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Molecular basis for a germline-biased neutralizing antibody response to SARS-CoV-2

Sarah A. Clark, Lars E. Clark, View ORCID ProfileJunhua Pan, Adrian Coscia, Lindsay G.A. McKay, Sundaresh Shankar, Rebecca I. Johnson, Anthony Griffiths, View ORCID ProfileJonathan Abraham
doi: https://doi.org/10.1101/2020.11.13.381533
Sarah A. Clark
1Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
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Lars E. Clark
1Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
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Junhua Pan
1Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
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Adrian Coscia
1Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
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Lindsay G.A. McKay
2Department of Microbiology and National Emerging Infectious Diseases Laboratories, Boston University School of Medicine, Boston, MA 02118, USA
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Sundaresh Shankar
1Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
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Rebecca I. Johnson
2Department of Microbiology and National Emerging Infectious Diseases Laboratories, Boston University School of Medicine, Boston, MA 02118, USA
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Anthony Griffiths
2Department of Microbiology and National Emerging Infectious Diseases Laboratories, Boston University School of Medicine, Boston, MA 02118, USA
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Jonathan Abraham
1Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
3Department of Medicine, Division of Infectious Diseases, Brigham and Women’s Hospital, Boston, MA 02115, USA
4Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA
5Massachusetts Consortium on Pathogen Readiness, Boston, MA, 02115, USA
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  • ORCID record for Jonathan Abraham
  • For correspondence: jonathan_abraham@hms.harvard.edu
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Abstract

The SARS-CoV-2 viral spike (S) protein mediates attachment and entry into host cells and is a major target of vaccine and drug design. Potent SARS-CoV-2 neutralizing antibodies derived from closely related antibody heavy chain genes (IGHV3-53 or 3-66) have been isolated from multiple COVID-19 convalescent individuals. These usually contain minimal somatic mutations and bind the S receptor-binding domain (RBD) to interfere with attachment to the cellular receptor angiotensin-converting enzyme 2 (ACE2). We used antigen-specific single B cell sorting to isolate S-reactive monoclonal antibodies from the blood of a COVID-19 convalescent individual. The seven most potent neutralizing antibodies were somatic variants of the same IGHV3-53-derived antibody and bind the RBD with varying affinity. We report X-ray crystal structures of four Fab variants bound to the RBD and use the structures to explain the basis for changes in RBD affinity. We show that a germline revertant antibody binds tightly to the SARS-CoV-2 RBD and neutralizes virus, and that gains in affinity for the RBD do not necessarily correlate with increased neutralization potency, suggesting that somatic mutation is not required to exert robust antiviral effect. Our studies clarify the molecular basis for a heavily germline-biased human antibody response to SARS-CoV-2.

Competing Interest Statement

S.A.C., L.E.C., and J.A. are inventors on a provisional patent application filed by Harvard University that includes antibodies reported in this work.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted November 13, 2020.
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Molecular basis for a germline-biased neutralizing antibody response to SARS-CoV-2
Sarah A. Clark, Lars E. Clark, Junhua Pan, Adrian Coscia, Lindsay G.A. McKay, Sundaresh Shankar, Rebecca I. Johnson, Anthony Griffiths, Jonathan Abraham
bioRxiv 2020.11.13.381533; doi: https://doi.org/10.1101/2020.11.13.381533
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Molecular basis for a germline-biased neutralizing antibody response to SARS-CoV-2
Sarah A. Clark, Lars E. Clark, Junhua Pan, Adrian Coscia, Lindsay G.A. McKay, Sundaresh Shankar, Rebecca I. Johnson, Anthony Griffiths, Jonathan Abraham
bioRxiv 2020.11.13.381533; doi: https://doi.org/10.1101/2020.11.13.381533

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