B.abortus-based vaccine against viral hemorrhagic fevers

描述(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。拉萨病毒、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的四种极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，恐怖分子使用这些致命病毒的可能性变得显而易见。此外，提供安全有效的VHF制剂疫苗将有助于保护接触这些病毒的高风险人群，如前往非洲流行地区或在非洲流行地区生活的人。到目前为止进行的研究表明，抗体和细胞介导的免疫反应对于保护VHFs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。具体地说，研究人员建议通过在布鲁氏菌流产株RB51中表达先前识别的埃博拉和拉萨病毒保护蛋白(S)来制备有效的VHF疫苗，布鲁氏菌RB51是一种具有独特佐剂特性的细菌载体，可以刺激强大的细胞介导的免疫反应。在目前的方案中，研究人员打算i)构建表达拉萨和埃博拉病毒核蛋白和部分糖蛋白的重组RB51菌株，以及ii)用辐照的重组RB51疫苗免疫小鼠，并鉴定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，暴露在低剂量伽马辐射下的重组RB51菌株无法复制，但仅在一次免疫后就能诱导强烈的免疫反应。因此，研究人员建议使用辐照后的重组RB51菌株对小鼠进行亲代免疫和粘膜免疫，并研究其特异性免疫应答。拟议的研究将清楚地证明，利用辐照的重组RB51毒株作为一种新的表达和递送平台，开发有效和安全的病毒疾病疫苗是可行的。

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.