Identification of T Cell Antigen For Q Fever Vaccination

描述（由申请人提供）：“q热”的病原体伯纳克希菌是一种对人和牲畜都有高度传染性的b类生物恐怖剂。人类感染主要是由气溶胶传播引起的，伯纳蒂胞杆菌可以经受住干燥，并在受污染的土壤中保持数年的传染性。容易通过气溶胶传播、环境持久性和高传染性（ID50=1）使伯纳蒂杆菌对军事人员和平民构成严重威胁。这种药剂已经被武器化并在各种生物战计划下大量生产。因此，迫切需要开发一种有效的疫苗，并可在假定或确认的疫情发生后安全地用于有针对性或大规模的疫苗接种。目前，没有符合这些标准的疫苗，我们提出了一种策略，以确定符合这些标准的定义伯纳蒂胞杆菌免疫原。

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.