Circulating SARS-CoV-2 spike N439K variants maintain 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., 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., Zhang I., Jarrett RF., Glass WG., Beltramello M., Nomikou K., Pizzuto M., Tong L., Cameroni E., Croll TI., Johnson N., Iulio JD., Wickenhagen A., Ceschi A., Harbison AM., Mair D., Ferrari P., Smollett K., Sallusto F., Carmichael S., Garzoni C., Nichols J., Galli M., Hughes J., Riva A., Ho A., Schiuma M., Semple MG., Openshaw PJM., Fadda E., Kenneth Baillie J., Chodera JD., Rihn SJ., Lycett SJ., Virgin HW., Telenti A., Corti D., Robertson DL., Snell G., Connor TR., Loman NJ., Robson SC., Golubchik T., Estee Torok M., Hamilton WL., Bonsall D., Awan AR., Corden S., Goodfellow I., Smith DL., Curran MD., Parmar S., Shepherd JG., Parker MD., Moore C., Fairley DJ., Loose MW., Watkins J., Bull M., Nicholls S., Aanensen DM., Glaysher S., Bashton M., Pacchiarini N., Underwood AP., de Silva TI., Wang D., Andersson M., Chauhan AJ., de Cesare M., Ludden C., Mahungu TW., Dewar R.
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.