Development of a novel live attenuated vaccine for eastern equine encephalitis virus

 描述（由申请方提供）：东方（EEEV）、委内瑞拉（VEEV）和西方（WEEV）马脑炎病毒是蚊媒甲病毒，可能在人类和家养动物中引起致命性神经侵入性疾病。这些病毒也可以通过气溶胶途径传播，因此具有作为生物恐怖分子制剂的巨大潜力。目前，没有批准用于甲病毒的抗病毒剂。现有的研究性VEEV减毒活疫苗（LAV; TC-83）是在>40年前生产的，具有高度反应原性，免疫原性差，并在高达20%的接受者中引起疾病。对于EEEV和WEEV，研究用福尔马林灭活疫苗已给予高危工人。虽然两者都能引起抗体反应，但它们提供的保护作用不确定，需要多次加强注射，事实上，WEEV疫苗已不再可用。在这里，我们建议开发一种安全有效的LAV疫苗对EEEV利用最新进展的了解病毒的毒力机制。这些进展使得EEEV的诱变能够特异性降低神经毒力并增加免疫原性。我们计划将联合收割机突变组合以创建最佳疫苗株，并且我们提出这种策略作为LAV对抗其他甲病毒的平台。我们将确定对EEEV的保护的相关性，并解决对VEEV的交叉保护的程度。针对脑炎甲病毒的安全和保护性疫苗的开发将提供针对疾病出现或生物恐怖分子引入的即时对策。对于甲病毒，将首次测试具有已知作用机制的突变的个体和组合效应对动物中病毒复制、疾病和免疫原性的影响。

 DESCRIPTION (provided by applicant): 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 bioterrorist agents. Currently, there are no antiviral agents approved for 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, require multiple booster injections, and in fact, the WEEV vaccine is no longer available. Here, we propose to develop a safe and effective LAV vaccine against EEEV using recent advances in understanding of the virulence mechanisms of the virus. These advances have allowed mutagenesis of EEEV that specifically reduces neurovirulence and increases immunogenicity. We plan to combine mutations to create an optimal vaccine strain and we propose this strategy as a platform for LAV versus other alphaviruses. We will identify correlates of protection against EEEV and address the extent of cross- protection against VEEV. The development of safe and protective vaccines against the encephalitic alphaviruses will provide an immediate counter-measure against disease emergence or bioterrorist introduction. For the first time with alphaviruses, the individua and combined effects of mutations with known mechanisms of action will be tested for effects on virus replication, disease and immunogenicity in animals.