Circulating SARS-CoV-2 spike N439K variants maintain fitness while evading antibody-mediated immunity

The ISARIC4C Investigators; The COVID-19 Genomics UK (COG-UK) Consortium

doi:10.1016/j.cell.2021.01.037

Circulating SARS-CoV-2 spike N439K variants maintain fitness while evading antibody-mediated immunity

The ISARIC4C Investigators
, The COVID-19 Genomics UK (COG-UK) Consortium

Mathematics

MRC-University of Glasgow Centre for Virus Research
London School of Hygiene and Tropical Medicine
a subsidiary of Vir Biotechnology
University of Glasgow, G11 6NT
University of Edinburgh
Advanced Light Source, Berkeley
Memorial Sloan Kettering Cancer Center
Weill Cornell Graduate School of Medical Sciences
Cambridge Institute for Medical Research
Università della Svizzera Italiana (USI)
Cardiocentro
University Hospital Zürich
Maynooth University
Ente Ospedaliero Cantonale
University of New South Wales
Universitá Svizzera italiana
ETH Zürich
Clinica Luganese Moncucco
University Hospital "Luigi Sacco"
University of Liverpool
Alder Hey Children's Hospital
National Heart and Lung Institute
University of Edinburgh, Roslin Institute
Royal Infirmary of Edinburgh
Washington University School of Medicine in St. Louis

Research output: Contribution to a Journal (Peer & Non Peer) › Article › peer-review

455 Citations (Scopus)

Abstract

SARS-CoV-2 can mutate and evade immunity, with consequences for efficacy of emerging vaccines and antibody therapeutics. Here, we demonstrate that the immunodominant SARS-CoV-2 spike (S) receptor binding motif (RBM) is a highly variable region of S and provide epidemiological, clinical, and molecular characterization of a prevalent, sentinel RBM mutation, N439K. We demonstrate N439K S protein has enhanced binding affinity to the hACE2 receptor, and N439K viruses have similar in vitro replication fitness and cause infections with similar clinical outcomes as compared to wild type. We show the N439K mutation confers resistance against several neutralizing monoclonal antibodies, including one authorized for emergency use by the US Food and Drug Administration (FDA), and reduces the activity of some polyclonal sera from 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. Epidemiological, clinical, molecular, and structural characterization of the N439K mutation in the SARS-CoV-2 spike receptor binding motif demonstrates that it results in similar viral fitness compared to wild-type while conferring resistance against some neutralizing monoclonal antibodies and reducing the activity of some polyclonal antibody responses.

Original language	English
Pages (from-to)	1171-1187.e20
Journal	Cell
Volume	184
Issue number	5
DOIs	https://doi.org/10.1016/j.cell.2021.01.037
Publication status	Published - 4 Mar 2021

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

COVID-19
monoclonal antibody escape
mutation
N439K
protein structure
receptor binding motif
SARS-CoV-2
Spike
variant

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10.1016/j.cell.2021.01.037

Cite this

@article{03e1522904e949d5921ff161fece1423,

title = "Circulating SARS-CoV-2 spike N439K variants maintain fitness while evading antibody-mediated immunity",

abstract = "SARS-CoV-2 can mutate and evade immunity, with consequences for efficacy of emerging vaccines and antibody therapeutics. Here, we demonstrate that the immunodominant SARS-CoV-2 spike (S) receptor binding motif (RBM) is a highly variable region of S and provide epidemiological, clinical, and molecular characterization of a prevalent, sentinel RBM mutation, N439K. We demonstrate N439K S protein has enhanced binding affinity to the hACE2 receptor, and N439K viruses have similar in vitro replication fitness and cause infections with similar clinical outcomes as compared to wild type. We show the N439K mutation confers resistance against several neutralizing monoclonal antibodies, including one authorized for emergency use by the US Food and Drug Administration (FDA), and reduces the activity of some polyclonal sera from 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. Epidemiological, clinical, molecular, and structural characterization of the N439K mutation in the SARS-CoV-2 spike receptor binding motif demonstrates that it results in similar viral fitness compared to wild-type while conferring resistance against some neutralizing monoclonal antibodies and reducing the activity of some polyclonal antibody responses.",

keywords = "COVID-19, monoclonal antibody escape, mutation, N439K, protein structure, receptor binding motif, SARS-CoV-2, Spike, variant",

