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 Chikungunya病毒（CHIKV），埃博拉病毒或寨卡病毒的最新发作已显示病毒的方式以前认为，可能会突然出现低威胁，从而破坏生命和经济。多价需要对潜水病毒菌株有效的治疗或疫苗来应对新兴威胁在他们达到流行状态之前。在此概念项目中，我们将使用蛋白质结构和表位 - 基于基于两种潜水蚊子αα病毒的多价疫苗的方法严重有效的人类健康以及包括美国在内的美洲周期性爆发马脑炎病毒（VEEV），该病毒在人的人畜共患爆发中具有很高的死亡率，chikv，可能导致慢性关节属。我们假设一种优化的减毒病毒表达来自Chikv和Veev的镶嵌膜蛋白投射表位，将诱导受保护针对母体病毒以及广泛的α病毒的抗体。与当前的“鸡尾酒”相比方法，将单个病毒组合在一起。信封E2蛋白将使用由PI开发的结构和计算工具设计他的合作者与麻疹，黄病毒，丝状病毒和α病毒一起进行项目，并将其纳入韦弗博士小组中开发了疫苗。一起，我们以前证明了代表E2的共识E2 可以将几种不同的VEEV菌株纳入传染病。即使没有优化，共识病毒疫苗保护小鼠免受VEEV的野生型（WT）菌株的影响，几乎和那些用相同的WT菌株接种疫苗。我们的第一个目的是表达和表征多价，物理化学 E2糖蛋白的共有蛋白，将代表CHIKV和VEEV菌株。这些将是优化可与潜水α病毒结合抗体并在小鼠中产生交叉保护的抗体。一个并发的第二个目标是引入已知的表位，已知是将抗体中和抗体中和的结合位点 Chikv和Veev的WT-E2蛋白，在整个病毒的背景下表达，并确定保护这些提供。在第三个目标中，优化的E2蛋白将掺入新的整个病毒中基于Alphavirus EILAT（EILV）的疫苗候选者，该疫苗在蚊子中复制而不是哺乳动物细胞。接种疫苗的小鼠将受到CHICV，VEEV和其他α病毒的潜水员菌株的挑战。韦弗博士组表明，用Chikv或Veev代替EILV的E蛋白可能会导致新的诊断工具和EILV/CHIKV疫苗候选者的生长限制为昆虫细胞，但对Chikv产生保护。预期的结果将是一个优化的，广泛的保护针对潜水α病毒菌株的疫苗。优化的多价E2蛋白也可以插入其他疫苗平台，例如α病毒复制颗粒或基于DNA的疫苗。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Repurposing approved drugs for cancer therapy.

DOI：
10.1093/bmb/ldaa045
发表时间：
2021-03-25
期刊：
British medical bulletin
影响因子：
6.7
作者：
Schein CH
通讯作者：
Schein CH

Designing multivalent immunogens for alphavirus vaccine optimization.

DOI：
10.1016/j.virol.2020.11.010
发表时间：
2021-09
期刊：
Virology
影响因子：
3.7
作者：
Read CM;Plante K;Rafael G;Rossi SL;Braun W;Weaver SC;Schein CH
通讯作者：
Schein CH

Regional and temporal coordinated mutation patterns in SARS-CoV-2 spike protein revealed by a clustering and network analysis.

DOI：
10.1038/s41598-022-04950-4
发表时间：
2022-01-21
期刊：
Scientific reports
影响因子：
4.6
作者：
Negi SS;Schein CH;Braun W
通讯作者：
Braun W

Synthetic proteins for COVID-19 diagnostics.

DOI：
10.1016/j.peptides.2021.170583
发表时间：
2021-09
期刊：
Peptides
影响因子：
3
作者：
Schein CH;Levine CB;McLellan SLF;Negi SS;Braun W;Dreskin SC;Anaya ES;Schmidt J
通讯作者：
Schmidt J

DGraph Clusters Flaviviruses and β-Coronaviruses According to Their Hosts, Disease Type, and Human Cell Receptors.