An Informed Approach to Live Attenuated Vaccines against Encephalitis Alphaviruses

针对脑炎甲病毒的减毒活疫苗的知情方法

基本信息

批准号：
10027464
负责人：
WILLIAM B KLIMSTRA
金额：
$ 47.22万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-12 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10027464
关键词：
Address Aerosols Alphavirus Animal Disease Models Animals Antibody Response Antigen Presentation Antiviral Agents Antiviral Therapy Arboviruses Attenuated Attenuated Live Virus Vaccine Biological Warfare Bioterrorism Competence Culicidae Death Records Development Disease Disease Outbreaks Domestic Animals Dose Encephalitis Encephalitis Viruses Equine Encephalomyelitis Equus caballus Evaluation Formalin Formulation Genetic Genome Gold Human Imaging Techniques Immune Immunization Immunize In Vitro Inactivated Vaccines Individual Infection Injections Investigation Mediating Mus Mutagenesis Mutation Nucleotides Pathogenicity Process Reporter Risk Route Safety Techniques Technology Testing Time Tropism Vaccinated Vaccine Design Vaccines Venezuelan Venezuelan Equine Encephalitis Virus Virulence Virus Virus Replication Western Equine Encephalitis Virus adaptive immune response arthropod-borne attenuation base blind cytokine design immunogenic immunogenicity in vivo mutant next generation preclinical study preservation protective efficacy vaccine candidate vaccine development vaccine efficacy vaccine evaluation

项目摘要

ABSTRACT Eastern (EEEV), Venezuelan (VEEV), and Western (WEEV) equine encephalitis viruses are mosquito-transmitted alphaviruses with the potential to cause fatal neuroinvasive disease in humans and domesticated animals. These viruses also can be spread by the aerosol route and thus, have significant potential as biowarfare/bioterrorism agents. In 2019, EEEV human infections increased to levels not seen since the 1950s. Currently, there are no antiviral therapies or vaccines licensed for these alphaviruses. The existing investigational live-attenuated VEEV vaccine (LAV; TC-83) was generated >40 years ago, is highly reactogenic, poorly immunogenic, and causes disease in up to 20% of recipients. For EEEV and WEEV, investigational formalin-inactivated vaccines have been given to at-risk workers. While both elicit antibody responses, they provide uncertain protection and require multiple booster injections. A trivalent veterinary vaccine against VEEV, EEEV and WEEV is available but is so poorly immunogenic that domestic animals must be boosted annually and disease is seen in vaccinated animals. Here, we propose to develop safe and effective LAVs vaccine against these alphaviruses using recent advances in understanding of the virulence mechanisms of each. These advances will allow mutagenesis of pathogenicity domains that specifically reduce virulence, increase cytokine induction and antigen presentation and provide long-lasting protection. Furthermore, the mechanism of action of each mutation will be known and each will be specifically designed to resist reversion. We will combine mutations to create an optimal vaccine strain for each virus and then investigate their use in multivalent formulations, critical to veterinary vaccine development and highly desired for human formulations. We will identify correlates of protection for each vaccine and address the extent of cross-protection versus encephalitic viruses. For the first time with alphaviruses, the individual and combined effects of mutations with known mechanisms of action will be tested for effects on virus replication, disease and immunogenicity in animals.

抽象的东部（EEEV），委内瑞拉（VEEV）和西部（Weev）马脑炎病毒是否有可能引起致命神经侵染剂的蚊子传播的α病毒人类和家养动物的疾病。这些病毒也可以通过气溶胶途径，因此具有生物肉饼/生物恐怖剂的巨大潜力。在 2019年，EEEV人类感染增加到自1950年代以来未见水平。现在，没有为这些α病毒许可的抗病毒疗法或疫苗。现有生成> 40年 AGO，具有高度反应性，免疫原性，并导致多达20％的疾病收件人。对于EEEV和WEEV，研究性福尔马林灭活的疫苗具有被授予高危工人。两者都引起抗体反应，但它们提供了不确定的保护，需要多次助推器注射。三价兽医疫苗反对Veev，EEEV和WEEV可用，但免疫原性很差，以至于国内必须每年增加动物，并在接种疫苗的动物中看到疾病。在这里，我们建议使用这些α病毒开发安全有效的LAV疫苗了解每种毒力机制的最新进展。这些进步将允许致病域的诱变，这些域特异性降低毒力，增加细胞因子诱导和抗原表现并提供持久保护。此外，每个突变的作用机理将是已知的，并且每个都将专门设计用于抵抗重新转换。我们将把突变结合在一起为每种病毒创建最佳的疫苗应变，然后研究其在多价配方，对兽医疫苗开发至关重要，高度希望人类配方。我们将确定每种疫苗的保护相关性解决跨保护与脑病病毒的程度。第一次 α病毒，具有已知机制的突变的个体和组合作用作用将测试对病毒复制，疾病和免疫原性的影响动物。