Antibodies elicited by infection accumulate somatic mutations in germinal centers that can increase affinity for cognate antigens. We analyzed 6 independent groups of clonally related severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) Spike receptor-binding domain (RBD)-specific antibodies from 5 individuals shortly after infection and later in convalescence to determine the impact of maturation over months. In addition to increased affinity and neutralization potency, antibody evolution changed the mutational pathways for the acquisition of viral resistance and restricted neutralization escape options. For some antibodies, maturation imposed a requirement for multiple substitutions to enable escape. For certain antibodies, affinity maturation enabled the neutralization of circulating SARS-CoV-2 variants of concern and heterologous sarbecoviruses. Antibody-antigen structures revealed that these properties resulted from substitutions that allowed additional variability at the interface with the RBD. These findings suggest that increasing antibody diversity through prolonged or repeated antigen exposure may improve protection against diversifying SARS-CoV-2 populations, and perhaps against other pandemic threat coronaviruses.

感染引起的抗体会在生发中心积累体细胞突变，从而增加对同源抗原的亲和力。我们分析了 6 组独立的克隆相关严重急性呼吸综合征冠状病毒-2 (SARS-CoV-2) 尖峰受体结合域 (RBD) 特异性抗体，这些抗体来自 5 名感染后不久和恢复期的个体，以确定成熟的影响几个月来。除了增加亲和力和中和效力之外，抗体进化还改变了获得病毒抗性和限制中和逃逸选择的突变途径。对于某些抗体来说，成熟需要多次替换才能逃脱。对于某些抗体，亲和力成熟能够中和所关注的循环 SARS-CoV-2 变体和异源 sarbeco 病毒。抗体-抗原结构揭示了这些特性是由取代引起的，这些取代使得与 RBD 的界面存在额外的可变性。这些发现表明，通过长期或重复的抗原暴露来增加抗体多样性可能会提高对多样化 SARS-CoV-2 群体的保护，或许还可以预防其他大流行威胁冠状病毒。