Identification of T Cell Antigen For Q Fever Vaccination

描述（由申请人提供）：贝氏柯克斯体是“Q热”的病原体，是一种B类生物恐怖主义病原体，对人类和牲畜具有高度感染性。人类感染主要是通过气溶胶传播和C。贝氏菌可以经受干燥，在受污染的土壤中保持感染性数年。易通过气溶胶传播，环境持久性和高感染性（ID 50 =1）使C。严重威胁到军事人员和平民。这种制剂已经在各种生物战计划下被武器化和大规模生产。因此，迫切需要开发一种有效的疫苗，并且可以在假定或确认的爆发后安全地用于靶向或大规模疫苗接种。目前，还没有符合这些标准的疫苗，我们提出了一个策略，以确定确定C。符合这些标准的Burnetti免疫原。 我们建议识别和测试定义的C。burnetti免疫原使用一种新的蛋白质组学方法结合筛选所需的细胞介导的反应，一种方法，利用最近完成的九英里株基因组序列。胞内杀伤C. Burnetti通过IFN-γ介导，并与一氧化氮产生的强烈刺激有关。因此，疫苗诱导的免疫依赖于CD 4 + T淋巴细胞的引发和扩增，所述T淋巴细胞可以通过C的MHC II类呈递来识别感染的巨噬细胞。Burnetti抗原并分泌高水平的IFN-γ。在这个项目中，我们将测试以下假设：i）定义C。通过刺激CD 4 + T细胞应答的能力鉴定的贝氏体蛋白将诱导与全细胞疫苗诱导的保护相当的针对毒性攻击的保护;和ii）使用这些确定的免疫刺激性C. Burnetti蛋白将显著降低疫苗接种后不良反应的发生率和严重程度。这些假设将在三个特定的目标进行测试：1）在保护性天然C。Burnetti全细胞; 2] C. burnetti菌株; 3）C.贝氏体抗原和测定针对同源和异源菌株攻击的保护性免疫。

DESCRIPTION (provided by applicant): Coxiella burnetii, the etiological agent of "Q-fever", is a category-B bioterrorism agent that is highly infective to both humans and livestock. Human infection arises primarily from aerosol transmission and C. burnetii can withstand desiccation and remain infectious in contaminated soils for several years. Ease of dissemination via aerosol, environmental persistence, and high infectivity (ID50=1) make C. burnetii a serious threat for military personnel and civilians. This agent has already been weaponized and mass-produced under various biological warfare programs. Consequently, there is an urgent need to develop a vaccine that is effective and can be safely used for targeted or mass vaccination following a presumed or confirmed outbreak. Currently, there is no vaccine that meets these criteria-we propose a strategy to identify defined C. burnetti immunogens that meet these criteria. We propose to identify and test defined C. burnetti immunogens using a novel proteomic approach combined with screening for the required cell-mediated response, an approach that takes advantage of the recent completion of the Nine Mile strain genomic sequence. Intracellular killing of C. burnetti is mediated via IFN-gamma and is associated with strong stimulation of nitric oxide production. Consequently, vaccine induced immunity is dependent upon priming and expansion of CD4+ T lymphocytes that can recognize infected macrophages via MHC class II presentation of C. burnetti antigens and secrete high levels of IFN-gamma. In this project we will test the following hypotheses: i) that defined C. burnetii proteins, identified by ability to stimulate a CD4+ T cell response, will induce protection against virulent challenge equivalent to that induced by the whole-cell vaccine; and ii) that immunization using these defined, immunostimulatory C. burnetti proteins will significantly reduce the incidence and severity of post-vaccination adverse reactions. These hypotheses will be tested in three specific aims: 1] Identification of novel T cell immunogens in protective native C. burnetti whole cells; 2] Conservation of T cell immunogens among C. burnetti strains; and 3] Immunization with C. burnetii antigens and determination of protective immunity against homologous and heterologous strain challenge.