Structures of Human Antibodies Bound to SARS-CoV-2 Spike Reveal Common Epitopes and Recurrent Features of Antibodies

• Published in: Cell Vol. 182; no. 4; pp. 828 - 842.e16
• Main Authors: 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, Lorenzi, Julio C. Cetrulo, Finkin, Shlomo, Hägglöf, 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.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20-08-2020; Elsevier; Cell Press
• Subjects: Antibodies, Neutralizing - blood; Antibodies, Neutralizing - chemistry; Antibodies, Neutralizing - isolation & purification; Antibodies, Viral - immunology; Antibodies, Viral - isolation & purification; BASIC BIOLOGICAL SCIENCES; Betacoronavirus - chemistry; Betacoronavirus - immunology; convalescent plasma; coronavirus; Coronavirus Infections - blood; Coronavirus Infections - immunology; Coronavirus Infections - therapy; COVID-19; COVID-19 Serotherapy; Cross Reactions; Cryoelectron Microscopy; electron microscopy; ELISA; Epitope Mapping; Epitopes; Fab; Humans; IgG; Immunization, Passive; Immunoglobulin Fab Fragments - blood; Immunoglobulin Fab Fragments - chemistry; Immunoglobulin Fab Fragments - isolation & purification; Immunoglobulin Fab Fragments - ultrastructure; Immunoglobulin G - blood; Immunoglobulin G - chemistry; Immunoglobulin G - isolation & purification; Immunoglobulin G - ultrastructure; MERS-CoV; Middle East Respiratory Syndrome Coronavirus - chemistry; Middle East Respiratory Syndrome Coronavirus - immunology; Models, Molecular; Pandemics; Pneumonia, Viral - blood; Pneumonia, Viral - immunology; SARS-CoV; SARS-CoV-2; Severe acute respiratory syndrome-related coronavirus - chemistry; Severe acute respiratory syndrome-related coronavirus - immunology; Spike Glycoprotein, Coronavirus - chemistry; Spike Glycoprotein, Coronavirus - immunology; COVID-19; SARS-CoV-2; Fab; SARS-CoV; IgG; coronavirus; electron microscopy; MERS-CoV; ELISA; convalescent plasma
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2020.06.025

Neutralizing antibody responses to coronaviruses mainly target the receptor-binding domain (RBD) of the trimeric spike. Here, we characterized polyclonal immunoglobulin Gs (IgGs) and Fabs from COVID-19 convalescent individuals for recognition of coronavirus spikes. Plasma IgGs differed in their focus on RBD epitopes, recognition of alpha- and beta-coronaviruses, and contributions of avidity to increased binding/neutralization of IgGs over Fabs. Using electron microscopy, we examined specificities of polyclonal plasma Fabs, revealing recognition of both S1A and RBD epitopes on SARS-CoV-2 spike. Moreover, a 3.4 Å cryo-electron microscopy (cryo-EM) structure of a neutralizing monoclonal Fab-spike complex revealed an epitope that blocks ACE2 receptor binding. Modeling based on these structures suggested different potentials for inter-spike crosslinking by IgGs on viruses, and characterized IgGs would not be affected by identified SARS-CoV-2 spike mutations. Overall, our 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.
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•COVID-19 plasma IgGs can recognize SARS-2, SARS, and MERS S proteins•EM reconstructions of polyclonal Fab-S complexes revealed S1A and RBD epitopes•3.4 Å cryo-EM structure of a neutralizing Fab-S complex showed binding to “up” RBDs•Structures define a recurrent VH3-53/VH3-66-derived anti-SARS-CoV-2 antibody class
Analysis of plasma from recovering COVID-19 patients identifies common features of antibodies that determine protection.