An Oral Vaccine Against Multiple Biowarfare Agents

描述（由申请人提供）：背景：美国公民，特别是 军事人员，很容易受到生物接触的威胁， 战剂两种这样的细菌剂，炭疽杆菌和弗朗西斯菌 土拉热，可以很容易地通过雾化传播，导致高水平的 死亡率，因此被认为是候选战剂。新 需要针对这些和其他潜在的战争试剂的疫苗， 易于管理，并提供高水平的保护， 雾化生物武器我们研制出一种鼠伤寒沙门氏菌 （delta-glnA delta-glnH）具有许多属性，使其成为一种有吸引力的 活减毒多价疫苗的候选者。我们的假设是 这种减毒的S.鼠伤寒菌株可用作单一口服疫苗， 递送多价抗原并提供粘膜和全身保护 对雾化生物战剂，特别是B的免疫力。 炭疽菌和F.土拉热。我们将利用特定的S。鼠伤寒启动子 (e.g., pmrH）以驱动B的高水平表达。anthracis和F. tularensis 淋巴组织内的抗原，从而产生足够的免疫 单次剂量的反应。 本项目的具体目标包括：（1）构建delta-glnA δ-glnH减毒S.具有pmrH启动子的鼠伤寒疫苗株 B的驱动表达式。炭疽病保护性抗原（PA）和F. tularensis FopA和TUL 4蛋白;（2）疫苗株效力的评价 （具体目的1）在免疫组织内表达异源抗原， 引发适当的免疫应答;和（3）攻击接种疫苗的动物 雾化的B。anthracis和F.土拉热，以确定疗效的 疫苗株。我们的研究设计包括协作疫苗 在圣安东尼奥的三个不同地点进行开发， 在每个网站上找到。色葡萄表达B的鼠伤寒疫苗株。炭疽 和F.将构建土拉菌抗原并接种到动物中， 两个S.鼠伤寒的研究人员，卡尔·克洛泽博士和约翰· 德克萨斯大学健康科学中心的古恩说。评价 免疫组织内抗原表达水平的测定将在 布鲁克斯空军基地，由约翰·洛曼博士。雾化B。炭疽菌和F. 接种动物的土拉热攻毒研究将在 西南基金会生物安全4级（BSL-4）实验室 在Jean Patterson博士的指导下进行生物医学研究。我们将 利用这个高水平的生物防护实验室来执行 气溶胶挑战，以证明这种疫苗的有效性。 相关性：开发单一口服疫苗， 提供对多种生物战剂的保护将是巨大的 有益于军事人员和其他暴露于 这些代理人。如果这种疫苗策略被证明成功，额外的抗原 可以从相同的疫苗株表达，提供了适应性和 保护健康的工具。

DESCRIPTION (provided by applicant): Background: U.S. citizens, particularly military personnel, are vulnerable to the threat of exposure to biological warfare agents. Two such bacterial agents, Bacillus anthracis and Francisella tularensis, can be easily spread by aerosolization causing a high level of mortality, and are therefore considered to be candidate warfare agents. New vaccines against these and other potential warfare agents are needed which can be easily administered and provide high levels of protection against aerosolized bio-weapons. We have developed a Salmonella typhimurium strain (delta-glnA delta-glnH) with a number of attributes that make it an attractive candidate for a live attenuated multivalent vaccine. Our hypothesis is that this attenuated S. typhimurium strain can be used as a single oral vaccine to deliver multivalent antigens and provide both mucosal and systemic protective immunity against aerosolized biological warfare agents, specifically B. anthracis and F. tularensis. We will exploit specific S. typhimurium promoters (e.g., pmrH) to drive high-level expression of B. anthracis and F. tularensis antigens within the lymphoid tissue, and thus generate a sufficient immune response with a single dose. The Specific Aims of this project entail: (1) Construction of delta-glnA delta-glnH attenuated S. typhimurium vaccine strains with the pmrH promoter driving expression of B. anthracis. Protective Antigen (PA) and F. tularensis FopA and TUL4 proteins; (2) Evaluation of the efficacy of vaccine strains (Specific Aim 1) to express heterologous antigens within immune tissue and elicit an appropriate immune response; and (3) Challenge vaccinated animals with aerosolized B. anthracis and F. tularensis to determine efficacy of the vaccine strains. Our Study Design incorporates collaborative vaccine development at three different sites in San Antonio, based upon the expertise found at each site. The S. typhimurium vaccine strains expressing B. anthracis and F. tularensis antigens will be constructed and inoculated into animals in the laboratories of two S. typhimurium researchers, Drs. Karl Klose and John Gunn, at the University of Texas Health Science Center. The evaluation of levels of antigen expression within immune tissue will be carried out at the Brooks Air Force Base by Dr. Kenton Lohman. Aerosolized B. anthracis and F. tularensis challenge studies of vaccinated animals will take place in the Biosafety Level 4 (BSL-4) laboratory at the Southwest Foundation for Biomedical Research under the guidance of Dr. Jean Patterson. We will be taking advantage of this high-level biocontainment laboratory to perform the aerosol challenges necessary to prove the efficacy of this vaccine approach. Relevance: The development of a single oral vaccine that can simultaneously provide protection against multiple bio-warfare agents would be of tremendous benefit to the health of military personnel and other citizens exposed to these agents. If this vaccine strategy proves successful, additional antigens can be expressed from the same vaccine strain, offering an adaptive and protective health tool.