Identification of rikettsial antigens for vaccine development

普氏立克次体是人类已知的最致命的细菌病原体之一；它已经使整个 军队，并已武器化。它是B类生物制剂，因为它具有传播性。 气雾剂、低感染剂量、高稳定性，以及具有高病死率的严重疾病的病因。这个 开发交叉反应疫苗是可行的，因为自然感染立克次体提供了保护 对流行性(以及鼠类)斑疹伤寒幸存者的免疫力，因为交叉保护一直 实验证明；然而，安全有效的疫苗并不存在，因为我们的 对保护的免疫相关性的了解不完全，而且因为保护性抗原 仍未确认身份。因此，该应用的目的是发现交叉保护性立克次体抗原。 由T和B淋巴细胞识别。我们假设一种基于交叉反应的亚单位疫苗 立克次体抗原将保护小鼠和一种新的人源化小鼠模型免受致死性同源和 异源立克次体挑战。这项调查将有助于实现发展的长期目标 用于人类对抗立克次体的免疫治疗剂。全基因组方法的五个具体目标 将解决以下假设：1)确定预防立克次体感染的免疫学相关因素；2) 鉴定CD8T淋巴细胞识别的新的MHC类L限制性交叉反应立克次体抗原； 识别CD4T淋巴细胞识别的MHC-11类限制性交叉反应立克次体抗原；4) 识别由抗立克次体抗体识别的交叉反应立克次体抗原；以及5)确定 亚单位疫苗对立克次体致命性挑战的保护作用。第一个目标将提供 免疫相关保护的关键定义，将指导选择和评估 疫苗接种方案。AIMS 2、3和4将通过系统的 对所有普罗瓦泽克乳杆菌基因的评估。第五个目标是确定疫苗配方和疫苗接种。 该方案将提供持久、多功能和交叉反应的保护性免疫反应。在这 通过这种方式，我们的研究直接满足了WRCE的战略计划和NIAID的生物防御研究议程。这个 本研究的创新之处在于系统定义了免疫保护相关因素，发现 通过全面的基因组筛查，多种疫苗配方的测试， 以及使用高度相关的小鼠模型和重组的功能性人类免疫系统。

Rickettsia prowazekii is one of the most lethal bacterial pathogens known to man; it has decimated entire armies and has been weaponized. It is a category B biothreat select agent because of transmissibility by aerosol, low infectious dose, high stability, and causation of severe illness with a high case-fatality ratio. The development of a cross-reactive vaccine is feasible because natural rickettsial infection provides protective immunity in survivors of epidemic (as well as murine) typhus, and because cross-protection has been demonstrated experimentally; nevertheless, safe and effective vaccines do not exist because of our incomplete understanding of the immune correlates of protection, and because the protective antigens remain unidentified. Thus, the objective of this application is to discover cross-protective rickettsial antigens recognized by T and B lymphocytes. We hypothesize that a subunit vaccine based on cross-reactive rickettsial antigens will protect mice, and a novel humanized mouse model, from lethal homologous and heterologous rickettsial challenges. This investigation will contribute to the long-term goal of developing immunotherapeutic agents for humans against rickettsiae. Five specific aims with genome-wide approaches will address the hypothesis: 1) identify immunological correlates of protection against rickettsial infection; 2) identify new MHC class l-restricted cross-reactive rickettsial antigens recognized by CD8+ T lymphocytes; 3) identify MHC class ll-restricted cross-reactive rickettsial antigens recognized by CD4+ T lymphocytes; 4) identify cross-reactive rickettsial antigens recognized by anti-rickettsial antibodies; and 5) determine the protection conferred by a subunit vaccine against a lethal challenge with Rickettsia. The first aim will provide critical definitions of immune correlates of protection that will guide the selection and evaluation of vaccination protocols. Aims 2, 3, and 4 will identify rickettsial T cell and B cell antigens through a systematic evaluation of all R. prowazekii genes. The fifth aim will identify a vaccine formulation and vaccination protocol that will provide a durable multifunctional and cross-reactive protective immune response. In this way, our research directly addresses WRCE's strategic plan and NIAID's Biodefense Research Agenda. The innovation of this research lies in the systematic definition of immune correlates of protection, the discovery of rickettsial antigens through a comprehensive genomic screen, the testing of multiple vaccine formulations, and the use of a highly relevant mouse model with a reconstituted functional human immune system.