Vaccine-elicited murine antibody WS6 neutralizes diverse beta-coronaviruses by recognizing a helical stem supersite of vulnerability

Summary Immunization with SARS-CoV-2 spike elicits diverse antibodies, but can any of these neutralize broadly? Here, we report the isolation and characterization of antibody WS6, from a mouse immunized with mRNA encoding the SARS-CoV-2 spike. WS6 bound diverse beta-coronavirus spikes and neutralized SARS-CoV-2 variants, SARS-CoV, and related sarbecoviruses. Epitope mapping revealed WS6 to target a region in the S2 subunit, which was conserved among SARS-CoV-2, MERS-CoV, and hCoV-OC43. The crystal structure at 2-Å resolution of WS6 with its S2 epitope revealed recognition to center on a conserved helix, which was occluded in both prefusion and post-fusion spike conformations. Structural and neutralization analyses indicated WS6 to neutralize by inhibiting fusion, post-viral attachment. Comparison of WS6 to other antibodies recently identified from convalescent donors or mice immunized with diverse spikes indicated a stem-helical supersite – centered on hydrophobic residues Phe1148, Leu1152, Tyr1155, and Phe1156 – to be a promising target for vaccine design. Highlights SARS-CoV-2 spike mRNA-immunized mouse elicited an antibody, WS6, that cross reacts with spikes of diverse human and bat beta-coronaviruses WS6 neutralizes SARS-CoV-2 variants, SARS-CoV, and related viruses Crystal structure at 2-Å resolution of WS6 in complex with a conserved S2 peptide reveals recognition of a helical epitope WS6 neutralizes by inhibition of fusion, post-viral attachment WS6 recognizes a supersite of vulnerability also recognized by other recently identified antibodies Helical supersite of vulnerability comprises a hydrophobic cluster spanning three helical turns, with acid residues framing the center turn Genetic and structural analysis indicate supersite recognition to be compatible with diverse antibody ontogenies