Rationally Designed Pan-Ebolavirus Vaccine

合理设计的泛埃博拉病毒疫苗

• 批准号: 10163786
• 负责人: M Javad Aman
• 金额: $ 88.67万
• 依托单位: INTEGRATED BIOTHERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-20 至 2023-01-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10163786
• 关键词: Aman; Amino Acid Sequence; Animal Model; Animals; Antibodies; Antibody Response; Antigens; Binding; Biochemical; Biophysics; Bundibugyo virus; Cavia; Clinical; Clinical Trials; Computational Biology; Cote d' Ivoire Ebola virus; Crystallization; Democratic Republic of the Congo; Directed Molecular Evolution; Disease Outbreaks; Ebola; Ebola Vaccines; Ebola virus; Engineering; Ensure; Epidemic; Epitopes; Evaluation; Family; Ferrets; Filovirus; Future; GP2 gene; Geography; Glycoproteins; Goals; HIV-1; Human; Immune response; Immunization; Immunologics; Immunology; Immunotherapeutic agent; Infection; Laboratories; Lead; Marburgvirus; Masks; Membrane; Membrane Glycoproteins; Methodology; Methods; Modeling; Modification; Molecular Conformation; Nature; Pathogenicity; Polysaccharides; Proteins; Regimen; Research; Reston Ebola virus; Side; Site; Structural Biologist; Structure; Sudan Ebola virus; Testing; Therapeutic; Travel; Vaccination; Vaccine Design; Vaccines; Variant; Vesicular stomatitis Indiana virus; Viral; Viral Hemorrhagic Fevers; Virus; Virus Diseases; Virus-like particle; Work; Zaire Ebola virus; base; design; dimer; immunogenic; immunogenicity; improved; innovation; nanoparticle; neutralizing antibody; neutralizing monoclonal antibodies; nonhuman primate; novel; pathogenic virus; programs; response; scaffold; structural biology; vaccine candidate; vaccine trial

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.

丝状病毒科包含多种引起出血热的高致病性病毒 在人类身上。埃博拉、苏丹、本迪布焦和马尔堡病毒的爆发是不可预测的， 可以迅速传播，并发生40-90%的人类致死率。扎伊尔的疫苗接种工作 埃博拉病毒（EBOV）显示出巨大的希望。然而，候选疫苗没有提供 对具有同等爆发潜力的其他丝状病毒的防护。我们和其他人已经 最近发现了埃博拉病毒糖蛋白（GP）上的两个表位，这些表位可以引发抗体， 在动物模型中与其他所有埃博拉病毒反应、中和和保护。这些 表位不与更丰富的分泌型可溶性GP（sGP）共享， 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 为了工程化优先展示这些独特的GP特异性（即非sGP）的免疫原， 关键和高度保守的结构，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。 这三个PI计划结合了（1）在基于结构的领域的先驱， 以表位为中心的疫苗设计，（2）已确定大多数丝状病毒的结构生物学家 GP-抗体结构和处理世界上大多数丝状病毒抗体，和（3） 丝状病毒疫苗和免疫学领域的顶尖专家。在这个高度合作的项目中， 创新设计和功能评估的迭代阶段将导致新的免疫原 它可以单独使用，也可以与目前使用的单病毒疫苗一起使用， 临床试验沿着沿着里程碑展示了在提供新颖结构方面的进展， 设计稳定和免疫原性的特征，并引发广泛反应性和广泛- 保护性免疫反应对抗一系列丝状病毒威胁。拟议方案是 设计用于提供已证实有效对抗扎伊尔埃博拉病毒的疫苗， 埃博拉病毒和本迪布焦埃博拉病毒感染豚鼠和雪貂模型以及 在苏丹和埃博拉病毒感染的NHP模型中的有效性。