Rocky Mountain Spotted Fever Vaccine Development

落基山斑疹热疫苗开发

• 批准号: 10814647
• 负责人: ROMAN R. GANTA
• 金额: $ 75.61万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10814647
• 关键词: Rocky; Mountain; Spotted; Fever; Vaccine

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.

项目概要： 无形体、埃利希体和立克次体属的蜱传播立克次体病仍在不断增长 美国和世界许多地区的公共卫生问题。这些疾病包括已知最古老的疾病之一 立克次体疾病，由立克次体引起的落基山斑疹热 (RMSF)。 RMSF 仍然是 人类的严重疾病，并且仍然是美国和一些北部、中部地区的公共卫生问题 和南美国家。 RMSF 的临床症状包括发烧、头痛、恶心、呕吐、肌肉酸痛 疼痛、食欲不振和皮疹。如果未经治疗，这种疾病可能会迅速发展为危及生命的疾病 导致患者死亡率高达30-80%。据 RMSF 报道，在过去的二十年里 北美部分地区的病例继续上升。蜱传疾病（TBD）需要人类的相互作用， 蜱虫和宿主动物宿主。我们相信，开发疫苗来预防这种疾病是可以的 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 具有共同广泛的研究兴趣。由于狗会患上与人类相似的疾病，因此需要疫苗来预防 该宿主体内的疾病很可能有效控制野生动物、蜱虫等疾病的传播 从狗到人的感染。我们最近测试了两种实验疫苗；亚单位疫苗， 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 提供针对剧毒立克次氏立克次体感染挑战的保护。 WCA 提供全面的保护 RMSF，而 RCA 没有。这项先前发表的工作为拟议的研究提供了强有力的科学前提 详细调查。特别是，我们的目标是在确定 A) 持续时间时进一步表征 WCA 保护，B) 佐剂在定义保护中的作用，C) 观察到的免疫反应类型，以及 D) 防止蜱传播同源和异源挑战。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。目标具有创新性 因为我们将是第一个使用生理相关动物来研究 RMSF 疫苗开发的小组 - 蜱病原体感染模型。我们应用程序的中心假设是 WCA 可以防止致命的 RMSF 由血液和蜱传感染引起，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 用于制备 WCA 和佐剂的灭活方法，以定义疫苗的保护作用。 2）评估WCA 防止蜱虫传播的挑战。 3) 评估 WCA 对异源立克次体的保护作用 菌株感染的挑战。在该项目结束时，我们期望我们的努力将转化为全面的成果 开发出疫苗，该疫苗在已知自然感染立克次体感染的动物模型中有效 来自受感染的蜱虫，导致危及生命的 RMSF。我们相信，实现该应用程序的目标将 为扩大疫苗研究铺平道路，以在不久的将来保护人们免受这种致命疾病的侵害。