Zhao Xuelian, Howell Katie A, He Shihua, Brannan Jennifer M, Wec Anna Z, Davidson Edgar, Turner Hannah L, Chiang Chi-I, Lei Lin, Fels J Maximilian, Vu Hong, Shulenin Sergey, Turonis Ashley N, Kuehne Ana I, Liu Guodong, Ta Mi, Wang Yimeng, Sundling Christopher, Xiao Yongli, Spence Jennifer S, Doranz Benjamin J, Holtsberg Frederick W, Ward Andrew B, Chandran Kartik, Dye John M, Qiu Xiangguo, Li Yuxing, Aman M Javad
Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20878, USA.
Integrated BioTherapeutics, Rockville, MD 20850, USA.
Cell. 2017 May 18;169(5):891-904.e15. doi: 10.1016/j.cell.2017.04.038.
While neutralizing antibodies are highly effective against ebolavirus infections, current experimental ebolavirus vaccines primarily elicit species-specific antibody responses. Here, we describe an immunization-elicited macaque antibody (CA45) that clamps the internal fusion loop with the N terminus of the ebolavirus glycoproteins (GPs) and potently neutralizes Ebola, Sudan, Bundibugyo, and Reston viruses. CA45, alone or in combination with an antibody that blocks receptor binding, provided full protection against all pathogenic ebolaviruses in mice, guinea pigs, and ferrets. Analysis of memory B cells from the immunized macaque suggests that elicitation of broadly neutralizing antibodies (bNAbs) for ebolaviruses is possible but difficult, potentially due to the rarity of bNAb clones and their precursors. Unexpectedly, germline-reverted CA45, while exhibiting negligible binding to full-length GP, bound a proteolytically remodeled GP with picomolar affinity, suggesting that engineered ebolavirus vaccines could trigger rare bNAb precursors more robustly. These findings have important implications for developing pan-ebolavirus vaccine and immunotherapeutic cocktails.
虽然中和抗体对埃博拉病毒感染具有高效性，但目前的实验性埃博拉病毒疫苗主要引发物种特异性抗体反应。在此，我们描述了一种免疫诱导的猕猴抗体（CA45），它能将内部融合环与埃博拉病毒糖蛋白（GP）的N端结合，并有效中和埃博拉、苏丹、本迪布焦和雷斯顿病毒。单独使用CA45或与阻断受体结合的抗体联合使用，能为小鼠、豚鼠和雪貂提供针对所有致病性埃博拉病毒的完全保护。对免疫猕猴的记忆B细胞分析表明，有可能诱导出针对埃博拉病毒的广泛中和抗体（bNAb），但具有难度，这可能是由于bNAb克隆及其前体稀少所致。出乎意料的是，种系回复的CA45虽然与全长GP的结合可忽略不计，但却以皮摩尔亲和力结合经蛋白水解重塑的GP，这表明工程化埃博拉病毒疫苗能更有力地触发罕见的bNAb前体。这些发现对开发泛埃博拉病毒疫苗和免疫治疗鸡尾酒具有重要意义。
