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The circulating SARS-CoV-2 spike variant N439K maintains fitness while evading antibody-mediated immunity

Emma C. Thomson, Laura E. Rosen, James G. Shepherd, Roberto Spreafico, Ana da Silva Filipe, Jason A. Wojcechowskyj, Chris Davis, Luca Piccoli, David J. Pascall, Josh Dillen, Spyros Lytras, Nadine Czudnochowski, Rajiv Shah, Marcel Meury, Natasha Jesudason, Anna De Marco, Kathy Li, Jessica Bassi, Aine O’Toole, Dora Pinto, Rachel M. Colquhoun, Katja Culap, Ben Jackson, Fabrizia Zatta, Andrew Rambaut, Stefano Jaconi, Vattipally B. Sreenu, Jay Nix, Ruth F. Jarrett, Martina Beltramello, Kyriaki Nomikou, Matteo Pizzuto, Lily Tong, Elisabetta Cameroni, Natasha Johnson, Arthur Wickenhagen, Alessandro Ceschi, Daniel Mair, Paolo Ferrari, Katherine Smollett, Federica Sallusto, Stephen Carmichael, Christian Garzoni, Jenna Nichols, Massimo Galli, Joseph Hughes, Agostino Riva, Antonia Ho, Malcolm G. Semple, Peter J.M. Openshaw, J. Kenneth Baillie, The ISARIC4C Investigators, the COVID-19 Genomics UK (COG-UK) consortium, Suzannah J. Rihn, Samantha J. Lycett, Herbert W. Virgin, Amalio Telenti, Davide Corti, David L. Robertson, Gyorgy Snell
doi: https://doi.org/10.1101/2020.11.04.355842
Emma C. Thomson
1MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, G61 1QH, UK
2Department of Clinical Research, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK
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Laura E. Rosen
3Vir Biotechnology, San Francisco, California 94158, USA
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James G. Shepherd
1MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, G61 1QH, UK
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Roberto Spreafico
3Vir Biotechnology, San Francisco, California 94158, USA
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Ana da Silva Filipe
1MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, G61 1QH, UK
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Jason A. Wojcechowskyj
3Vir Biotechnology, San Francisco, California 94158, USA
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Chris Davis
1MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, G61 1QH, UK
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Luca Piccoli
4Humabs Biomed SA, a subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland
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David J. Pascall
5Institute of Biodiversity, Animal Health and Comparative Medicine, Boyd Orr Centre for Population and Ecosystem Health, University of Glasgow, Glasgow, G61 1QH, UK
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Josh Dillen
3Vir Biotechnology, San Francisco, California 94158, USA
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Spyros Lytras
1MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, G61 1QH, UK
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Nadine Czudnochowski
3Vir Biotechnology, San Francisco, California 94158, USA
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Rajiv Shah
1MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, G61 1QH, UK
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Marcel Meury
3Vir Biotechnology, San Francisco, California 94158, USA
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Natasha Jesudason
1MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, G61 1QH, UK
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Anna De Marco
4Humabs Biomed SA, a subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland
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Kathy Li
1MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, G61 1QH, UK
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Jessica Bassi
4Humabs Biomed SA, a subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland
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Aine O’Toole
6Institute of Evolutionary Biology, University of Edinburgh, Edinburgh, UK
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Dora Pinto
4Humabs Biomed SA, a subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland
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Rachel M. Colquhoun
6Institute of Evolutionary Biology, University of Edinburgh, Edinburgh, UK
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Katja Culap
4Humabs Biomed SA, a subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland
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Ben Jackson
6Institute of Evolutionary Biology, University of Edinburgh, Edinburgh, UK
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Fabrizia Zatta
4Humabs Biomed SA, a subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland
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Andrew Rambaut
6Institute of Evolutionary Biology, University of Edinburgh, Edinburgh, UK
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Stefano Jaconi
4Humabs Biomed SA, a subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland
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Vattipally B. Sreenu
1MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, G61 1QH, UK
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Jay Nix
7Molecular Biology Consortium, Advanced Light Source, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA
