The emergence of current SARS-CoV-2 variants of concern (VOCs) and potential future spillovers of SARS-like coronaviruses into humans pose a major threat to human health and the global economy ^1–7. Development of broadly effective coronavirus vaccines that can mitigate these threats is needed ^{8, 9}. Notably, several recent studies have revealed that vaccination of recovered COVID-19 donors results in enhanced nAb responses compared to SARS-CoV-2 infection or vaccination alone ^10–13. Here, we utilized a targeted donor selection strategy to isolate a large panel of broadly neutralizing antibodies (bnAbs) to sarbecoviruses from two such donors. Many of the bnAbs are remarkably effective in neutralization against sarbecoviruses that use ACE2 for viral entry and a substantial fraction also show notable binding to non-ACE2-using sarbecoviruses. The bnAbs are equally effective against most SARS-CoV-2 VOCs and many neutralize the Omicron variant. Neutralization breadth is achieved by bnAb binding to epitopes on a relatively conserved face of the receptor binding domain (RBD) as opposed to strain-specific nAbs to the receptor binding site that are commonly elicited in SARS-CoV-2 infection and vaccination ^14–18. Consistent with targeting of conserved sites, select RBD bnAbs exhibited in vivo protective efficacy against diverse SARS-like coronaviruses in a prophylaxis challenge model. The generation of a large panel of potent bnAbs provides new opportunities and choices for next-generation antibody prophylactic and therapeutic applications and, importantly, provides a molecular basis for effective design of pan-sarbecovirus vaccines.

中文翻译：

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针对 SARS 样病毒的多种人类保护性广泛中和抗体的靶向分离

当前关注的 SARS-CoV-2 变体 (VOC) 的出现以及未来可能向人类传播的 SARS 样冠状病毒对人类健康和全球经济构成重大威胁^1-7。需要开发可以减轻这些威胁的广泛有效的冠状病毒疫苗^{8, 9}。值得注意的是，最近的几项研究表明，与 SARS-CoV-2 感染或单独接种疫苗相比，对康复的 COVID-19 供体进行疫苗接种会导致 nAb 反应增强^10-13. 在这里，我们利用有针对性的供体选择策略从两个这样的供体中分离出一大组针对 sarbecovirus 的广泛中和抗体 (bnAb)。许多 bnAb 在中和使用 ACE2 进行病毒进入的 sarbecovirus 方面非常有效，并且相当一部分还显示出与不使用 ACE2 的 sarbecovirus 的显着结合。bnAbs 对大多数 SARS-CoV-2 VOCs 同样有效，并且许多中和 Omicron 变体。中和广度是通过 bnAb 与受体结合域 (RBD) 相对保守面上的表位结合来实现的，而不是在 SARS-CoV-2 感染和疫苗接种中通常引发的针对受体结合位点的菌株特异性 nAb ^14-18 . 与靶向保守位点一致，选择 RBD bnAbs 展示在预防挑战模型中对多种类 SARS 冠状病毒的体内保护功效。大量强效 bnAb 的产生为下一代抗体的预防和治疗应用提供了新的机会和选择，更重要的是，为有效设计泛病毒疫苗提供了分子基础。