The number and variability of the neutralizing epitopes targeted by polyclonal antibodies in individuals who are SARS-CoV-2 convalescent and vaccinated are key determinants of neutralization breadth and the genetic barrier to viral escape^1,2,3,4. Using HIV-1 pseudotypes and plasma selection experiments with vesicular stomatitis virus/SARS-CoV-2 chimaeras⁵, here we show that multiple neutralizing epitopes, within and outside the receptor-binding domain, are variably targeted by human polyclonal antibodies. Antibody targets coincide with spike sequences that are enriched for diversity in natural SARS-CoV-2 populations. By combining plasma-selected spike substitutions, we generated synthetic ‘polymutant’ spike protein pseudotypes that resisted polyclonal antibody neutralization to a similar degree as circulating variants of concern. By aggregating variant of concern-associated and antibody-selected spike substitutions into a single polymutant spike protein, we show that 20 naturally occurring mutations in the SARS-CoV-2 spike protein are sufficient to generate pseudotypes with near-complete resistance to the polyclonal neutralizing antibodies generated by individuals who are convalescent or recipients who received an mRNA vaccine. However, plasma from individuals who had been infected and subsequently received mRNA vaccination neutralized pseudotypes bearing this highly resistant SARS-CoV-2 polymutant spike, or diverse sarbecovirus spike proteins. Thus, optimally elicited human polyclonal antibodies against SARS-CoV-2 should be resilient to substantial future SARS-CoV-2 variation and may confer protection against potential future sarbecovirus pandemics.

在 SARS-CoV-2 恢复期并接种疫苗的个体中，多克隆抗体靶向的中和表位的数量和变异性是中和广度和病毒逃逸遗传屏障的关键决定因素^1,2,3,4 。使用 HIV-1 假型和水泡性口炎病毒/SARS-CoV-2 嵌合体的血浆选择实验⁵ ，我们在此表明​​，受体结合域内外的多个中和表位是人多克隆抗体不同的靶标。抗体靶标与天然 SARS-CoV-2 群体中多样性丰富的刺突序列一致。通过结合血浆选择的刺突取代，我们生成了合成的“多突变”刺突蛋白假型，其抵抗多克隆抗体中和的程度与所关注的循环变体相似。通过将关注相关的变体和抗体选择的刺突取代聚合成单个多突变刺突蛋白，我们发现 SARS-CoV-2 刺突蛋白中的 20 个自然发生的突变足以产生对多克隆中和剂几乎完全耐药的假型。恢复期个体或接受 mRNA 疫苗的接受者产生的抗体。然而，来自已感染并随后接受 mRNA 疫苗接种的个体的血浆中和了携带这种高度耐药的 SARS-CoV-2 多突变体刺突或多种 sarbecovirus 刺突蛋白的假型病毒。因此，最佳诱导的抗 SARS-CoV-2 人类多克隆抗体应该能够抵御未来 SARS-CoV-2 的大量变异，并可能针对未来潜在的 sarbecovirus 流行病提供保护。