Rationally Designed Pan-Ebolavirus Vaccine

丝状病毒科包含多种可引起出血热的高致病性病毒 在人类身上。埃博拉、苏丹、本迪布乔和马尔堡病毒的爆发是不可预测的， 可迅速传播，发生时可造成40%-90%的人类死亡。扎伊尔人的疫苗接种工作 埃博拉病毒(EBOV)显示出巨大的前景。然而，候选疫苗没有提供 对其他具有同等爆发潜力的丝状病毒的保护。我们和其他人有 最近发现了埃博拉病毒糖蛋白(GP)的两个表位，它们可以诱导产生交叉抗体。 在动物模型中对其他所有埃博拉病毒进行反应、中和和保护。这些 表位不与更丰富的分泌型可溶性糖蛋白(SGP)共享，SGP可能 在感染期间充当抗体诱饵。在这里，我们建议使用结构导向设计 为了设计优先显示这些独特的GP特异性(即非SGP)的免疫原， 关键的和高度保守的结构，并引发高水平的这种广泛中和和 针对这些表位的广泛保护性抗体。 这一三PI计划结合了(1)基于结构和 以表位为中心的疫苗设计，(2)确定了大多数丝状病毒的结构生物学家 GP-抗体构成并处理世界上大多数丝状病毒抗体，以及(3)a 丝状病毒疫苗和免疫学方面的领先专家。在这个高度协作的项目中， 创新设计和功能评估的迭代阶段将导致新的免疫原 这种疫苗可以单独使用，也可以与目前正在研制中的单病毒疫苗一起使用。 临床试验。沿途的里程碑表明在提供新结构方面取得了进展， 设计稳定和免疫原性的特征，并诱导广反应性和广泛性- 针对丝状病毒威胁的保护性免疫反应。拟议的计划是 旨在提供一种对扎伊尔埃博拉病毒有效的疫苗，苏丹 豚鼠和雪貂模型中的埃博拉病毒和本迪布乔埃博拉病毒感染 在苏丹和埃博拉病毒感染的NHP模型中的有效性。

The Filoviridae family contains multiple highly pathogenic viruses that cause hemorrhagic fever in humans. Outbreaks of Ebola, Sudan, Bundibugyo, and Marburg viruses are unpredictable, can spread rapidly, and occur with 40-90% human lethality. Vaccination efforts for the Zaire ebolavirus (EBOV) show tremendous promise. The candidate vaccines, however, provides no protection against the other filoviruses with equivalent outbreak potential. We and others have recently identified two epitopes on Ebola virus glycoprotein (GP) that elicit antibodies that cross- react with, neutralize, and protect against other all ebolaviruses in animal models. These epitopes are not shared with the much more abundant, secreted soluble GP (sGP), which may serve as an antibody decoy during infection. Here, we propose to use structure-guided design to engineer immunogens that preferentially display these unique GP-specific (i.e. non-sGP), critical, and highly conserved structures and elicit high levels of such broadly-neutralizing and broadly protective antibodies against these epitopes. This three-PI program combines the expertise of (1) a pioneer in the field of structure-based and epitope-focused vaccine design, (2) the structural biologist who has determined most filovirus GP-antibody structures and handles the majority of the world’s filovirus antibodies, and (3) a leading expert in filovirus vaccines and immunology. In this highly collaborative program, iterative stages of innovative design and functional evaluation will lead to novel immunogens that could be used alone or in a prime-boost regimen with single-virus vaccines currently in clinical trials. Milestones along the way demonstrate progress in provision of novel structures, design of stable and immunogenic features, and elicitation of broadly-reactive and broadly- protective immune responses against the array of filovirus threats. The proposed program is designed to deliver a vaccine with demonstrated efficacy against Zaire ebolavirus, Sudan ebolavirus, and Bundibugyo ebolavirus infections in guinea pig and ferret models as well as efficacy in NHP models of Sudan and Ebola virus infections.