State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Clinical Laboratory Medicine Department, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Nat Commun. 2024 Jan 29;15(1):842. doi: 10.1038/s41467-024-45050-3.
The constant emergence of SARS-CoV-2 variants continues to impair the efficacy of existing neutralizing antibodies, especially XBB.1.5 and EG.5, which showed exceptional immune evasion properties. Here, we identify a highly conserved neutralizing epitope targeted by a broad-spectrum neutralizing antibody BA7535, which demonstrates high neutralization potency against not only previous variants, such as Alpha, Beta, Gamma, Delta and Omicron BA.1-BA.5, but also more recently emerged Omicron subvariants, including BF.7, CH.1.1, XBB.1, XBB.1.5, XBB.1.9.1, EG.5. Structural analysis of the Omicron Spike trimer with BA7535-Fab using cryo-EM indicates that BA7535 recognizes a highly conserved cryptic receptor-binding domain (RBD) epitope, avoiding most of the mutational hot spots in RBD. Furthermore, structural simulation based on the interaction of BA7535-Fab/RBD complexes dissects the broadly neutralizing effect of BA7535 against latest variants. Therapeutic and prophylactic treatment with BA7535 alone or in combination with BA7208 protected female mice from the circulating Omicron BA.5 and XBB.1 variant infection, suggesting the highly conserved neutralizing epitope serves as a potential target for developing highly potent therapeutic antibodies and vaccines.
不断出现的 SARS-CoV-2 变体继续削弱现有中和抗体的效力，尤其是 XBB.1.5 和 EG.5，它们表现出了非凡的免疫逃逸特性。在这里，我们鉴定了一个广谱中和抗体 BA7535 靶向的高度保守中和表位，该抗体对以前的变体（如 Alpha、Beta、Gamma、Delta 和 Omicron BA.1-BA.5）具有很高的中和效力，而且对最近出现的 Omicron 亚变体（包括 BF.7、CH.1.1、XBB.1、XBB.1.5、XBB.1.9.1 和 EG.5）也具有很高的中和效力。使用 cryo-EM 对带有 BA7535-Fab 的 Omicron Spike 三聚体进行结构分析表明，BA7535 识别一个高度保守的隐蔽受体结合域（RBD）表位，避开了 RBD 中的大多数突变热点。此外，基于 BA7535-Fab/RBD 复合物相互作用的结构模拟解析了 BA7535 对最新变体的广泛中和作用。单独使用 BA7535 或与 BA7208 联合治疗和预防治疗可保护雌性小鼠免受循环 Omicron BA.5 和 XBB.1 变体感染，这表明高度保守的中和表位可作为开发高效治疗性抗体和疫苗的潜在靶标。
