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Prevalent, protective, and convergent IgG recognition of SARS-CoV-2 non-RBD spike epitopes in COVID-19 convalescent plasma

William N. Voss, Yixuan J. Hou, Nicole V. Johnson, Jin Eyun Kim, George Delidakis, Andrew P. Horton, Foteini Bartzoka, Chelsea J. Paresi, Yuri Tanno, Shawn A. Abbasi, Whitney Pickens, Katia George, Daniel R. Boutz, Dalton M. Towers, Jonathan R. McDaniel, Daniel Billick, Jule Goike, Lori Rowe, Dhwani Batra, Jan Pohl, Justin Lee, Shivaprakash Gangappa, Suryaprakash Sambhara, Michelle Gadush, Nianshuang Wang, Maria D. Person, Brent L. Iverson, Jimmy D. Gollihar, John Dye, Andrew Herbert, Ralph S. Baric, Jason S. McLellan, George Georgiou, Jason J. Lavinder, Gregory C. Ippolito
doi: https://doi.org/10.1101/2020.12.20.423708
William N. Voss
1Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, USA
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Yixuan J. Hou
2Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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Nicole V. Johnson
1Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, USA
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Jin Eyun Kim
3Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, USA
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George Delidakis
4Department of Chemical Engineering, The University of Texas at Austin, Austin, TX, USA
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Andrew P. Horton
1Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, USA
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Foteini Bartzoka
1Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, USA
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Chelsea J. Paresi
5Department of Chemistry, The University of Texas at Austin, Austin, TX, USA
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Yuri Tanno
4Department of Chemical Engineering, The University of Texas at Austin, Austin, TX, USA
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Shawn A. Abbasi
6U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD, USA
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Whitney Pickens
1Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, USA
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Katia George
1Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, USA
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Daniel R. Boutz
1Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, USA
7CCDC Army Research Laboratory-South, The University of Texas at Austin, Austin, TX, USA
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Dalton M. Towers
4Department of Chemical Engineering, The University of Texas at Austin, Austin, TX, USA
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Jonathan R. McDaniel
8Biomedicine Design, Pfizer, Cambridge, MA, USA
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Daniel Billick
1Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, USA
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Jule Goike
1Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, USA
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Lori Rowe
9Biotechnology Core Facility Branch, Division of Scientific Resources, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA
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Dhwani Batra
9Biotechnology Core Facility Branch, Division of Scientific Resources, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA
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Jan Pohl
9Biotechnology Core Facility Branch, Division of Scientific Resources, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA
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Justin Lee
9Biotechnology Core Facility Branch, Division of Scientific Resources, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA
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Shivaprakash Gangappa
10Immunology and Pathogenesis Branch, Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA
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Suryaprakash Sambhara
10Immunology and Pathogenesis Branch, Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA
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Michelle Gadush
11Center for Biomedical Research Support, The University of Texas at Austin, Austin, TX, USA
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Nianshuang Wang
1Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, USA
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Maria D. Person
11Center for Biomedical Research Support, The University of Texas at Austin, Austin, TX, USA
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Brent L. Iverson
5Department of Chemistry, The University of Texas at Austin, Austin, TX, USA
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Jimmy D. Gollihar
1Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, USA
7CCDC Army Research Laboratory-South, The University of Texas at Austin, Austin, TX, USA
12Center for Molecular and Translational Human Infectious Diseases Research, Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, USA
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John Dye
6U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD, USA
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Andrew Herbert
6U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD, USA
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Ralph S. Baric
2Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
13Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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Jason S. McLellan
1Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, USA
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George Georgiou
1Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, USA
3Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, USA
4Department of Chemical Engineering, The University of Texas at Austin, Austin, TX, USA
14Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, TX, USA
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Jason J. Lavinder
1Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, USA
4Department of Chemical Engineering, The University of Texas at Austin, Austin, TX, USA
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  • For correspondence: jlavinder@utexas.edu gci@utexas.edu
Gregory C. Ippolito
1Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, USA
14Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, TX, USA
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  • For correspondence: jlavinder@utexas.edu gci@utexas.edu
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SUMMARY

