Vaccines for Eastern and Western Equine Encephalitis Viruses

描述(申请人提供)：委内瑞拉、东部和西部马脑炎病毒(分别为VEEV、EEEV和WeEV)是节肢动物传播的甲型病毒，在美洲引起周期性流行性疫情。目前还没有针对这些病原体的许可疫苗，在研究新药状态下使用的实验疫苗具有高反应性或低免疫原性。针对引起脑炎的特定病毒的疫苗，包括EEEV和Weev，被NIAID视为高度优先的生物防御产品。Veev已经被“武器化”用于生物武器，这主要是因为它相当稳定，在气雾剂中具有很高的传染性。EEEV和WeEV的研究不如VEEV，但两者都有潜在的生物武器或生物恐怖主义的用途。事实上，EEEV是最致命的虫媒病毒。Weev自然获得性感染的临床数据表明，这种疾病没有那么严重。然而，与VEEV类似，暴露于EEEV和WeEV的气雾剂可能更致命。目前关于开发针对EEEV和WeEV疫苗的改进免疫原的提议涉及Maxygen和康妮·施马尔约翰博士的USAMRIID实验室之间的合作。通过体外多基因DNA重组和定向分子进化，VEEV囊膜糖蛋白的免疫原性已经得到了实质性的改善。这证明了这种方法在改善EEEV和WeEV免疫原方面的潜力。在这一阶段的SBIR提交中，我们将专注于分别提高EEEV和WeEV包膜糖蛋白的免疫原性。单独的第二阶段SBIR应用程序将针对VEEV、EEEV和WeEV创建单一多价疫苗。目前第一阶段SBIR提交的具体目标是：(1)创建产生EEEV和WeEV包膜糖蛋白变体的重组基因的表达文库；(2)从表达文库中对单个克隆进行预筛选；以及(3)使用DNA疫苗评估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.