Structures of human antibodies bound to SARS-CoV-2 spike reveal common epitopes and recurrent features of antibodies

Barnes, Christopher O.; West, Anthony P.; Huey-Tubman, Kathryn E.; Hoffmann, Magnus A.G.; Sharaf, Naima G.; Hoffman, Pauline R.; Koranda, Nicholas; Gristick, Harry B.; Gaebler, Christian; Muecksch, Frauke; Cetrulo Lorenzi, Julio C.; Finkin, Shlomo; Hagglof, Thomas; Hurley, Arlene; Millard, Katrina G.; Weisblum, Yiska; Schmidt, Fabian; Hatziioannou, Theodora; Bieniasz, Paul D.; Caskey, Marina; Robbiani, Davide F.; Nussenzweig, Michel C.; Bjorkman, Pamela J.

Neutralizing antibody responses to coronaviruses focus on the trimeric spike, with most against the receptor-binding domain (RBD). Here we characterized polyclonal IgGs and Fabs from COVID-19 convalescent individuals for recognition of coronavirus spikes. Plasma IgGs differed in their degree of focus on RBD epitopes, recognition of SARS-CoV, MERS-CoV, and mild coronaviruses, and how avidity effects contributed to increased binding/neutralization of IgGs over Fabs. Electron microscopy reconstructions of polyclonal plasma Fab-spike complexes showed recognition of both S1(A) and RBD epitopes. A 3.4Å cryo-EM structure of a neutralizing monoclonal Fab-S complex revealed an epitope that blocks ACE2 receptor-binding on “up” RBDs. Modeling suggested that IgGs targeting these sites have different potentials for inter-spike crosslinking on viruses and would not be greatly affected by identified SARS-CoV-2 spike mutations. These studies structurally define a recurrent anti-SARS-CoV-2 antibody class derived from VH3–53/VH3–66 and similarity to a SARS-CoV VH3–30 antibody, providing criteria for evaluating vaccine-elicited antibodies.