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

Thomson, EC

; Rosen, LE; Shepherd, JG; Spreafico, R; da Silva Filipe, A; Wojcechowskyj, JA; Davis, C; Piccoli, L; Pascall, DJ; Dillen, J; +48 more...Lytras, S; Czudnochowski, N; Shah, R; Meury, M; Jesudason, N; De Marco, A; Li, K; Bassi, J; O’Toole, A; Pinto, D; Colquhoun, RM; Culap, K; Jackson, B; Zatta, F; Rambaut, A; Jaconi, S; Sreenu, VB; Nix, J; Jarrett, RF; Beltramello, M; Nomikou, K; Pizzuto, M; Tong, L; Cameroni, E; Johnson, N; Wickenhagen, A; Ceschi, A; Mair, D; Ferrari, P; Smollett, K; Sallusto, F; Carmichael, S; Garzoni, C; Nichols, J; Galli, M; Hughes, J; Riva, A; Ho, A; Semple, MG; Openshaw, PJ; Baillie, JK; Rihn, SJ; Lycett, SJ; Virgin, HW; Telenti, A; Corti, D; Robertson, DL; Snell, G and (2020) The circulating SARS-CoV-2 spike variant N439K maintains fitness while evading antibody-mediated immunity. bioRXiv preprints. DOI: 10.1101/2020.11.04.355842

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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.