author = "\{The ISARIC4C Investigators\} and \{The COVID-19 Genomics UK (COG-UK) Consortium\} and Thomson, \{Emma C.\} and Rosen, \{Laura E.\} and Shepherd, \{James G.\} and Roberto Spreafico and \{da Silva Filipe\}, Ana and Wojcechowskyj, \{Jason A.\} and Chris Davis and Luca Piccoli and Pascall, \{David J.\} and Josh Dillen and Spyros Lytras and Nadine Czudnochowski and Rajiv Shah and Marcel Meury and Natasha Jesudason and \{De Marco\}, Anna and Kathy Li and Jessica Bassi and Aine O{\textquoteright}Toole and Dora Pinto and Colquhoun, \{Rachel M.\} and Katja Culap and Ben Jackson and Fabrizia Zatta and Andrew Rambaut and Stefano Jaconi and Sreenu, \{Vattipally B.\} and Jay Nix and Ivy Zhang and Jarrett, \{Ruth F.\} and Glass, \{William G.\} and Martina Beltramello and Kyriaki Nomikou and Matteo Pizzuto and Lily Tong and Elisabetta Cameroni and Croll, \{Tristan I.\} and Natasha Johnson and Iulio, \{Julia Di\} and Arthur Wickenhagen and Alessandro Ceschi and Harbison, \{Aoife M.\} and Daniel Mair and Paolo Ferrari and Katherine Smollett and Federica Sallusto and Stephen Carmichael and Christian Garzoni and Jenna Nichols and Massimo Galli and Joseph Hughes and Agostino Riva and Antonia Ho and Marco Schiuma and Semple, \{Malcolm G.\} and Openshaw, \{Peter J.M.\} and Elisa Fadda and \{Kenneth Baillie\}, J. and Chodera, \{John D.\} and Rihn, \{Suzannah J.\} and Lycett, \{Samantha J.\} and Virgin, \{Herbert W.\} and Amalio Telenti and Davide Corti and Robertson, \{David L.\} and Gyorgy Snell and Connor, \{Thomas R.\} and Loman, \{Nicholas J.\} and Robson, \{Samuel C.\} and Tanya Golubchik and \{Estee Torok\}, M. and Hamilton, \{William L.\} and David Bonsall and Awan, \{Ali R.\} and Sally Corden and Ian Goodfellow and Smith, \{Darren L.\} and Curran, \{Martin D.\} and Surendra Parmar and Shepherd, \{James G.\} and Parker, \{Matthew D.\} and Catherine Moore and Fairley, \{Derek J.\} and Loose, \{Matthew W.\} and Joanne Watkins and Matthew Bull and Sam Nicholls and Aanensen, \{David M.\} and Sharon Glaysher and Matthew Bashton and Nicole Pacchiarini and Underwood, \{Anthony P.\} and \{de Silva\}, \{Thushan I.\} and Dennis Wang and Monique Andersson and Chauhan, \{Anoop J.\} and \{de Cesare\}, Mariateresa and Catherine Ludden and Mahungu, \{Tabitha W.\} and Dorman, \{Matthew J.\}",

note = "Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2021",

month = mar,

day = "4",

doi = "10.1016/j.cell.2021.01.037",

language = "English",

volume = "184",

pages = "1171--1187.e20",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier B.V.",

number = "5",

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TY - JOUR

T1 - Circulating SARS-CoV-2 spike N439K variants maintain fitness while evading antibody-mediated immunity

AU - The ISARIC4C Investigators

AU - The COVID-19 Genomics UK (COG-UK) Consortium

AU - Thomson, Emma C.

AU - Rosen, Laura E.

AU - Shepherd, James G.

AU - Spreafico, Roberto

AU - da Silva Filipe, Ana

AU - Wojcechowskyj, Jason A.

AU - Davis, Chris

AU - Piccoli, Luca

AU - Pascall, David J.

AU - Dillen, Josh

AU - Lytras, Spyros

AU - Czudnochowski, Nadine

AU - Shah, Rajiv

AU - Meury, Marcel

AU - Jesudason, Natasha

AU - De Marco, Anna

AU - Li, Kathy

AU - Bassi, Jessica

AU - O’Toole, Aine

AU - Pinto, Dora

AU - Colquhoun, Rachel M.

AU - Culap, Katja

AU - Jackson, Ben

AU - Zatta, Fabrizia

AU - Rambaut, Andrew

AU - Jaconi, Stefano

AU - Sreenu, Vattipally B.

AU - Nix, Jay

AU - Zhang, Ivy

AU - Jarrett, Ruth F.

AU - Glass, William G.

AU - Beltramello, Martina

AU - Nomikou, Kyriaki

AU - Pizzuto, Matteo

AU - Tong, Lily

AU - Cameroni, Elisabetta

AU - Croll, Tristan I.

AU - Johnson, Natasha

AU - Iulio, Julia Di

AU - Wickenhagen, Arthur

AU - Ceschi, Alessandro

AU - Harbison, Aoife M.

