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

远交兔热病模型中疫苗诱导的可调节保护的相关性

• 批准号: 9077642
• 负责人: Eileen M. Barry
• 金额: $ 78.98万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-15 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9077642
• 关键词: Adjuvant; Aerosols; Animal Model; Animals; Antigens; Attenuated; Attenuated Live Virus Vaccine; Attenuated Vaccines; Biological; Breathing; Cells; Characteristics; Collaborations; Collection; Columbidae; Disease; Engineering; Enzymes; Exhibits; Fatality rate; Fever; Francisella tularensis; Genes; Goals; Gram-Negative Bacteria; Grant; Health; Human; Immune; Immune response; Immunity; Immunologist; Inbred Mouse; Inbreeding; Infection; Knowledge; Lead; Literature; Mediator of activation protein; Metabolic; Modeling; Morbidity - disease rate; Mus; Mutation; Oryctolagus cuniculus; Population; Positioning Attribute; Predisposition; Prevention; Property; Proteome; Reagent; Recording of previous events; Regimen; Resistance; Respiratory Tract Infections; Role; Route; Series; Subunit Vaccines; Survival Rate; System; T-Lymphocyte Subsets; Tail; Testing; Tissues; Tularemia; Vaccinated; Vaccination; Vaccine Research; Vaccines; Virulence; Virulent; aerosolized; base; design; human disease; improved; mortality; pathogen; protective efficacy; respiratory; response; vaccine candidate; vaccine development; vaccine efficacy; vaccine evaluation; vaccine response; weapons

 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.

 描述（由申请方提供）：土拉热弗朗西斯菌是土拉菌病的致病因子，土拉菌病是一种严重的人畜共患病，未经治疗的受试者死亡率超过30%。吸入后的感染引起最严重的疾病，加上其高毒性和武器化历史，使这种病原体成为一种令人关切的生物武器。研制一种预防气溶胶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菌株的减毒活疫苗候选物，其在小鼠和兔呼吸道攻击模型中表现出一系列保护能力。我们的研究已经证实，兔是人肺炎土拉菌病的优良模型，也是评价土拉菌病疫苗的高度相关模型，因为它们显示出与人相似的对减毒株的抗性和对强毒株的敏感性。我们假设远系繁殖的人类相关的兔模型将允许我们使用疫苗株的集合来鉴定保护的相关性，所述疫苗株赋予范围（0%至83%）的保护性。 对致命气溶胶攻击的效力。本补助金旨在了解这种保护的机制。我们的假设是，兔模型中的有效疫苗接种是i）特定Ag特异性应答的诱导和/或ii）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应答特异性识别的细菌Ag。第二个目的是探讨F.土拉菌衍生物在对抗挑战的保护中的作用。第三个目标是评估亚单位疫苗和优化的减毒活疫苗对吸入性F。土拉热。根据该提案获得的信息将扩大我们对兔热病疫苗的体液和细胞免疫应答的理解，这些应答在兔兔热病保护中的重要性以及与人类保护的相关性。