The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for virus infection through the engagement of the human ACE2 protein¹ and is a major antibody target. Here we show that chronic infection with SARS-CoV-2 leads to viral evolution and reduced sensitivity to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma, by generating whole-genome ultra-deep sequences for 23 time points that span 101 days and using in vitro techniques to characterize the mutations revealed by sequencing. There was little change in the overall structure of the viral population after two courses of remdesivir during the first 57 days. However, after convalescent plasma therapy, we observed large, dynamic shifts in the viral population, with the emergence of a dominant viral strain that contained a substitution (D796H) in the S2 subunit and a deletion (ΔH69/ΔV70) in the S1 N-terminal domain of the spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype were reduced in frequency, before returning during a final, unsuccessful course of convalescent plasma treatment. In vitro, the spike double mutant bearing both ΔH69/ΔV70 and D796H conferred modestly decreased sensitivity to convalescent plasma, while maintaining infectivity levels that were similar to the wild-type virus.The spike substitution mutant D796H appeared to be the main contributor to the decreased susceptibility to neutralizing antibodies, but this mutation resulted in an infectivity defect. The spike deletion mutant ΔH69/ΔV70 had a twofold higher level of infectivity than wild-type SARS-CoV-2, possibly compensating for the reduced infectivity of the D796H mutation. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy, which is associated with the emergence of viral variants that show evidence of reduced susceptibility to neutralizing antibodies in immunosuppressed individuals.

^{严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 的刺突蛋白通过与人类 ACE2 蛋白1}的结合对病毒感染至关重要并且是主要的抗体靶标。在这里，我们通过生成跨越 101 天的 23 个时间点的全基因组超深序列并使用体外技术来表征测序揭示的突变。在前 57 天接受两个疗程的瑞德西韦后，病毒种群的整体结构几乎没有变化。然而，在恢复期血浆治疗后，我们观察到病毒种群发生了巨大的动态变化，出现了一种显性病毒株，该株在 S2 亚基中包含替换 (D796H)，在 S1 N- 中包含缺失 (ΔH69/ΔV70)刺突蛋白的末端结构域。随着被动转移的血清抗体减少，具有逃逸基因型的病毒频率降低，然后在最后一次不成功的恢复期血浆治疗过程中返回。在体外，携带 ΔH69/ΔV70 和 D796H 的刺突双突变体对恢复期血浆的敏感性适度降低，同时保持与野生型病毒相似的感染性水平。刺突替代突变体 D796H 似乎是降低的主要贡献者对中和抗体易感，但这种突变导致感染性缺陷。刺突缺失突变体 ΔH69/ΔV70 的传染性水平是野生型 SARS-CoV-2 的两倍，可能弥补了 D796H 突变的传染性降低。这些数据表明在恢复期血浆治疗期间对 SARS-CoV-2 的强烈选择，