B.abortus-based vaccine against viral hemorrhagic fevers

描述（申请人提供）：病毒性出血热（VHF）是由多种病毒引起的严重的危及生命的疾病。拉沙病毒、克里米亚/刚果出血热病毒、马尔堡病毒和埃博拉病毒是已知容易在人与人之间传播的四种甚高频致病因子。目前还没有针对这些病毒性疾病的疫苗。随着最近生物恐怖威胁的加剧，这些致命病毒被恐怖分子利用的可能性已变得显而易见。此外，获得安全有效的甚高频疫苗将有助于保护有接触这些病毒高风险的人，例如前往或生活在非洲流行区的人。迄今为止进行的研究表明，抗体和细胞介导的免疫反应对vhf的保护是必要的。拟议研究项目的总体目标是研制一种高效和安全的甚高频疫苗。具体而言，研究人员建议通过在流产布鲁氏菌菌株RB51中表达先前鉴定的埃博拉病毒和拉沙病毒保护蛋白来制备有效的VHF疫苗。流产布鲁氏菌菌株RB51是一种具有独特佐剂特性的细菌载体，可以刺激强烈的细胞介导免疫反应。在目前的提案中，研究人员打算i)构建表达拉沙和埃博拉病毒核蛋白和部分糖蛋白的重组RB51菌株，ii)用辐照的重组RB51疫苗免疫小鼠，并表征其抗原特异性抗体和细胞介导的免疫反应。研究人员最近进行的研究表明，暴露于低剂量伽马辐射的重组RB51菌株在一次免疫后不能复制，但会诱导强烈的免疫反应。因此，本研究拟采用辐照重组RB51菌株对小鼠进行亲本和粘膜免疫，研究其特异性免疫应答。拟议的研究将清楚地证明使用辐照重组RB51菌株作为新的表达和递送平台开发有效和安全的病毒性疾病疫苗的概念验证。

DESCRIPTION (provided by applicant): Viral hemorrhagic fevers (VHF) are severe and life-threatening diseases caused by several viruses. Lassa virus, Crimean/Congo hemorrhagic fever virus, Marburg and Ebola viruses are four of the VHF causing agents known to be readily capable of person-to-person spread. No vaccines against these viral diseases are currently available. With the recent heightened bioterror threat, the potential use of these deadly viruses by terrorist elements has become apparent. Moreover, availability of safe and effective vaccines against VHF agents will be useful for protecting people with high risk of getting exposed to these viruses, such as people traveling to or living in the endemic regions of Africa. Research conducted to date demonstrates that both antibody and cell-mediated immune responses are necessary for protection to VHFs. The overall objective of the proposed research project is to develop a highly efficacious and safe vaccine for VHF. Specifically, the investigators propose to prepare an effective vaccine against VHF by expressing previously identified protective protein(s) of Ebola and Lassa viruses in Brucella abortus strain RB51, a bacterial vector with unique adjuvant properties and can stimulate a strong cell-mediated immune response. In the current proposal, the investigators intend to i) construct recombinant RB51 strains that express nucleoprotein and partial glycoprotein of Lassa and Ebola viruses, and ii) immunize mice with irradiated recombinant RB51 vaccines and characterize their antigen-specific antibody and cell-mediated immune responses. Recent research conducted by the investigators indicate that recombinant RB51 strains exposed to low doses of gamma radiation are unable to replicate but induce strong immune responses after just one immunization. Therefore, the investigators propose to use irradiated recombinant RB51 strains to immunize mice parentally and mucosally and study the specific immune responses. The proposed studies will clearly demonstrate the proof-of-concept for the development of efficacious and safe vaccines against viral diseases using irradiated, recombinant RB51 strain as a novel expression and delivery platform.