迄今为止,仅描述了一种能够有效中和所有五种埃博拉病毒的天然存在的人抗体。这里我们介绍了这种罕见的两种晶体结构,泛-埃博拉病毒中和人抗体与埃博拉病毒和Bundibugyo病毒糖蛋白(GPs)复合,分别。这些结构描绘了在整个埃博拉病毒中保守的关键蛋白质和聚糖接触的结合,解释抗体独特的广泛特异性和中和活性,并揭示了GP2融合环区已知逃逸突变背后的可能机制。我们发现这种抗体的表位,ADI-15878沿着融合环的疏水桨延伸,然后浸入GP2N末端尾部下方的高度保守的口袋中,这种识别方式不同于针对埃博拉病毒的任何其他抗体,可能对其广泛的活动至关重要。Bundibugyo病毒糖蛋白的折叠,以前没有可视化,类似于埃博拉病毒GP的折叠,ADI-15878以相似的策略和攻击角度与每种病毒的GP结合。这些发现可用于将该抗体部署为广谱治疗剂和设计引发针对埃博拉病毒属和丝状病毒家族的所有成员的所需的广泛中和免疫应答的免疫原。重要性埃博拉病毒属有五种不同的成员。提供能够预防五种埃博拉病毒中的任何一种的疫苗和治疗是公共卫生的重要目标。抗体是疫苗的期望结果,并且可以作为治疗剂直接递送。大多数抗体,然而,只对一两个有效,不是全部,这些病原体。到目前为止,只有一种人类抗体被描述可以中和所有五种埃博拉病毒,抗体ADI-15878。在这里,我们描述了与埃博拉病毒和Bundibugyo病毒的相关靶蛋白结合的ADI-15878的分子结构。我们解释了它如何实现其罕见的活性广度,并提出了设计能够引发更多抗体如ADI-15878的改进疫苗的策略。
Only one naturally occurring human antibody has been described thus far that is capable of potently neutralizing all five ebolaviruses. Here we present two crystal structures of this rare, pan-ebolavirus neutralizing human antibody in complex with Ebola virus and Bundibugyo virus glycoproteins (GPs), respectively. The structures delineate the key protein and glycan contacts for binding that are conserved across the ebolaviruses, explain the antibody\'s unique broad specificity and neutralization activity, and reveal the likely mechanism behind a known escape mutation in the fusion loop region of GP2. We found that the epitope of this antibody, ADI-15878, extends along the hydrophobic paddle of the fusion loop and then dips down into a highly conserved pocket beneath the N-terminal tail of GP2, a mode of recognition unlike any other antibody elicited against Ebola virus, and likely critical for its broad activity. The fold of Bundibugyo virus glycoprotein, not previously visualized, is similar to the fold of Ebola virus GP, and ADI-15878 binds to each virus\'s GP with a similar strategy and angle of attack. These findings will be useful in deployment of this antibody as a broad-spectrum therapeutic and in the design of immunogens that elicit the desired broadly neutralizing immune response against all members of the ebolavirus genus and filovirus family.IMPORTANCE There are five different members of the Ebolavirus genus. Provision of vaccines and treatments able to protect against any of the five ebolaviruses is an important goal of public health. Antibodies are a desired result of vaccines and can be delivered directly as therapeutics. Most antibodies, however, are effective against only one or two, not all, of these pathogens. Only one human antibody has been thus far described to neutralize all five ebolaviruses, antibody ADI-15878. Here we describe the molecular structure of ADI-15878 bound to the relevant target proteins of Ebola virus and Bundibugyo virus. We explain how it achieves its rare breadth of activity and propose strategies to design improved vaccines capable of eliciting more antibodies like ADI-15878.