Huang Yang, Song Feibo, Zeng Yuanjun, Sun Hui, Sheng Roufang, Wang Xuechun, Liu Liqin, Luo Guoxing, Jiang Yanan, Chen Yaling, Zhang Mengxuan, Zhang Shiyin, Gu Ying, Yu Hai, Li Shaowei, Li Tingdong, Zheng Qingbing, Ge Shengxiang, Zhang Jun, Xia Ningshao
State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, PR China.
National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, Xiamen University, Xiamen, PR China.
Nat Commun. 2025 Jan 20;16(1):838. doi: 10.1038/s41467-025-56114-3.
Broadly neutralizing antibodies (bNAbs) could offer escape-tolerant and lasting protection against viral infections and therefore guide development of broad-spectrum vaccines. The increasing challenge posed by viral evolution and immune evasion intensifies the importance of the discovery of bNAbs and their underlying neutralization mechanism. Here, focusing on the pivotal viral protein VP4 of rotavirus (RV), we identify a potent bNAb, 7H13, exhibiting broad-spectrum neutralization across diverse RV genotypes and demonstrating strong prevention of virus infection in female mice. A combination of time-resolved cryo-electron microscopy (cryo-EM) and in situ cryo-electron tomography (cryo-ET) analysis reveals a counterintuitive dynamic process of virus inactivation, in which 7H13 asymmetrically binds to a conserved epitope in the capsid-proximal aspect of VP4, triggers a conformational switch in a critical residue-F418-thereby disrupts the meta-stable conformation of VP4 essential for normal viral infection. Structure-guided mutagenesis corroborates the essential role of the 7H13 heavy chain I54 in activating F418 switch and destabilizing VP4. These findings define an atypical NAbs' neutralization mechanism and reveal a potential type of virus vulnerable site for universal vaccine and therapeutics design.
广谱中和抗体（bNAbs）可为病毒感染提供耐受性逃逸和持久保护，因此可指导广谱疫苗的研发。病毒进化和免疫逃逸带来的挑战日益增加，这凸显了发现bNAbs及其潜在中和机制的重要性。在此，我们聚焦于轮状病毒（RV）的关键病毒蛋白VP4，鉴定出一种强效bNAb——7H13，它对多种RV基因型具有广谱中和作用，并在雌性小鼠中表现出对病毒感染的强大预防作用。结合时间分辨冷冻电子显微镜（cryo-EM）和原位冷冻电子断层扫描（cryo-ET）分析，揭示了一个违反直觉的病毒失活动态过程，其中7H13不对称地结合到VP4衣壳近端区域的一个保守表位上，触发关键残基F418的构象转换，从而破坏正常病毒感染所必需的VP4亚稳态构象。结构导向诱变证实了7H13重链I54在激活F418转换和使VP4不稳定方面的关键作用。这些发现定义了一种非典型中和抗体的中和机制，并揭示了一种潜在的病毒易损位点类型，可用于通用疫苗和治疗药物设计。