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Ruth F. Jarrett
1MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, G61 1QH, UK
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Martina Beltramello
4Humabs Biomed SA, a subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland
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Kyriaki Nomikou
1MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, G61 1QH, UK
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Matteo Pizzuto
4Humabs Biomed SA, a subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland
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Lily Tong
1MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, G61 1QH, UK
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Elisabetta Cameroni
4Humabs Biomed SA, a subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland
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Natasha Johnson
1MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, G61 1QH, UK
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Arthur Wickenhagen
1MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, G61 1QH, UK
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Alessandro Ceschi
8Faculty of Biomedical Sciences, Università della Svizzera italiana, Lugano, Switzerland
9Division of Clinical Pharmacology and Toxicology, Institute of Pharmacological Sciences of Southern Switzerland, Ente Ospedaliero Cantonale, Lugano, Switzerland
10Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland
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Daniel Mair
1MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, G61 1QH, UK
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Paolo Ferrari
11Department of Nephrology, Ospedale Civico Lugano, Ente Ospedaliero Cantonale, Lugano, Switzerland
12Prince of Wales Hospital Clinical School, University of New South Wales, Sydney, Australia
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Katherine Smollett
1MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, G61 1QH, UK
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Federica Sallusto
13Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland
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Stephen Carmichael
1MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, G61 1QH, UK
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Christian Garzoni
14Clinic of Internal Medicine and Infectious Diseases, Clinica Luganese Moncucco, 6900 Lugano, Switzerland
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Jenna Nichols
1MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, G61 1QH, UK
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Massimo Galli
15III Division of Infectious Diseases, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, 20157 Milan, Italy
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Joseph Hughes
1MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, G61 1QH, UK
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Agostino Riva
15III Division of Infectious Diseases, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, 20157 Milan, Italy
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Antonia Ho
1MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, G61 1QH, UK
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Malcolm G. Semple
16NIHR Health Protection Research Unit, Institute of Infection, Veterinary and Ecological Sciences, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK
17Respiratory Medicine, Alder Hey Children’s Hospital, Institute in The Park, University of Liverpool, Alder Hey Children’s Hospital, Liverpool L12 2AP, UK
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Peter J.M. Openshaw
18National Heart and Lung Institute, Imperial College London, London, UK
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J. Kenneth Baillie
19The Roslin Institute, University of Edinburgh, EH25 9RG Edinburgh, UK
20Intensive Care Unit, Royal Infirmary Edinburgh, Edinburgh, UK
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Suzannah J. Rihn
1MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, G61 1QH, UK
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Samantha J. Lycett
19The Roslin Institute, University of Edinburgh, EH25 9RG Edinburgh, UK
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Herbert W. Virgin
3Vir Biotechnology, San Francisco, California 94158, USA
23Washington University School of Medicine, Saint Louis, Missouri 63110, USA
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Amalio Telenti
3Vir Biotechnology, San Francisco, California 94158, USA
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Davide Corti
4Humabs Biomed SA, a subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland
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David L. Robertson
1MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, G61 1QH, UK
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Gyorgy Snell
3Vir Biotechnology, San Francisco, California 94158, USA
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  • For correspondence: gsnell@vir.bio david.l.robertson@glasgow.ac.uk
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Abstract

