The Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Department of Microbiology & Immunology, The University of Texas Medical Branch, Galveston, TX 77555, USA.
Cell. 2020 Dec 10;183(6):1536-1550.e17. doi: 10.1016/j.cell.2020.11.023.
Hendra (HeV) and Nipah (NiV) viruses are emerging zoonotic pathogens in the Henipavirus genus causing outbreaks of disease with very high case fatality rates. Here, we report the first naturally occurring human monoclonal antibodies (mAbs) against HeV receptor binding protein (RBP). All isolated mAbs neutralized HeV, and some also neutralized NiV. Epitope binning experiments identified five major antigenic sites on HeV-RBP. Animal studies demonstrated that the most potent cross-reactive neutralizing mAbs, HENV-26 and HENV-32, protected ferrets in lethal models of infection with NiV Bangladesh 3 days after exposure. We solved the crystal structures of mAb HENV-26 in complex with both HeV-RBP and NiV-RBP and of mAb HENV-32 in complex with HeV-RBP. The studies reveal diverse sites of vulnerability on RBP recognized by potent human mAbs that inhibit virus by multiple mechanisms. These studies identify promising prophylactic antibodies and define protective epitopes that can be used in rational vaccine design.
亨德拉病毒（HeV）和尼帕病毒（NiV）是新兴的人畜共患病原体，属于亨尼帕病毒属，可引发高病死率的疾病爆发。在此，我们报告了针对亨德拉病毒受体结合蛋白（RBP）的首例天然存在的人源单克隆抗体（mAb）。所有分离的 mAb 均可中和 HeV，部分 mAb 也可中和 NiV。表位聚类实验鉴定了 HeV-RBP 上的五个主要抗原表位。动物研究表明，最有效的交叉反应性中和 mAb HENV-26 和 HENV-32，在暴露后 3 天可保护雪貂免受致死性 NiV 孟加拉国感染模型的感染。我们解析了 mAb HENV-26 分别与 HeV-RBP 和 NiV-RBP 以及 mAb HENV-32 与 HeV-RBP 复合物的晶体结构。这些研究揭示了 RBP 上可被强效人源 mAb 识别的不同脆弱位点，这些 mAb 可通过多种机制抑制病毒。这些研究鉴定了有前景的预防性抗体，并定义了可用于合理疫苗设计的保护性表位。
