Vaccines for Eastern and Western Equine Encephalitis Viruses

描述（由申请方提供）：委内瑞拉、东部和西部马脑炎病毒（分别为VEEV、EEEV、WEEV）是节肢动物传播的甲病毒，在美洲引起周期性动物流行病。这些病原体没有获得许可的疫苗，并且在试验性新药状态下使用的实验性疫苗具有高反应原性或低免疫原性。针对引起脑炎的特定病毒（包括EEEV和WEEV）的疫苗被NIAID视为高优先级生物防御产品。VEEV已被“武器化”用于生物战，主要是由于其相当稳定和气溶胶中的高传染性。EEEV和WEEV的研究不如VEEV，但两者都有潜在的生物战或生物恐怖主义的用途。EEEV实际上是最致命的虫媒病毒。WEEV自然获得性感染的临床数据表明，该疾病不太严重。然而，与VEEV类似，暴露于EEEV和WEEV的气溶胶可能更具致命性。目前关于开发针对EEEV和WEEV的疫苗的改进免疫原的提议涉及Maxygen和Connie Schmaljohn博士的USAMRIID实验室之间的合作。已经使用体外多基因DNA重组和定向分子进化获得了VEEV包膜糖蛋白免疫原性的实质性改善。这证明了该方法用于改善EEEV和WEEV免疫原的潜力。在本次I期SBIR申报中，我们将分别关注EEEV和WEEV包膜糖蛋白的免疫原性改善。单独的II期SBIR申请将针对VEEV、EEEV和WEEV创建单一多价疫苗。当前I期SBIR提交的具体目的是：（1）创建产生EEEV和WEEV包膜糖蛋白变体的重组基因表达文库;（2）对表达文库中的单个克隆进行预筛选;（3）使用DNA疫苗评价嵌合克隆在小鼠中的免疫原性。

DESCRIPTION (provided by applicant): Venezuelan, eastern, and western equine encephalitis viruses (VEEV, EEEV, WEEV respectively) are arthropod-borne alphaviruses that cause periodic epizootics in the Americas. No licensed vaccines exist for these pathogens, and the experimental vaccines used under Investigational New Drug status suffer from high reactogenicity or poor immunogenicity. Vaccines against specific viruses causing encephalitis, including EEEV and WEEV, are regarded as High Priority Biodefense Products by the NIAID. VEEV has been "weaponized" for use in biowarfare, due largely to its considerable stability and high infectivity in aerosols. EEEV and WEEV are less well studied than VEEV, but both have potential uses as agents of biowarfare or bioterrorism. EEEV is in fact the most lethal of arboviruses. Clinical data of naturally acquired infection by WEEV suggest that the disease is less severe. However, by analogy to VEEV, aerosol exposure to EEEV and WEEV could be even more lethal. The present Proposal to develop improved immunogens for vaccines against EEEV and WEEV involves a collaboration between Maxygen and the USAMRIID laboratory of Dr. Connie Schmaljohn. Substantial improvements in the immunogenicity of the envelope glycoproteins of VEEV have already been obtained using in vitro multigene DNA recombination and directed molecular evolution. This demonstrates the potential of this approach for improving EEEV and WEEV immunogens. In this Phase I SBIR submission, we will focus on improving the immunogenicity of envelope glycoproteins from each of EEEV and WEEV separately. A separate Phase II SBIR application will target the creation of a single multivalent vaccine for VEEV, EEEV, and WEEV. The Specific Aims of the current Phase I SBIR submission are: (1) create expression libraries of recombined genes producing variants of the envelope glycoproteins from EEEV and WEEV; (2) perform prescreening of individual clones from the expression libraries; and (3) evaluate the immunogenicity of chimeric clones in mice using DNA vaccines.