New threats posed by the emerging circulating variants of SARS-CoV-2 highlight the need to find conserved neutralizing epitopes for therapeutic antibodies and efficient vaccine design. Here, we identified a receptor-binding domain (RBD)-binding antibody, XG014, which potently neutralizes β-coronavirus lineage B (β-CoV-B), including SARS-CoV-2, its circulating variants, SARS-CoV and bat SARSr-CoV WIV1. Interestingly, antibody family members competing with XG014 binding show reduced levels of cross-reactivity and induce antibody-dependent SARS-CoV-2 spike (S) protein-mediated cell-cell fusion, suggesting a unique mode of recognition by XG014. Structural analyses reveal that XG014 recognizes a conserved epitope outside the ACE2 binding site and completely locks RBD in the non-functional “down” conformation, while its family member XG005 directly competes with ACE2 binding and position the RBD “up”. Single administration of XG014 is effective in protection against and therapy of SARS-CoV-2 infection in vivo. Our findings suggest the potential to develop XG014 as pan-β-CoV-B therapeutics and the importance of the XG014 conserved antigenic epitope for designing broadly protective vaccines against β-CoV-B and newly emerging SARS-CoV-2 variants of concern.

新出现的 SARS-CoV-2 循环变体带来的新威胁凸显了为治疗性抗体和有效疫苗设计寻找保守的中和表位的必要性。在这里，我们鉴定了一种受体结合域 (RBD) 结合抗体 XG014，它可以有效中和 β-冠状病毒谱系 B (β-CoV-B)，包括 SARS-CoV-2、其循环变体、SARS-CoV 和蝙蝠SARSr-CoV WIV1。有趣的是，与 XG014 结合竞争的抗体家族成员显示交叉反应水平降低，并诱导抗体依赖性 SARS-CoV-2 刺突 (S) 蛋白介导的细胞-细胞融合，这表明 XG014 具有独特的识别模式。结构分析表明，XG014 识别 ACE2 结合位点外的保守表位，并将 RBD 完全锁定在非功能性“向下”构象中，而其家族成员 XG005 则直接与 ACE2 结合竞争并将 RBD 定位“向上”。XG014单次给药可有效预防和治疗SARS-CoV-2感染在体内。我们的研究结果表明了将 XG014 开发为泛β-CoV-B 疗法的潜力，以及 XG014 保守抗原表位对于设计针对 β-CoV-B 和新出现的 SARS-CoV-2 变体的广泛保护性疫苗的重要性。