Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
Electron Microscopy Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Maryland.
J Infect Dis. 2018 Nov 22;218(suppl_5):S537-S544. doi: 10.1093/infdis/jiy450.
The membrane-proximal external regions (MPER) of the human immunodeficiency virus envelope glycoprotein (GP) generate broadly reactive antibody responses and are the focus of vaccine development efforts. The conservation of amino acids within filovirus GP heptad repeat region (HR)2/MPER suggests that it may also represent a target for a pan-filovirus vaccine. We immunized a cynomolgus macaque against Ebola virus (EBOV) using a deoxyribonucleic acid/adenovirus 5 prime/boost strategy, sequenced memory B-cell receptors, and tested the antibodies for functional activity against EBOV GP. Antibody ma-C10 bound to GP with an affinity of 48 nM and was capable of inducing antibody-dependent cellular cytotoxicity. Three-dimensional reconstruction of single-particle, negative-stained, electron microscopy showed that ma-C10 bound to the HR2/MPER, and enzyme-linked immunosorbent assay reveals it binds to residues 621-631. More importantly, ma-C10 was found to bind to the GP of the 3 most clinically relevant Ebolavirus species, suggesting that a cross-species immunogen strategy targeting the residues in this region may be a feasible approach for producing a pan-filovirus vaccine.
人类免疫缺陷病毒包膜糖蛋白（GP）的膜近端外部区域（MPER）产生广泛反应性的抗体应答，是疫苗开发工作的重点。丝状病毒 GP 七肽重复区（HR）2/MPER 内氨基酸的保守性表明，它也可能是泛丝状病毒疫苗的一个靶标。我们使用 DNA/腺病毒 5 型的核酸/腺病毒 5 型的启动/增强策略，对食蟹猴进行埃博拉病毒（EBOV）免疫接种，对记忆 B 细胞受体进行测序，并测试了针对 EBOV GP 的抗体的功能活性。抗体 ma-C10 与 GP 的亲和力为 48 nM，能够诱导抗体依赖性细胞毒性。单颗粒、负染、电子显微镜的三维重建显示，ma-C10 与 HR2/MPER 结合，酶联免疫吸附试验显示其与残基 621-631 结合。更重要的是，发现 ma-C10 与 3 种最具临床相关性的埃博拉病毒种的 GP 结合，这表明针对该区域残基的跨物种免疫原策略可能是产生泛丝状病毒疫苗的可行方法。
