B.abortus-based vaccine against viral hemorrhagic fevers

描述（由申请人提供）：病毒性出血热（VHF）是由几种病毒引起的严重和危及生命的疾病。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四种已知容易在人与人之间传播的甚高频病原体。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，恐怖分子利用这些致命病毒的可能性已变得显而易见。此外，针对VHF病原体的安全有效疫苗的可用性将有助于保护暴露于这些病毒的高风险人群，例如前往或生活在非洲流行地区的人群。迄今为止进行的研究表明，抗体和细胞介导的免疫应答对于保护VHF是必要的。拟议研究项目的总体目标是开发一种高效安全的VHF疫苗。具体而言，研究人员建议通过在牛种布鲁氏菌菌株RB 51中表达先前鉴定的埃博拉和拉沙病毒的保护性蛋白来制备针对VHF的有效疫苗，这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的免疫应答。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RB 51毒株，ii）用辐照重组RB 51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应答。研究人员最近进行的研究表明，暴露于低剂量γ辐射的重组RB 51菌株无法复制，但仅在一次免疫后就诱导了强烈的免疫反应。 因此，研究者建议使用辐射重组RB 51菌株胃肠外和粘膜免疫小鼠，并研究特异性免疫应答。拟议的研究将清楚地证明使用辐照的重组RB 51菌株作为新型表达和递送平台开发针对病毒性疾病的有效和安全疫苗的概念验证。

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.