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N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2

Matthew McCallum, Anna De Marco, Florian Lempp, M. Alejandra Tortorici, Dora Pinto, Alexandra C. Walls, Martina Beltramello, Alex Chen, Zhuoming Liu, Fabrizia Zatta, Samantha Zepeda, Julia di Iulio, John E. Bowen, Martin Montiel-Ruiz, Jiayi Zhou, Laura E. Rosen, Siro Bianchi, Barbara Guarino, Chiara Silacci Fregni, Rana Abdelnabi, Shi-Yan Caroline Foo, Paul W. Rothlauf, Louis-Marie Bloyet, Fabio Benigni, Elisabetta Cameroni, Johan Neyts, Agostino Riva, Gyorgy Snell, Amalio Telenti, Sean P.J. Whelan, Herbert W. Virgin, Davide Corti, Matteo Samuele Pizzuto, View ORCID ProfileDavid Veesler
doi: https://doi.org/10.1101/2021.01.14.426475
Matthew McCallum
1Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA
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Anna De Marco
2Humabs Biomed SA, a subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland
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Florian Lempp
3Vir Biotechnology, San Francisco, CA 94158, USA
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M. Alejandra Tortorici
1Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA
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Dora Pinto
2Humabs Biomed SA, a subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland
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Alexandra C. Walls
1Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA
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Martina Beltramello
2Humabs Biomed SA, a subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland
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Alex Chen
3Vir Biotechnology, San Francisco, CA 94158, USA
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Zhuoming Liu
4Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, 63110, USA
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Fabrizia Zatta
2Humabs Biomed SA, a subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland
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Samantha Zepeda
1Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA
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Julia di Iulio
3Vir Biotechnology, San Francisco, CA 94158, USA
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John E. Bowen
1Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA
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Martin Montiel-Ruiz
3Vir Biotechnology, San Francisco, CA 94158, USA
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Jiayi Zhou
3Vir Biotechnology, San Francisco, CA 94158, USA
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Laura E. Rosen
3Vir Biotechnology, San Francisco, CA 94158, USA
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Siro Bianchi
2Humabs Biomed SA, a subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland
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Barbara Guarino
2Humabs Biomed SA, a subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland
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Chiara Silacci Fregni
2Humabs Biomed SA, a subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland
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Rana Abdelnabi
5Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, KU Leuven, Belgium
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Shi-Yan Caroline Foo
5Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, KU Leuven, Belgium
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Paul W. Rothlauf
4Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, 63110, USA
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Louis-Marie Bloyet
4Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, 63110, USA
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Fabio Benigni
2Humabs Biomed SA, a subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland
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Elisabetta Cameroni
2Humabs Biomed SA, a subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland
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Johan Neyts
5Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, KU Leuven, Belgium
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Agostino Riva
6III Division of Infectious Diseases, Luigi Sacco Hospital, University of Milan, 20157 Milan, Italy
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Gyorgy Snell
3Vir Biotechnology, San Francisco, CA 94158, USA
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Amalio Telenti
3Vir Biotechnology, San Francisco, CA 94158, USA
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Sean P.J. Whelan
4Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, 63110, USA
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Herbert W. Virgin
3Vir Biotechnology, San Francisco, CA 94158, USA
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Davide Corti
2Humabs Biomed SA, a subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland
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  • For correspondence: dveesler@uw.edu mpizzuto@vir.bio dcorti@vir.bio
Matteo Samuele Pizzuto
2Humabs Biomed SA, a subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland
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  • For correspondence: dveesler@uw.edu mpizzuto@vir.bio dcorti@vir.bio
David Veesler
1Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA
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  • ORCID record for David Veesler
  • For correspondence: dveesler@uw.edu mpizzuto@vir.bio dcorti@vir.bio
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Abstract

SARS-CoV-2 entry into host cells is orchestrated by the spike (S) glycoprotein that contains an immunodominant receptor-binding domain (RBD) targeted by the largest fraction of neutralizing antibodies (Abs) in COVID-19 patient plasma. Little is known about neutralizing Abs binding to epitopes outside the RBD and their contribution to protection. Here, we describe 41 human monoclonal Abs (mAbs) derived from memory B cells, which recognize the SARS-CoV-2 S N-terminal domain (NTD) and show that a subset of them neutralize SARS-CoV-2 ultrapotently. We define an antigenic map of the SARS-CoV-2 NTD and identify a supersite recognized by all known NTD-specific neutralizing mAbs. These mAbs inhibit cell-to-cell fusion, activate effector functions, and protect Syrian hamsters from SARS-CoV-2 challenge. SARS-CoV-2 variants, including the 501Y.V2 and B.1.1.7 lineages, harbor frequent mutations localized in the NTD supersite suggesting ongoing selective pressure and the importance of NTD-specific neutralizing mAbs to protective immunity.

Competing Interest Statement

A.D.M., F.L., DP, M.B., F.Z., J.D.I., M.M.R., J.Z., L.E.R., S.B., B.G., C.S.F., F.B., E.C., G.S., A.T., H.W.V., D.C., and M.S.P. are employees of Vir Biotechnology Inc. and may hold shares in Vir Biotechnology Inc. D.C. is currently listed as an inventor on multiple patent applications, which disclose the subject matter described in this manuscript. The Neyts laboratories have received sponsored research agreements from Vir Biotechnology Inc. H.W.V. is a founder of PierianDx and Casma Therapeutics. Neither company provided funding for this work or is performing related work. D.V. is a consultant for Vir Biotechnology Inc. The Veesler laboratory has received a sponsored research agreement from Vir Biotechnology Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of 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 January 14, 2021.
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N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2
Matthew McCallum, Anna De Marco, Florian Lempp, M. Alejandra Tortorici, Dora Pinto, Alexandra C. Walls, Martina Beltramello, Alex Chen, Zhuoming Liu, Fabrizia Zatta, Samantha Zepeda, Julia di Iulio, John E. Bowen, Martin Montiel-Ruiz, Jiayi Zhou, Laura E. Rosen, Siro Bianchi, Barbara Guarino, Chiara Silacci Fregni, Rana Abdelnabi, Shi-Yan Caroline Foo, Paul W. Rothlauf, Louis-Marie Bloyet, Fabio Benigni, Elisabetta Cameroni, Johan Neyts, Agostino Riva, Gyorgy Snell, Amalio Telenti, Sean P.J. Whelan, Herbert W. Virgin, Davide Corti, Matteo Samuele Pizzuto, David Veesler
bioRxiv 2021.01.14.426475; doi: https://doi.org/10.1101/2021.01.14.426475
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N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2
Matthew McCallum, Anna De Marco, Florian Lempp, M. Alejandra Tortorici, Dora Pinto, Alexandra C. Walls, Martina Beltramello, Alex Chen, Zhuoming Liu, Fabrizia Zatta, Samantha Zepeda, Julia di Iulio, John E. Bowen, Martin Montiel-Ruiz, Jiayi Zhou, Laura E. Rosen, Siro Bianchi, Barbara Guarino, Chiara Silacci Fregni, Rana Abdelnabi, Shi-Yan Caroline Foo, Paul W. Rothlauf, Louis-Marie Bloyet, Fabio Benigni, Elisabetta Cameroni, Johan Neyts, Agostino Riva, Gyorgy Snell, Amalio Telenti, Sean P.J. Whelan, Herbert W. Virgin, Davide Corti, Matteo Samuele Pizzuto, David Veesler
bioRxiv 2021.01.14.426475; doi: https://doi.org/10.1101/2021.01.14.426475

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