Correlates of Vaccine-Induced, Tunable-Protection in an Outbred Tularemia Model

 描述(申请人提供)：图拉方济氏菌是图拉热症的致烧剂，图拉热症是一种严重的人畜共患病，在未经治疗的受试者中死亡率超过30%。吸入后的感染导致最严重的疾病形式，加上其高毒力和武器化历史，使这种病原体成为用作生物武器的一个令人担忧的问题。开发预防气雾剂感染的疫苗是当务之急。我们已经设计了一系列基于高毒力Schu S4毒株的减毒活疫苗候选者，这些毒株在呼吸道攻击的小鼠和兔模型中显示出一系列保护能力。我们的研究证实，兔是人类肺炎性兔热病的优秀模型，也是评价兔热病疫苗的高度相关的模型，因为它们对弱毒株的抵抗力和对强毒株的敏感性与人类相似。我们假设，远交的与人类相关的兔子模型将允许我们使用提供一定范围(0%到83%)保护的疫苗毒株的集合来识别保护相关因素 对抗致命气雾剂挑战的效果。这笔赠款旨在了解这种保护背后的机制(S)。我们的假设是，在兔模型中有效的疫苗接种是1)诱导特定的抗原特异性反应和/或2)免疫原的持久性和免疫刺激特性的产物。第一个目标是鉴定保护性免疫反应特异性识别的细菌抗原(S)。第二个目标将探索体液和细胞免疫反应，以及图拉夫酵母衍生物在保护免受攻击中的持久性和免疫刺激的作用。第三个目标将评估亚单位疫苗和优化的减毒活疫苗对吸入土拉氏原虫的效果。根据这一建议获得的信息将扩大我们对兔热病疫苗的体液和细胞免疫反应的理解，这些反应在预防兔热病方面的重要性，以及与人类保护的相关性。

 DESCRIPTION (provided by applicant): Francisella tularensis is the causitive agent of tularemia, a severe zoonotic disease in humans with fatality rates exceeding 30% in untreated subjects. Infection following inhalation causes the most severe form of disease and combind with its high virulence and history of weaponization makes this pathogen a concern for use as a biological weapon. Development of a vaccine that protects against aerosol infection is a priority. We have engineered a series of live attenuated vaccine candidates based on the highly virulent Schu S4 strain that exhibit a range of protective capacities in the mouse and rabbit models of respiratory challenge. Our studies have confirmed that rabbits are an excellent model of human pneumonic tularemia and a highly relevant model for evaluating tularemia vaccines as they display similar resistance to attenuated strains and susceptibility to virulent strains as humans. We hypothesize that the outbred human-relevant, rabbit model will allow us to identify correlates of protection using the collection of vaccine strains that confer a range (0% to 83%) of protective efficacies against lethal aerosol challenge. This grant seeks to understand the mechanism(s) underlying this protection. Our hypothesis is that effective vaccination in the rabbit model is a product of i) induction of particular, Ag-specific responses and/or ii) the immunogen's persistence and immuno-stimulatory properties. The first aim will identify the bacterial Ag(s) recognized specifically by protective immune responses. The second aim will explore the humoral and cellular immune response as well as the role of persistence and immune stimulation by F. tularensis derivatives in protection against challenge. The third aim will evaluate the efficacy of a subunit vaccine and an optimized live attenuated vaccine against inhalation of F. tularensis. The information gained under this proposal will expand our understanding of the humoral and cellular immune response to tularemia vaccines, the importance of these responses in protection against tularemia in the rabbit and the relevance to protection in humans.