Summary 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. Graphical Abstract Highlights • The receptor-binding motif (RBM) is a highly variable region of SARS-CoV-2 spike • RBM mutation N439K has emerged independently in multiple lineages • N439K increases spike affinity for hACE2; viral fitness and disease are unchanged • N439K confers resistance to several mAbs and escapes some polyclonal responses 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.
【저자키워드】 COVID-19, SARS-CoV-2, Mutation, spike, variant, protein structure, N439K, receptor binding motif, monoclonal antibody escape, 【초록키워드】 viruses, Efficacy, Vaccine, Immunity, S protein, antibody, Therapeutics, Infection, drug, FDA, virus, binding affinity, hACE2, Clinical outcome, Antibody therapeutics, Replication, Viral, Surveillance, response, Lineage, epidemiological, fitness, molecular, virulence, receptor-binding motif, disease, wild type, N439K, mAbs, neutralizing monoclonal antibodies, neutralizing monoclonal antibody, SARS-CoV-2 spike, mAb, Emergency use, food, polyclonal antibody, variable region, US Food and Drug Administration, Usage, hACE2 receptor, wild-type, viral fitness, SARS-CoV-2 S, immunodominant, polyclonal sera, responses, consequence, polyclonal, prevalent, increase, reducing, maintain, evade, reduce, mutate, highlighting, RBM, the SARS-CoV-2, 【제목키워드】 Immunity, maintain,