Japanese encephalitis virus (JEV), closely related to dengue, Zika, yellow fever and West Nile viruses, remains neglected and not well characterized ¹ . JEV is the leading causative agent of encephalitis, and is responsible for thousands of deaths each year in Asia. Humoral immunity is essential for protecting against flavivirus infections and passive immunization has been demonstrated to be effective in curing disease^2,3. Here, we demonstrate that JEV-specific monoclonal antibodies, 2F2 and 2H4, block attachment of the virus to its receptor and also prevent fusion of the virus. Neutralization of JEV by these antibodies is exceptionally potent and confers clear therapeutic benefit in mouse models. A single 20 μg dose of these antibodies resulted in 100% survival and complete clearance of JEV from the brains of mice. The 4.7 Å and 4.6 Å resolution cryo-electron microscopy structures of JEV-2F2-Fab and JEV-2H4-Fab complexes, together with the crystal structure of 2H4 Fab and our recent near-atomic structure of JEV ⁴ , unveil the nature and location of epitopes targeted by the antibodies. Both 2F2 and 2H4 Fabs bind quaternary epitopes that span across three adjacent envelope proteins. Our results provide a structural and molecular basis for the application of 2F2 and 2H4 to treat JEV infection.

中文翻译：

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通过两种有效的治疗性抗体中和日本脑炎病毒的结构基础。

与登革热，寨卡病毒，黄热病和西尼罗河病毒密切相关的日本脑炎病毒（JEV）仍然被忽略，并且没有很好的特征¹。JEV是脑炎的主要病因，在亚洲每年造成数千人死亡。体液免疫对于预防黄病毒感染是必不可少的，被动免疫已被证明可有效治愈疾病^2,3。在这里，我们证明了JEV特异性单克隆抗体2F2和2H4阻止了病毒与其受体的结合，并且还阻止了病毒的融合。这些抗体对JEV的中和作用异常强大，在小鼠模型中具有明显的治疗效果。这些抗体的单次剂量为20μg，可以100％存活并从小鼠的大脑中完全清除JEV。JEV-2F2-Fab和JEV-2H4-Fab配合物的4.7 A和4.6 A分辨率冷冻电子显微镜结构，以及2H4 Fab的晶体结构和我们最近的JEV ^4的近原子结构揭示抗体靶向表位的性质和位置。2F2和2H4 Fab都结合跨三个相邻包膜蛋白的四级表位。我们的结果为2F2和2H4在治疗JEV感染中的应用提供了结构和分子基础。