An Informed Approach to Live Attenuated Vaccines against Encephalitis Alphaviruses

摘要 东部(EEEV)、委内瑞拉(VEEV)和西部(WeEV)马脑炎病毒 蚊子传播的甲型病毒有可能导致致命的神经侵袭吗？ 人类和家养动物中的疾病。这些病毒也可以通过 因此，它们具有作为生物武器/生物恐怖主义制剂的巨大潜力。在……里面 2019年，EEEV人类感染增加到自20世纪50年代以来未曾见过的水平。目前， 目前还没有针对这些甲型病毒的抗病毒疗法或疫苗。现有的 研究中的VEEV减毒活疫苗(LAV；TC-83)问世40年 是高度反应性的，免疫原性差的，并导致高达20%的疾病 收件人。对于EEEV和WeEV，正在研究的福尔马林灭活疫苗有 给了处于危险中的工人。虽然两者都会引发抗体反应，但它们提供了 保护不确定，需要多次注射助推器。一种三价兽用疫苗 针对VEEV，EEEV和WeEV是可用的，但免疫原性很差，国内 动物必须每年接种疫苗，并且在接种疫苗的动物中会出现疾病。在这里，我们 建议开发安全有效的针对这些甲型病毒的LAVS疫苗 每种细菌毒力机制的最新研究进展。这些 进展将允许特定减少致病性域的突变 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 每一种都将被专门设计来抵抗回归。我们将结合突变来 为每种病毒创建一种最佳疫苗株，然后研究它们在 多价制剂，对兽用疫苗开发至关重要，非常受欢迎 人类配方。我们将确定每种疫苗的保护相关因素，并 解决针对脑炎病毒的交叉保护范围。第一次有了 甲型病毒，具有已知机制的突变的单独和联合影响 将测试对病毒复制、疾病和免疫原性的影响 动物。

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.