Rocky Mountain Spotted Fever Vaccine Development

项目概要： 蜱传播的立克次体疾病的属无形体，埃立克体，立克次体仍然是一个增长的 在美国和世界许多地方的公共卫生问题。这些疾病包括已知最古老的 立克次体病，由立克次体引起的落基山斑疹热（RMSF）。RMSF仍然是 严重的疾病的人，并继续是一个公共卫生问题，在美国和几个北，中 和南美国家。RMSF的临床体征包括发热、头痛、恶心、呕吐、肌肉痉挛 疼痛食欲不振和皮疹这种疾病在未经治疗的情况下可迅速发展为危及生命的疾病。 患者，导致30- 80%的高死亡率。在过去的二十年里，报告RMSF 北美部分地区的病例继续上升。蜱传疾病需要人类的相互作用， 蜱和宿主动物宿主。我们相信，开发疫苗来预防这种疾病， 通过与具有不同专业知识的专家团队进行合作研究来完成， 具有广泛的研究兴趣。由于狗患的疾病与人相似， 这种宿主的疾病很可能有效地控制野生动物、蜱虫和 从狗传染给人。我们最近测试了两种实验性疫苗，一种是亚单位疫苗， 包括两个R。立克次氏体重组蛋白（RCA）和全细胞灭活抗原疫苗（WCA）， 赋予对毒性R的保护。立克次体感染挑战。WCA提供全面保护， RMSF，而RCA没有。这项先前发表的工作为拟议的 详细调查。特别是，我们的目标是进一步表征WCA在确定A）的持续时间 保护，B）佐剂在定义保护中的作用，C）观察到的免疫应答类型，以及D） 防止蜱传播的同源和异源攻击。我们相信这个项目， 在强有力的科学前提支持下，解决了一个重大的公共卫生问题。目标具有创新性 因为我们将是第一个使用生理学相关动物研究RMSF疫苗开发的小组- 蜱-病原体感染模型我们的应用程序的中心假设是，WCA防止致命的 由血液和蜱传播感染引起的RMSF，由地理上遥远的病原体菌株引起， 刺激免疫保护一年或更长时间。该应用程序的具体目标是：1）评估 灭活方法用于制备WCA和佐剂以确定疫苗的保护性。2)评估WCA 防止蜱虫传播的挑战。3)评估WCA对R的保护。异源立克次体 菌株感染的挑战。在这个项目结束时，我们希望我们的努力将转化为一个全面的 开发的疫苗，这是有效的动物模型已知自然获得R。立克次体感染 导致危及生命的RMSF我们相信，实现这一应用程序的目标将 为扩大疫苗研究铺平道路，以保护人们在不久的将来免受这种致命疾病的侵害。

PROJECT SUMMARY: Tick-transmitted rickettsial diseases of the genera Anaplasma, Ehrlichia, and Rickettsia remain a growing public health concern in the USA and many parts of the world. The diseases include one of the oldest known rickettsial diseases, Rocky Mountain spotted fever (RMSF) caused by Rickettsia rickettsii. RMSF remains a serious disease of people and continues to be a public health concern in the USA and several North, Central and South American countries. Clinical signs of RMSF include fever, headache, nausea, vomiting, muscle pain, lack of appetite, and rash. The disease can progress rapidly to a life-threatening illness in untreated patients, resulting in high mortality rates ranging from 30-80%. During the last two decades, reported RMSF cases continue rising in parts of North America. Tick-borne diseases (TBDs) require the interplay of humans, ticks and reservoir animal hosts. We believe that developing a vaccine to prevent the disease can be accomplished by engaging in collaborative research with a team of experts having diverse expertise and yet having common broad research interests. Since dogs develop disease similar to people, a vaccine to prevent the disease in this host will most likely be effective in controlling the disease spread from wildlife, ticks and also infections from dogs to people. We recently tested two experimental vaccines; a subunit vaccine, which included two R. rickettsii recombinant proteins (RCA) and a whole cell inactivated antigen vaccine (WCA), to confer protection against virulent R. rickettsii infection challenge. WCA offered complete protection against RMSF, while RCA did not. This prior published work offers a strong scientific premise for the proposed detailed investigation. In particular, we aim to further characterize WCA in determining A) the duration of protection, B) the role of adjuvants in defining protection, C) the type of immune response observed, and D) the protection against tick transmitted homologous and heterologous challenges. We believe that this project, supported by strong scientific premise, addresses a significant public health problem. The goals are innovative as we will be the first group to investigate RMSF vaccine development using a physiologically relevant animal- tick-pathogen infection model. The central hypothesis of our application is that WCA protects against lethal RMSF caused by blood- and tick-borne infections, resulting from geographically distant pathogen strains, by stimulating immune protection for one year or longer. The specific aims of this application are: 1) Evaluate inactivation methods for preparing WCA and adjuvants in defining the vaccine protection. 2) Evaluate WCA protection against tick-transmitted challenges. 3) Evaluate WCA protection against R. rickettsii heterologous strain infection challenges. At the conclusion of this project, we expect that our efforts will translate to a fully developed vaccine, which is efficacious in an animal model known to naturally acquire R. rickettsii infections from an infected tick leading to life-threatening RMSF. We believe that achieving goals of this application will pave the way for extending vaccine studies to protect people from this lethal disease in the very near future.