Frequent outbreaks of coronaviruses underscore the need for antivirals and vaccines that can counter a broad range of coronavirus types. We isolated a human antibody named 76E1 from a COVID-19 convalescent patient, and report that it has broad-range neutralizing activity against multiple α- and β-coronaviruses, including the SARS-CoV-2 variants. 76E1 also binds its epitope in peptides from γ- and δ-coronaviruses. 76E1 cross-protects against SARS-CoV-2 and HCoV-OC43 infection in both prophylactic and therapeutic murine animal models. Structural and functional studies revealed that 76E1 targets a unique epitope within the spike protein that comprises the highly conserved S2’ site and the fusion peptide. The epitope that 76E1 binds is partially buried in the structure of the SARS-CoV-2 spike trimer in the prefusion state, but is exposed when the spike protein binds to ACE2. This observation suggests that 76E1 binds to the epitope at an intermediate state of the spike trimer during the transition from the prefusion to the postfusion state, thereby blocking membrane fusion and viral entry. We hope that the identification of this crucial epitope, which can be recognized by 76E1, will guide epitope-based design of next-generation pan-coronavirus vaccines and antivirals.

冠状病毒的频繁爆发凸显了对能够对抗多种冠状病毒类型的抗病毒药物和疫苗的需求。我们从一名 COVID-19 恢复期患者中分离出一种名为 76E1 的人类抗体，并报告说它对多种 α 和 β 冠状病毒（包括 SARS-CoV-2 变体）具有广泛的中和活性。76E1 还结合来自 γ- 和 δ- 冠状病毒的肽中的表位。76E1 在预防性和治疗性鼠类动物模型中交叉保护免受 SARS-CoV-2 和 HCoV-OC43 感染。结构和功能研究表明，76E1 靶向刺突蛋白内的独特表位，该表位包含高度保守的 S2' 位点和融合肽。76E1结合的表位部分埋藏在融合前状态下的SARS-CoV-2刺突三聚体结构中，但是当刺突蛋白与ACE2结合时就会暴露出来。这一观察结果表明，在从融合前到融合后状态的转变过程中，76E1 在刺突三聚体的中间状态与表位结合，从而阻断膜融合和病毒进入。我们希望这个可以被 76E1 识别的关键表位的鉴定将指导基于表位的下一代泛冠状病毒疫苗和抗病毒药物的设计。