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：
10674134
负责人：
WILLIAM B KLIMSTRA
金额：
$ 45.52万
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/10674134
关键词：
Address Aerosols Alphavirus Animal Disease Models Animals Antibody Response Antigen Presentation Antiviral Agents Antiviral Therapy Arboviruses Attenuated Attenuated Vaccines 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 cross immunity cytokine design immunogenic immunogenicity in vivo mutant next generation preclinical study preservation protective efficacy vaccine access vaccine candidate vaccine development vaccine efficacy vaccine evaluation vaccine formulation vaccine strategy

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) 马脑炎病毒蚊子传播的甲病毒是否有可能导致致命的神经侵袭人类和家养动物的疾病。这些病毒也可以通过以下途径传播因此，气溶胶途径具有作为生物战/生物恐怖主义制剂的巨大潜力。在 2019 年，EEEV 人类感染增加到 20 世纪 50 年代以来的最高水平。现在，目前还没有针对这些甲病毒的抗病毒疗法或疫苗获得许可。现有的研究性 VEEV 减毒活疫苗（LAV；TC-83）的诞生超过 40 年以前，具有高反应原性、低免疫原性，并导致高达 20% 的疾病收件人。对于 EEEV 和 WEEV，研究性福尔马林灭活疫苗已已提供给高危工人。虽然两者都会引起抗体反应，但它们提供保护作用不确定，需要多次加强注射。三价兽用疫苗针对 VEEV、EEEV 和 WEEV 的疫苗已上市，但其免疫原性很差，因此国内动物必须每年进行加强免疫，接种疫苗的动物会出现疾病。在这里，我们建议开发安全有效的 LAV 疫苗来对抗这些甲病毒对每种毒力机制的了解的最新进展。这些进展将允许致病性域的诱变，从而特异性地减少毒力，增加细胞因子诱导和抗原呈递，并提供持久的保护。此外，每个突变的作用机制将是已知的并且每一个都经过专门设计以防止逆转。我们将结合突变为每种病毒创建最佳疫苗株，然后研究它们的用途多价制剂，对兽用疫苗开发至关重要，并且非常需要人类配方。我们将确定每种疫苗的保护相关性解决与脑炎病毒的交叉保护程度。第一次与甲病毒，已知机制突变的个体和组合效应将测试其对病毒复制、疾病和免疫原性的影响动物。