Published August 20, 2020
| Supplemental Material + Published + Submitted
Journal Article
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Structures of Human Antibodies Bound to SARS-CoV-2 Spike Reveal Common Epitopes and Recurrent Features of Antibodies
- Creators
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Barnes, Christopher O.
- West, Anthony P., Jr.
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Huey-Tubman, Kathryn E.
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Hoffmann, Magnus A. G.
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Sharaf, Naima G.
- Hoffman, Pauline R.
- Koranda, Nicholas
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Gristick, Harry B.
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Gaebler, Christian
- Muecksch, Frauke
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Cetrulo Lorenzi, Julio C.
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Finkin, Shlomo
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Hägglöf, Thomas
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Hurley, Arlene
- Millard, Katrina G.
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Weisblum, Yiska
- Schmidt, Fabian
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Hatziioannou, Theodora
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Bieniasz, Paul D.
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Caskey, Marina
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Robbiani, Davide F.
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Nussenzweig, Michel C.
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Bjorkman, Pamela J.
Abstract
Neutralizing antibody responses to coronaviruses mainly target the receptor-binding domain (RBD) of the trimeric spike. Here, we characterized polyclonal 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 S1^A and RBD epitopes on SARS-CoV-2 spike. Moreover, a 3.4Å 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 that 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.
Additional Information
© 2020 The Author(s). Published by Elsevier Under a Creative This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Received 11 May 2020, Revised 27 May 2020, Accepted 15 June 2020, Available online 24 June 2020. We gratefully acknowledge all labs and authors for making SARS-CoV-2 genome sequence data available for this research. We thank all study participants who devoted time to our research, Drs. Barry Coller and Sarah Schlesinger, and the Rockefeller University Hospital Clinical Research Support Office and nursing staff. We thank the Global Initiative on Sharing Avian Influenza Data (GISAID) and the originating and submitting laboratories for sharing the SARS-CoV-2 genome sequences; see Table S4 for a list of sequence contributors. We thank members of the Bjorkman, Nussenzweig, and Bienasz laboratories for helpful discussions, Drs. John Pak (Chan Zuckerberg Biohub) and Florian Krammer (Icahn School of Medicine at Mount Sinai) for CoV expression plasmids, Drs. Songye Chen and Andrey Malyutin (Caltech) for maintaining electron microscopes, Dr. Jost Vielmetter and the Protein Expression Center in the Beckman Institute at Caltech for expression assistance, and Ms. Marta Murphy for help with figures. Electron microscopy was performed in the Caltech Beckman Institute Resource Center for Transmission Electron Microscopy. We thank the Gordon and Betty Moore and Beckman Foundations for gifts to Caltech to support the Molecular Observatory (Dr. Jens Kaiser, director), and Drs. Silvia Russi, Aina Cohen, and Clyde Smith and the beamline staff at SSRL for data collection assistance. Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences (DE-AC02-76SF00515). The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research, and by the NIH, National Institute of General Medical Sciences (P41GM103393). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS or NIH. This work was supported by NIH (P01-AI138938-S1 to P.J.B. and M.C.N., P50 8 P50 AI150464-13 to P.J.B., and 2U19AI111825 to M.C.N.), the Caltech Merkin Institute for Translational Research (to P.J.B.), George Mason University Fast Grants (to P.J.B. and D.F.R.), and the Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (CAVD) (INV-002143 to P.J.B. and M.C.N.). C.O.B was supported by the Hanna Gray Fellowship Program from the Howard Hughes Medical Institute and the Postdoctoral Enrichment Program from the Burroughs Wellcome Fund. C.G. is a fellow of the Robert S. Wennett and Mario Cader-Frech Foundation and was supported in part by the National Center for Advancing Translational Sciences (NCATS, National Institutes of Health Clinical and Translational Science Award [CTSA] program) (UL1 TR001866), and by the Shapiro-Silverberg Fund for the Advancement of Translational Research. P.D.B. and M.C.N. are Howard Hughes Medical Institute Investigators. Author Contributions: C.O.B., A.P.W., D.F.R., M.C.N., and P.J.B. conceived the study and analyzed data. C.O.B. performed protein characterization, nsEMPEM, and cryo-EM and interpreted structures. N.G.S. and C.O.B. performed and analyzed crystallographic structures. C.O.B. and K.E.H.-T. prepared plasma IgGs and Fabs. M.A.G.H., K.E.H.-T., N.G.S., and C.O.B. performed and analyzed ELISAs. P.R.H. and N.K. expressed and purified proteins. A.P.W. and H.B.G. performed computational modeling. A.P.W. analyzed antibody sequences. F.M., J.C.C.L., Y.W., F.S., T.H., and P.D.B. developed and performed in vitro neutralization assays. C.G., S.F., A.H., K.G.M., M.C., and D.F.R. collected and processed human plasma samples. C.O.B., A.P.W., M.C.N., and P.J.B. wrote the paper with contributions from other authors. Declaration of Interests: In connection with this work, The Rockefeller University has filed a provisional patent application on which D.F.R. and M.C.N. are inventors.Attached Files
Published - 1-s2.0-S0092867420307571-main.pdf
Submitted - 2020.05.28.121533v1.full.pdf
Supplemental Material - 1-s2.0-S0092867420307571-mmc1.pdf
Supplemental Material - 1-s2.0-S0092867420307571-mmc2.xlsx
Files
1-s2.0-S0092867420307571-main.pdf
Additional details
- PMCID
- PMC7311918
- Eprint ID
- 103584
- DOI
- 10.1016/j.cell.2020.06.025
- Resolver ID
- CaltechAUTHORS:20200601-100510853
- Gordon and Betty Moore Foundation
- Arnold and Mabel Beckman Foundation
- DE-AC02-76SF00515
- Department of Energy (DOE)
- P41GM103393
- NIH
- P01-AI138398-S1
- NIH
- Caltech Merkin Institute for Translational Research
- P50 8 P50 AI150464-13
- NIH
- 2U19AI111825
- NIH
- George Mason University
- INV-002143
- Bill and Melinda Gates Foundation
- Howard Hughes Medical Institute (HHMI)
- Burroughs Wellcome Fund
- Robert S. Wennett and Mario Cader-Frech Foundation
- UL1 TR001866
- NIH
- Shapiro-Silverberg Fund
- Created
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2020-06-01Created from EPrint's datestamp field
- Updated
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2023-06-01Created from EPrint's last_modified field
- Caltech groups
- Richard N. Merkin Institute for Translational Research, COVID-19, Division of Biology and Biological Engineering