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

Thomson, Emma C., Rosen, Laura E., Shepherd, James G., Spreafico, Roberto, da Silva Filipe, Ana, Wojcechowskyj, Jason A., Davis, Chris, Piccoli, Luca, Pascall, David J., Dillen, Josh, Lytras, Spyros, Czudnochowski, Nadine, Shah, Rajiv, Meury, Marcel, Jesudason, Natasha, De Marco, Anna, Li, Kathy, Bassi, Jessica, O’Toole, Aine, Pinto, Dora, Colquhoun, Rachel M., Culap, Katja, Jackson, Ben, Zatta, Fabrizia, Rambaut, Andrew, Jaconi, Stefano, Sreenu, Vattipally B., Nix, Jay, Zhang, Ivy, Jarrett, Ruth F., Glass, William G., Beltramello, Martina, Nomikou, Kyriaki, Pizzuto, Matteo, Tong, Lily, Cameroni, Elisabetta, Croll, Tristan I., Johnson, Natasha, Di Iulio, Julia, Wickenhagen, Arthur, Ceschi, Alessandro, Harbison, Aoife M., Mair, Daniel, Ferrari, Paolo, Smollett, Katherine, Sallusto, Federica, Carmichael, Stephen, Garzoni, Christian, Nichols, Jenna, Galli, Massimo, Hughes, Joseph, Riva, Agostino, Ho, Antonia, Schiuma, Marco, Semple, Malcolm G., Openshaw, Peter J.M., Fadda, Elisa, Baillie, J. Kenneth, Chodera, John D., Rihn, Suzannah J., Lycett, Samantha J., Virgin, Herbert W., Telenti, Amalio, Corti, Davide, Robertson, David L., Snell, Gyorgy, Bashton, Matthew, Smith, Darren, Nelson, Andrew, Young, Greg and the COVID-19 Genomics UK (COG-UK) Consortium, (2021) Circulating SARS-CoV-2 spike N439K variants maintain fitness while evading antibody-mediated immunity. Cell, 184 (5). 1171-1187.e20. ISSN 0092-8674

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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.

Item Type: Article
Additional Information: Matthew Bashton, Darren Smith, Greg Young and Andrew Nelson are the members of the COVID-19 Genomics UK (COG-UK) Consortium. Funding information: We thank all Scottish NHS virology laboratories who provided samples for sequencing and Scott Arkison for HPC maintenance. We thank Chiara Silacci-Fregni from Humabs BioMed, Sandra Jovic, Blanca Fernandez Rodriguez, and Federico Mele, from the Institute for Research in Biomedicine in Bellinzona, and Tatiana Terrot from Ente Ospedaliero Cantonale in Lugano for the help in collecting serum samples. We thank Cindy Ng for help with protein production, Jesse Bloom for helpful comments, and Siro Bianchi for help with the graphical abstract. We gratefully acknowledge the authors originating and submitting laboratories of the sequences from GISAID ( Our genome sequence acknowledgments can be found in Data S2. Molecular Biology Consortium beamline 4.2.2 of the Advanced Light Source, a DOE Office of Science User Facility under Contract DE-AC02-05CH11231, is supported in part by the ALS-ENABLE program funded by the NIH, National Institute of General Medical Sciences (P30 GM124169-01). The ISARIC WHO CCP-UK study protocol is available at; study registry This work uses data provided by patients and collected by the NHS as part of their care and support #DataSavesLives. We are grateful to the 2,648 frontline NHS clinical and research staff and volunteer medical students who collected the data in challenging circumstances and the generosity of the participants and their families for their individual contributions in these difficult times. We also acknowledge the support of Jeremy J. Farrar and Nahoko Shindo. We are grateful to Gregory R. Bowman at Washington University in St. Louis, Joseph Coffland at Cauldron Development, Peter K. Eastman at Stanford University for developing and maintaining the Folding@home infrastructure, Amazon Web Services for critical Folding@home infrastructure support, and the many Folding@home volunteers who contributed their computational resources to this project (FAH Project 17311). We are also grateful to Rafal P. Wiewiora at Memorial Sloan Kettering Cancer Center and Redesign Science and Sukrit Singh at Washington University in St. Louis for their guidance on setting up and managing simulations on Folding@home. For funding, we thank the Medical Research Council (MRC) (MC UU 1201412), Wellcome Trust (Collaborators Award 206298/Z/17/Z-ARTIC Network), and Chief Scientist Office (Project COV/EDI/20/11). COG-UK is supported by funding from the MRC part of UK Research & Innovation (UKRI), the NIH Research (NIHR) and Genome Research Limited, operating as the Wellcome Sanger Institute. We also thank NIHR (CO-CIN-01), MRC (MC_PC_19059), the NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool in partnership with Public Health England (PHE) and in collaboration with Liverpool School of Tropical Medicine and the University of Oxford (200907), NIHR HPRU in Respiratory Infections at Imperial College London with PHE (200927), Wellcome Trust and Department for International Development (DID; 215091/Z/18/Z), the Bill and Melinda Gates Foundation (OPP1209135), Liverpool Experimental Cancer Medicine Centre (C18616/A25153), NIHR Biomedical Research Centre at Imperial College London (IS-BRC-1215-20013), EU Platform for European Preparedness Against (Re-)emerging Epidemics (PREPARE; FP7 project 602525), and NIHR Clinical Research Network for providing infrastructure support for this research. P.J.M.O. is supported by an NIHR senior investigator award (201385). The views expressed are those of the authors and not necessarily those of the Department of Health and Social Care, DID, NIHR, MRC, Wellcome Trust, or PHE. J.D.C. acknowledges support from NIH (P30 CA008748, R01 GM121505, and R01 GM132386), NSF (CHI-1904822), and the Sloan Kettering Institute. F.S. is supported by the Henry Krenter Foundation. F.S. and the Institute for Research in Biomedicine are supported by the Helmut Horten Foundation. I.Z. acknowledges support from the Tri-Institutional PhD Program in Computational Biology and Medicine, Vir Biotechnology, the Molecular Sciences Software Institute, and the Sloan Kettering Institute. W.G.G. acknowledges support from Bayer and the Sloan Kettering Institute. T.I.C acknowledges support from Randy Read’s Wellcome Trust (209407/Z/17/Z).
Subjects: B100 Anatomy, Physiology and Pathology
C500 Microbiology
C700 Molecular Biology, Biophysics and Biochemistry
Department: Faculties > Health and Life Sciences > Applied Sciences
Depositing User: Elena Carlaw
Date Deposited: 10 Mar 2021 11:47
Last Modified: 31 Jul 2021 15:21

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