Although humoral immunity is essential for control of SARS-CoV-2, the molecular composition, binding epitopes and effector functions of the immunoglobulin G (IgG) antibodies that circulate in blood plasma following infection are unknown. Proteomic deconvolution of the circulating IgG repertoire (Ig-Seq1) to the spike ectodomain (S-ECD2) in four convalescent study subjects revealed that the plasma response is oligoclonal and directed predominantly (>80%) to S-ECD epitopes that lie outside the receptor binding domain (RBD). When comparing antibodies directed to either the RBD, the N-terminal domain (NTD) or the S2 subunit (S2) in one subject, just four IgG lineages (1 anti-S2, 2 anti-NTD and 1 anti-RBD) accounted for 93.5% of the repertoire. Although the anti-RBD and one of the anti-NTD antibodies were equally potently neutralizing in vitro, we nonetheless found that the anti-NTD antibody was sufficient for protection to lethal viral challenge, either alone or in combination as a cocktail where it dominated the effect of the other plasma antibodies. We identified in vivo protective plasma anti-NTD antibodies in 3/4 subjects analyzed and discovered a shared class of antibodies targeting the NTD that utilize unmutated or near-germline IGHV1-24, the most electronegative IGHV gene in the human genome. Structural analysis revealed that binding to NTD is dominated by interactions with the heavy chain, accounting for 89% of the entire interfacial area, with germline residues uniquely encoded by IGHV1-24 contributing 20% (149 Å2). Together with recent reports of germline IGHV1-24 antibodies isolated by B-cell cloning3,4 our data reveal a class of shared IgG antibodies that are readily observed in convalescent plasma and underscore the role of NTD-directed antibodies in protection against SARS-CoV-2 infection.

Competing Interest Statement

The authors have declared no competing interest.

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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 December 21, 2020.
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Prevalent, protective, and convergent IgG recognition of SARS-CoV-2 non-RBD spike epitopes in COVID-19 convalescent plasma
William N. Voss, Yixuan J. Hou, Nicole V. Johnson, Jin Eyun Kim, George Delidakis, Andrew P. Horton, Foteini Bartzoka, Chelsea J. Paresi, Yuri Tanno, Shawn A. Abbasi, Whitney Pickens, Katia George, Daniel R. Boutz, Dalton M. Towers, Jonathan R. McDaniel, Daniel Billick, Jule Goike, Lori Rowe, Dhwani Batra, Jan Pohl, Justin Lee, Shivaprakash Gangappa, Suryaprakash Sambhara, Michelle Gadush, Nianshuang Wang, Maria D. Person, Brent L. Iverson, Jimmy D. Gollihar, John Dye, Andrew Herbert, Ralph S. Baric, Jason S. McLellan, George Georgiou, Jason J. Lavinder, Gregory C. Ippolito
bioRxiv 2020.12.20.423708; doi: https://doi.org/10.1101/2020.12.20.423708
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Prevalent, protective, and convergent IgG recognition of SARS-CoV-2 non-RBD spike epitopes in COVID-19 convalescent plasma
William N. Voss, Yixuan J. Hou, Nicole V. Johnson, Jin Eyun Kim, George Delidakis, Andrew P. Horton, Foteini Bartzoka, Chelsea J. Paresi, Yuri Tanno, Shawn A. Abbasi, Whitney Pickens, Katia George, Daniel R. Boutz, Dalton M. Towers, Jonathan R. McDaniel, Daniel Billick, Jule Goike, Lori Rowe, Dhwani Batra, Jan Pohl, Justin Lee, Shivaprakash Gangappa, Suryaprakash Sambhara, Michelle Gadush, Nianshuang Wang, Maria D. Person, Brent L. Iverson, Jimmy D. Gollihar, John Dye, Andrew Herbert, Ralph S. Baric, Jason S. McLellan, George Georgiou, Jason J. Lavinder, Gregory C. Ippolito
bioRxiv 2020.12.20.423708; doi: https://doi.org/10.1101/2020.12.20.423708

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