Mosaic Immunogens as Multivalent Alphavirus Vaccines

作为多价甲病毒疫苗的嵌合免疫原

基本信息

批准号：
10212942
负责人：
WERNER A BRAUN
金额：
$ 47.44万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-21 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10212942
关键词：
3-Dimensional Aerosols Alphavirus Americas Amino Acid Sequence Antibodies Antibody Response Antigens Area Arthralgia Attenuated Binding Binding Sites Biochemical Bioinformatics Cells Chikungunya virus Chimera organism Chronic Cloning Consensus Cryoelectron Microscopy Culicidae DNA Data Databases Disease Outbreaks E protein Ebola virus Encephalitis Viruses Enzyme-Linked Immunosorbent Assay Epidemic Epitopes Equine Encephalomyelitis Equus caballus Event Filovirus Flavivirus Foundations General Population Glycoproteins Goals Growth Health Human Hybrids Immune response Immunize Individual Infection Insecta International Latin America Lead Measles Measles virus Military Personnel Modeling Molecular Conformation Mosaicism Mus Mutation Oryctolagus cuniculus Outcome Parents Periodicity Property Proteins Replicon Research Personnel Series Serotyping Structural Protein Structure Surface Survivors Testing Travel Vaccinated Vaccines Variant Venezuelan Equine Encephalitis Virus Virion Virus Virus Assembly Virus-like particle Western Blotting Work Zika Virus Zoonoses aerosolized base bioweapon chikungunya computerized tools cost cross reactivity deep sequencing design env Gene Products genome sequencing immunogenic immunogenicity mortality mosquito-borne neutralizing antibody neutralizing monoclonal antibodies novel novel diagnostics pandemic disease particle protein structure three dimensional structure tool vaccine access vaccine candidate vaccine development whole genome

项目摘要

Abstract Recent epidemics of chikungunya virus (CHIKV), Ebola virus or Zika virus have shown how viruses previously considered a low threat can emerge suddenly, destroying lives and economies. Multivalent treatments or vaccines that are effective against diverse virus strains are needed to deal with emerging threats before they reach epidemic status. In this proof of concept project, we will use a protein structure- and epitope- based approach to construct a multivalent vaccine against two quite diverse mosquito borne alphaviruses, both severely effecting human health and with periodic outbreaks in the Americas, including the US, Venezuelan equine encephalitis virus (VEEV), which has a high mortality in zoonotic outbreaks in humans, and CHIKV, which can cause chronic arthralgia. We hypothesize that an optimized attenuated virus, expressing mosaic envelope proteins projecting epitopes from both CHIKV and VEEV, will induce protective antibodies against both parent viruses as well as a wide spectrum of alphaviruses. A vaccine incorporating this would substantially reduce the cost and regulatory burden compared to the current “cocktail” approach, where individual viruses are combined. The envelope E2 proteins will be designed using structural and computational tools, developed by the PI and his collaborators on projects with measles, flaviviruses, filovirus and alphaviruses, and incorporated into vaccines developed in Dr. Weaver’s group. Together, we previously showed that a consensus E2 representing several different VEEV strains could be incorporated into infectious virus. Even without optimization, the consensus virus vaccine protected mice against a wild type (wt) strain of VEEV nearly as well as those vaccinated with the same wt strain. Our first aim is to express and characterize multivalent, physicochemical consensus proteins of the E2 glycoprotein that will represent both CHIKV and VEEV strains. These will be optimized to bind antibodies against diverse alphaviruses and generate cross protective antibodies in mice. A concurrent second aim is to introduce epitopes known to be the binding site for neutralizing antibodies into the wt-E2 proteins of CHIKV and VEEV, expressed in the context of a whole virus, and determine the range of protection these provide. In a third aim, the optimized E2 proteins will be incorporated into a novel whole virus vaccine candidate based on the alphavirus Eilat (EILV), which replicates in mosquito but not mammalian cells. Vaccinated mice will be challenged with diverse strains of CHICV, VEEV, and other alphaviruses. Dr. Weaver’s group has shown that replacing the E proteins of EILV with those of CHIKV or VEEV can lead to new diagnostic tools and an EILV/CHIKV vaccine candidate that remains restricted in its growth to insect cells but generates protection against CHIKV. The anticipated outcome will be an optimized, broadly protective vaccine against diverse alphavirus strains. The optimized, multivalent E2 proteins can also be inserted into other vaccine platforms, such as alpha-virus replicon particles or DNA-based vaccines.

抽象的最近基孔肯雅病毒（CHIKV）、埃博拉病毒或寨卡病毒的流行已经表明病毒如何以前被认为是低威胁的威胁可能会突然出现，摧毁生命和经济。需要有效对抗不同病毒株的治疗方法或疫苗来应对新出现的威胁在他们达到流行状态之前，在这个概念验证项目中，我们将使用蛋白质结构和表位。基于方法构建针对两种截然不同的蚊媒甲病毒的多价疫苗，两者严重影响人类健康，并在美洲（包括美国、委内瑞拉）定期爆发马脑炎病毒（VEEV）和 CHIKV，在人类人畜共患疫情中死亡率很高我们捕获了一种优化的减毒病毒，可引起慢性关节痛。镶嵌包膜蛋白投射来自 CHIKV 和 VEEV 的表位，将诱导保护性针对两种亲本病毒以及多种甲病毒的抗体 A 疫苗。与当前的“鸡尾酒”相比，纳入这一点将大大降低成本和监管负担方法，将单个病毒组合在一起。包膜 E2 蛋白将使用 PI 开发的结构和计算工具进行设计和他的合作者关于麻疹、黄病毒、丝状病毒和甲病毒的项目，并纳入 Weaver 博士小组开发的疫苗之前，我们共同证明了代表 E2 的共识。即使没有优化，也可以将几种不同的 VEEV 病毒株合并到传染性病毒中。病毒疫苗保护小鼠对 VEEV 野生型 (wt) 株的抵抗力几乎与那些我们的首要目标是表达和表征多价、理化特征。代表 CHIKV 和 VEEV 毒株的 E2 糖蛋白的蛋白质这些将是共有蛋白质。优化以结合针对不同甲病毒的抗体并在小鼠 A 中产生交叉保护抗体。同时的第二个目标是将已知为中和抗体结合位点的表位引入到 CHIKV 和 VEEV 的 wt-E2 蛋白，在整个病毒的背景下表达，并确定第三个目标是，优化的 E2 蛋白将被整合到一种新型的完整病毒中。基于埃拉特甲病毒（EILV）的候选疫苗，该病毒在蚊子中复制，但不能在哺乳动物细胞中复制。接种疫苗的小鼠将受到不同毒株的 CHICV、VEEV 和 Weaver 博士的其他甲病毒的攻击。研究小组表明，用 CHIKV 或 VEEV 的 E 蛋白替换 EILV 的 E 蛋白可以产生新的诊断工具和 EILV/CHIKV 候选疫苗，其在昆虫细胞中的生长仍然受到限制，但产生针对 CHIKV 的保护，预期结果将是优化的、广泛的保护。针对不同甲病毒株的疫苗也可以插入优化的多价 E2 蛋白。其他疫苗平台，例如甲病毒复制子颗粒或基于 DNA 的疫苗。