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

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.

Authors: 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 JM Openshaw, Kenneth Baillie, The ISARIC4C Investigators, 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