TY - JOUR
T1 - Circulating SARS-CoV-2 spike N439K variants maintain fitness while evading antibody-mediated immunity
AU - The ISARIC4C Investigators
AU - COVID-19 Genomics UK (COG-UK) Consortium
AU - Thomson, Emma C.
AU - Rosen, Laura E.
AU - Shepherd, James G.
AU - Spreafico, Roberto
AU - Da Silva Filipe, Ana
AU - Wojcechowskyj, Jason A.
AU - Davis, Chris
AU - Piccoli, Luca
AU - Pascall, David J.
AU - Dillen, Josh
AU - Lytras, Spyros
AU - Czudnochowski, Nadine
AU - Shah, Rajiv
AU - Meury, Marcel
AU - Jesudason, Natasha
AU - De Marco, Anna
AU - Li, Kathy
AU - Bassi, Jessica
AU - O’toole, Aine
AU - Pinto, Dora
AU - Colquhoun, Rachel M.
AU - Culap, Katja
AU - Jackson, Ben
AU - Zatta, Fabrizia
AU - Rambaut, Andrew
AU - Jaconi, Stefano
AU - Sreenu, Vattipally B.
AU - Nix, Jay
AU - Zhang, Ivy
AU - Jarrett, Ruth F.
AU - Glass, William G.
AU - Beltramello, Martina
AU - Nomikou, Kyriaki
AU - Pizzuto, Matteo
AU - Tong, Lily
AU - Cameroni, Elisabetta
AU - Croll, Tristan I.
AU - Johnson, Natasha
AU - Di Iulio, Julia
AU - Wickenhagen, Arthur
AU - Ceschi, Alessandro
AU - Harbison, Aoife M.
AU - Mair, Daniel
AU - Ferrari, Paolo
AU - Smollett, Katherine
AU - Sallusto, Federica
AU - Carmichael, Stephen
AU - Garzoni, Christian
AU - Nichols, Jenna
AU - Galli, Massimo
AU - Beggs, Andrew
PY - 2021/3/4
Y1 - 2021/3/4
N2 - 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.
AB - 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.
KW - COVID-19
KW - N439K
KW - SARS-CoV-2
KW - Spike
KW - monoclonal antibody escape
KW - mutation
KW - protein structure
KW - receptor binding motif
KW - variant
UR - http://www.scopus.com/inward/record.url?scp=85100498920&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2021.01.037
DO - 10.1016/j.cell.2021.01.037
M3 - Article
SN - 0092-8674
VL - 184
SP - 1171-1187.e20
JO - Cell
JF - Cell
IS - 5
ER -
