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.

SARS-CoV-2 可以突变并逃避免疫，从而影响新兴疫苗和抗体疗法的功效。在这里，我们证明免疫显性的 SARS-CoV-2 刺突 (S) 受体结合基序 (RBM) 是 S 的高度可变区域，并提供了流行的前哨 RBM 突变 N439K 的流行病学、临床和分子特征。我们证明 N439K S 蛋白与 hACE2 受体的结合亲和力增强，并且与野生型病毒相比，N439K 病毒具有相似的体外复制适应性，并引起具有相似临床结果的感染。我们发现，N439K 突变赋予了对几种中和单克隆抗体的抗性，其中包括美国食品和药物管理局 (FDA) 授权紧急使用的一种单克隆抗体，并降低了感染康复者的一些多克隆血清的活性。 SARS-CoV-2 S 中可能会出现保持毒力和适应性的免疫逃避突变（例如 N439K），这凸显了持续进行分子监测以指导疫苗和治疗方法的开发和使用的必要性。