AU - Mair, Daniel

AU - Ferrari, Paolo

AU - Smollett, Katherine

AU - Sallusto, Federica

AU - Carmichael, Stephen

AU - Garzoni, Christian

AU - Nichols, Jenna

AU - Galli, Massimo

AU - Hughes, Joseph

AU - Riva, Agostino

AU - Ho, Antonia

AU - Schiuma, Marco

AU - Semple, Malcolm G.

AU - Openshaw, Peter J.M.

AU - Fadda, Elisa

AU - Kenneth Baillie, J.

AU - Chodera, John D.

AU - Rihn, Suzannah J.

AU - Lycett, Samantha J.

AU - Virgin, Herbert W.

AU - Telenti, Amalio

AU - Corti, Davide

AU - Robertson, David L.

AU - Snell, Gyorgy

AU - Connor, Thomas R.

AU - Loman, Nicholas J.

AU - Robson, Samuel C.

AU - Golubchik, Tanya

AU - Estee Torok, M.

AU - Hamilton, William L.

AU - Bonsall, David

AU - Awan, Ali R.

AU - Corden, Sally

AU - Goodfellow, Ian

AU - Smith, Darren L.

AU - Curran, Martin D.

AU - Parmar, Surendra

AU - Shepherd, James G.

AU - Parker, Matthew D.

AU - Moore, Catherine

AU - Fairley, Derek J.

AU - Loose, Matthew W.

AU - Watkins, Joanne

AU - Bull, Matthew

AU - Nicholls, Sam

AU - Aanensen, David M.

AU - Glaysher, Sharon

AU - Bashton, Matthew

AU - Pacchiarini, Nicole

AU - Underwood, Anthony P.

AU - de Silva, Thushan I.

AU - Wang, Dennis

AU - Andersson, Monique

AU - Chauhan, Anoop J.

AU - de Cesare, Mariateresa

AU - Ludden, Catherine

AU - Mahungu, Tabitha W.

AU - Dorman, Matthew J.

PY - 2021/3/4

Y1 - 2021/3/4

N2 - SARS-CoV-2 can mutate and evade immunity, with consequences for efficacy of emerging vaccines and antibody therapeutics. Here, we demonstrate that the immunodominant SARS-CoV-2 spike (S) receptor binding motif (RBM) is a highly variable region of S and provide epidemiological, clinical, and molecular characterization of a prevalent, sentinel RBM mutation, N439K. We demonstrate N439K S protein has enhanced binding affinity to the hACE2 receptor, and N439K viruses have similar in vitro replication fitness and cause infections with similar clinical outcomes as compared to wild type. We show the N439K mutation confers resistance against several neutralizing monoclonal antibodies, including one authorized for emergency use by the US Food and Drug Administration (FDA), and reduces the activity of some polyclonal sera from 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. Epidemiological, clinical, molecular, and structural characterization of the N439K mutation in the SARS-CoV-2 spike receptor binding motif demonstrates that it results in similar viral fitness compared to wild-type while conferring resistance against some neutralizing monoclonal antibodies and reducing the activity of some polyclonal antibody responses.

AB - SARS-CoV-2 can mutate and evade immunity, with consequences for efficacy of emerging vaccines and antibody therapeutics. Here, we demonstrate that the immunodominant SARS-CoV-2 spike (S) receptor binding motif (RBM) is a highly variable region of S and provide epidemiological, clinical, and molecular characterization of a prevalent, sentinel RBM mutation, N439K. We demonstrate N439K S protein has enhanced binding affinity to the hACE2 receptor, and N439K viruses have similar in vitro replication fitness and cause infections with similar clinical outcomes as compared to wild type. We show the N439K mutation confers resistance against several neutralizing monoclonal antibodies, including one authorized for emergency use by the US Food and Drug Administration (FDA), and reduces the activity of some polyclonal sera from 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. Epidemiological, clinical, molecular, and structural characterization of the N439K mutation in the SARS-CoV-2 spike receptor binding motif demonstrates that it results in similar viral fitness compared to wild-type while conferring resistance against some neutralizing monoclonal antibodies and reducing the activity of some polyclonal antibody responses.

KW - COVID-19

KW - monoclonal antibody escape

KW - mutation

KW - N439K

KW - protein structure

KW - receptor binding motif

KW - SARS-CoV-2

KW - Spike

KW - variant

UR - https://www.scopus.com/pages/publications/85100498920

U2 - 10.1016/j.cell.2021.01.037

DO - 10.1016/j.cell.2021.01.037

M3 - Article

AN - SCOPUS:85100498920

SN - 0092-8674

VL - 184

SP - 1171-1187.e20

JO - Cell

JF - Cell

IS - 5

ER -

Circulating SARS-CoV-2 spike N439K variants maintain fitness while evading antibody-mediated immunity

Abstract

UN SDGs

Keywords

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