SARS-CoV-2 can mutate to evade immunity, with consequences for the efficacy of emerging vaccines and antibody therapeutics. Herein we demonstrate that the immunodominant SARS-CoV-2 spike (S) receptor binding motif (RBM) is the most divergent region of S, and provide epidemiological, clinical, and molecular characterization of a prevalent RBM variant, N439K. We demonstrate that N439K S protein has enhanced binding affinity to the hACE2 receptor, and that N439K virus has similar clinical outcomes and in vitro replication fitness as compared to wild- type. We observed that the N439K mutation resulted in immune escape from a panel of neutralizing monoclonal antibodies, including one in clinical trials, as well as from polyclonal sera from a sizeable fraction of persons recovered from infection. Immune evasion mutations that maintain virulence and fitness such as N439K can emerge within SARS-CoV-2 S, highlighting the need for ongoing molecular surveillance to guide development and usage of vaccines and therapeutics.

Competing Interest Statement

L.E.R., R. Sp., J.A.W., L.P., J.D., N.C., M.M., A.D.M., J.B., D.P., K.C., F.Z., S.J., M.B., M.P., E.C., H.W.V., A.T., D.C., and G.S. are or were employees of Vir Biotechnology Inc. and may hold shares in Vir Biotechnology Inc. C.G. is a consultant to Humabs BioMed SA. J.Nix is a consultant with Vir Biotechnology Inc. The other authors declare no competing interests.

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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The circulating SARS-CoV-2 spike variant N439K maintains fitness while evading antibody-mediated immunity
Emma C. Thomson, Laura E. Rosen, James G. Shepherd, Roberto Spreafico, Ana da Silva Filipe, Jason A. Wojcechowskyj, Chris Davis, Luca Piccoli, David J. Pascall, Josh Dillen, Spyros Lytras, Nadine Czudnochowski, Rajiv Shah, Marcel Meury, Natasha Jesudason, Anna De Marco, Kathy Li, Jessica Bassi, Aine O’Toole, Dora Pinto, Rachel M. Colquhoun, Katja Culap, Ben Jackson, Fabrizia Zatta, Andrew Rambaut, Stefano Jaconi, Vattipally B. Sreenu, Jay Nix, Ruth F. Jarrett, Martina Beltramello, Kyriaki Nomikou, Matteo Pizzuto, Lily Tong, Elisabetta Cameroni, Natasha Johnson, Arthur Wickenhagen, Alessandro Ceschi, Daniel Mair, Paolo Ferrari, Katherine Smollett, Federica Sallusto, Stephen Carmichael, Christian Garzoni, Jenna Nichols, Massimo Galli, Joseph Hughes, Agostino Riva, Antonia Ho, Malcolm G. Semple, Peter J.M. Openshaw, J. Kenneth Baillie, The ISARIC4C Investigators, the COVID-19 Genomics UK (COG-UK) consortium, Suzannah J. Rihn, Samantha J. Lycett, Herbert W. Virgin, Amalio Telenti, Davide Corti, David L. Robertson, Gyorgy Snell
bioRxiv 2020.11.04.355842; doi: https://doi.org/10.1101/2020.11.04.355842
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The circulating SARS-CoV-2 spike variant N439K maintains fitness while evading antibody-mediated immunity
Emma C. Thomson, Laura E. Rosen, James G. Shepherd, Roberto Spreafico, Ana da Silva Filipe, Jason A. Wojcechowskyj, Chris Davis, Luca Piccoli, David J. Pascall, Josh Dillen, Spyros Lytras, Nadine Czudnochowski, Rajiv Shah, Marcel Meury, Natasha Jesudason, Anna De Marco, Kathy Li, Jessica Bassi, Aine O’Toole, Dora Pinto, Rachel M. Colquhoun, Katja Culap, Ben Jackson, Fabrizia Zatta, Andrew Rambaut, Stefano Jaconi, Vattipally B. Sreenu, Jay Nix, Ruth F. Jarrett, Martina Beltramello, Kyriaki Nomikou, Matteo Pizzuto, Lily Tong, Elisabetta Cameroni, Natasha Johnson, Arthur Wickenhagen, Alessandro Ceschi, Daniel Mair, Paolo Ferrari, Katherine Smollett, Federica Sallusto, Stephen Carmichael, Christian Garzoni, Jenna Nichols, Massimo Galli, Joseph Hughes, Agostino Riva, Antonia Ho, Malcolm G. Semple, Peter J.M. Openshaw, J. Kenneth Baillie, The ISARIC4C Investigators, the COVID-19 Genomics UK (COG-UK) consortium, Suzannah J. Rihn, Samantha J. Lycett, Herbert W. Virgin, Amalio Telenti, Davide Corti, David L. Robertson, Gyorgy Snell
bioRxiv 2020.11.04.355842; doi: https://doi.org/10.1101/2020.11.04.355842

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