Rocky Mountain Spotted Fever Vaccine Development

项目总结： 硬体传播的无浆体、埃立克体和立克次体属立克次体疾病仍在增长 美国和世界许多地区的公共卫生问题。这些疾病包括已知的最古老的疾病之一 立克次体病，由立克次体引起的落基山斑点热病。RMSF仍然是一个 严重的人类疾病，在美国和一些北部、中部地区仍然是一个公共卫生问题 和南美国家。RMSF的临床症状包括发热、头痛、恶心、呕吐、肌肉 疼痛，食欲不振，皮疹。在不治疗的情况下，这种疾病可以迅速发展为危及生命的疾病 导致高死亡率，从30%到80%不等。在过去的二十年里，据RMSF报道 北美部分地区的病例继续上升。壁虱传播的疾病需要人类的相互作用， 扁虱和水库动物宿主。我们相信，开发一种疫苗来预防这种疾病可以 通过与具有不同专业知识的专家团队进行协作研究来完成，但 具有共同的广泛的研究兴趣。由于狗会患上与人类相似的疾病，因此预防疾病的疫苗 这种宿主的疾病很可能有效地控制从野生动物、扁虱和其他动物传播的疾病 从狗到人的感染。我们最近测试了两种实验性疫苗；一种亚单位疫苗，它 包括两种立克次体重组蛋白(RCA)和一种全细胞灭活抗原疫苗(WCA)，以 提供对强毒立克次体感染的保护挑战。WCA提供全面的保护，防止 RMSF，而RCA不是。这项先前发表的工作为提出的 详细调查。特别是，我们的目标是在确定A)持续时间方面进一步表征WCA 保护，B)佐剂在确定保护中的作用，C)观察到的免疫反应的类型，以及D) 对硬虱的保护传递了同源和异源挑战。我们相信这个项目， 在强有力的科学前提的支持下，解决了一个重大的公共卫生问题。这些目标是创新的。 因为我们将是第一个使用与生理相关的动物研究RMSF疫苗开发的小组- 蜱类病原体感染模型。我们应用程序的中心假设是WCA可防止致命 RMSF由血液和扁虱传播的感染引起，由地理上相距较远的病原体菌株引起，由 刺激一年或更长时间的免疫保护。本申请的具体目的是：1)评估 制备WCA的灭活方法和确定疫苗保护的佐剂。2)评估WCA 针对扁虱传播的挑战提供保护。3)评价WCA对异源立克次体的保护作用 菌株感染挑战。在这个项目结束时，我们希望我们的努力将转化为 开发了疫苗，在已知的自然感染立克次体的动物模型中有效 从感染的扁虱导致危及生命的RMSF。我们相信，实现这一应用程序的目标将 为在不久的将来扩大疫苗研究以保护人们免受这种致命疾病的影响铺平道路。

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.