The circulating SARS-CoV-2 spike variant N439K maintains 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; Jarrett, Ruth F.; Beltramello, Martina; Nomikou, Kyriaki; Pizzuto, Matteo; Tong, Lily; Cameroni, Elisabetta; Johnson, Natasha; Wickenhagen, Arthur; Ceschi, Alessandro; Mair, Daniel; Ferrari, Paolo; Smollett, Katherine; Sallusto, Federica; Carmichael, Stephen; Garzoni, Christian; Nichols, Jenna; Galli, Massimo; Hughes, Joseph; Riva, Agostino; Ho, Antonia; Semple, Malcolm G.; Openshaw, Peter J.M.; Baillie, J. Kenneth; Rihn, Suzannah J.; Lycett, Samantha J.; Virgin, Herbert W.; Telenti, Amalio; Corti, Davide; Robertson, David L.; Snell, Gyorgy

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.