Enteroviruses contain multiple serotypes and can cause severe neurological complications. The intricate life cycle of enteroviruses involving dynamic virus–receptor interaction hampers the development of broad therapeutics and vaccines. Here, using function-based screening, we identify a broadly therapeutic antibody h1A6.2 that potently protects mice in lethal models of infection with both enterovirus A71 and coxsackievirus A16 through multiple mechanisms, including inhibition of the virion–SCARB2 interactions and monocyte/macrophage-dependent Fc effector functions. h1A6.2 mitigates inflammation and improves intramuscular mechanics, which are associated with diminished innate immune signalling and preserved tissue repair. Moreover, cryogenic electron microscopy structures delineate an adaptive binding of h1A6.2 to the flexible and dynamic nature of the VP2 EF loop with a binding angle mimicking the SCARB2 receptor. The coordinated binding mode results in efficient binding of h1A6.2 to all viral particle types and facilitates broad neutralization of enterovirus, therefore informing a promising target for the structure-guided design of pan-enterovirus vaccine.

肠道病毒包含多种血清型，可引起严重的神经系统并发症。肠道病毒错综复杂的生命周期涉及动态病毒-受体相互作用，阻碍了广泛疗法和疫苗的开发。在这里，使用基于功能的筛选，我们确定了一种广泛治疗性的抗体 h1A6.2，它通过多种机制在肠道病毒 A71 和柯萨奇病毒 A16 感染的致死模型中有效保护小鼠，包括抑制病毒粒子-SCARB2 相互作用和单核细胞/巨噬细胞依赖性 Fc 效应子功能。h1A6.2 减轻炎症并改善肌内力学，这与先天免疫信号减弱和保留的组织修复有关。此外，低温电子显微镜结构描绘了 h1A6.2 与 VP2 EF 环的柔性和动态性质的适应性结合，其结合角模拟 SCARB2 受体。协调结合模式导致 h1A6.2 与所有病毒颗粒类型有效结合，并促进肠道病毒的广泛中和，因此为泛肠道病毒疫苗的结构引导设计提供了有前途的靶标。