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

 描述(申请人提供)：东部(EEEV)、委内瑞拉(VEEV)和西部(WeEV)马脑炎病毒是蚊子传播的甲型病毒，有可能在人类和家养动物中引起致命的神经侵袭性疾病。这些病毒也可以通过气溶胶途径传播，因此，有很大的潜力成为生物恐怖分子。目前，还没有被批准用于甲型病毒的抗病毒药物。现有的研究中的VEEV减毒活疫苗(LAV；TC-83)是40年前生产的，具有高度反应性，免疫原性差，可导致高达20%的接受者患病。对于EEEV和WeEV，研究中的福尔马林灭活疫苗已经接种给了高危工人。虽然这两种疫苗都会引起抗体反应，但它们提供的保护不确定，需要多次加强注射，事实上，Weev疫苗不再可用。在这里，我们建议利用对EEEV毒力机制的最新了解进展，开发一种安全有效的针对EEEV的LAV疫苗。这些进展使EEEV的突变成为可能，这种突变专门降低了神经毒力，提高了免疫原性。我们计划结合突变来创造一种最佳的疫苗株，我们提出这一策略作为LAV对抗其他甲型病毒的平台。我们将确定针对EEEV的保护相关因素，并解决针对VEEV的交叉保护的程度。针对脑型甲型病毒的安全和保护性疫苗的开发将立即提供应对疾病出现或生物恐怖分子引入的对策。甲型病毒将首次测试具有已知作用机制的突变对动物体内病毒复制、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.