike protein have been deployed as therapeutics against SARS-CoV-2. However, emergence of variants diminished efficacy almost all antiviral antibodies. Moreover, most specific are inactive divergent sarbecoviruses and larger Orthocoronavirinae subfamily. Thus, continued development immunotherapies resilient to viral evolution, capable recognizing zoonotic coronaviruses with spillover potential is necessary. Using coldspot-guided antibody discovery, a screening approach focuses on portions virus glycoprotein both functionally relevant averse change, we identified human neutralizing highly conserved epitopes. We structurally-characterized fusion peptide, stem helix near heptad repeat 2 region subdomain 1 glycoprotein, broadly cross-reactive protective in vivo. Collectively, our data adds growing body evidence suggesting use for prophylaxis or therapy emerging VOC future events. C.O.B. supported by Howard Hughes Medical Institute Hanna Gray Fellowship Chan Zuckerberg Biohub investigator.