Preclinical Development of a Tularemia Vaccine

描述（由申请人提供）：土拉热弗朗西丝菌是一种革兰氏阴性细胞内细菌，能够在包括人类在内的许多哺乳动物中引起致死性全身性疾病（土拉菌病）。该细菌被广泛认为是已知的最危险的细菌病原体之一，因为其易于雾化、低感染剂量（ID 50 < 10个生物体）、多种感染途径、快速发病、严重的发病率和死亡率（如果不治疗，33%的人死亡率）以及需要BSL 3实验室操作。尽管有人担心故意使用F。由于土拉菌病是一种生物武器，目前还没有获得许可的土拉菌疫苗，并且对保护性免疫的相关性知之甚少。虽然目前正在计划对F.在土拉热病中，关于LVS回复到野生型毒力、免疫受损个体中的安全性以及针对气溶胶暴露的功效存在有充分记载的担忧。鉴于明确需要一种安全有效的兔热病疫苗，本提案的目标是在多种动物模型中测试源自细菌外膜囊泡（OMV）的新型无细胞（亚单位）疫苗制剂的有效性和安全性。在初步研究中，我们已经证明，OMV提供高达100%的保护，防止A型F。小鼠土拉菌肺攻击。因此，该提案将通过以下方式扩展这些发现：（1）评估OMV保护小鼠和大鼠免受A型F感染的能力。土拉热肺部感染;（2）评价OMV免疫小鼠和大鼠的安全性：（3）比较OMV和LVS对A型F的保护能力。（4）开发和测试新的重组蛋白疫苗制剂以保护免受A型F。土拉热菌肺攻击，基于定义OMV组分的最近数据;（5）表征由OMV免疫诱导的免疫应答;（6）表征保护免受和消除A型F所需的免疫应答。土拉热肺激发试验。综上所述，所提出的实验具有巨大的潜力，以推进铅兔热病疫苗制剂，并测试针对A型F的新疫苗制剂的安全性和有效性。土拉热肺激发试验。 公共卫生相关声明：土拉热弗朗西斯菌（土拉菌病）已被列为A类选择剂，这表明它可以被用作生物武器，造成大量人员死亡。由于目前没有疫苗被许可用于人类，因此开发新的疫苗配方仍应是国家的优先事项。本提案中概述的项目旨在推进一种领先的兔热病候选疫苗，并测试新疫苗制剂的有效性和安全性。

DESCRIPTION (provided by applicant): Francisella tularensis is a Gram-negative intracellular bacterium capable of causing fatal systemic disease (tularemia) in a number of mammals, including humans. The bacterium is widely recognized as one of the most dangerous bacterial pathogens known because of its ease of aerosolization, low infectious dose (ID50 < 10 organisms), multiple routes of infection, rapid disease onset, severe morbidity and mortality (33% human mortality rate if left untreated), and requirement for BSL3 laboratory manipulation. Despite concerns over the deliberate use of F. tularensis as a biological weapon, a licensed tularemia vaccine is not currently available and little is known about the correlates of protective immunity. Although phase 2 clinical trials are currently being planned for the live vaccine strain (LVS) of F. tularensis, there are well-documented concerns about LVS reversion to wild-type virulence, safety in immunocompromised individuals, and efficacy against an aerosol exposure. Given the clear need for a safe and effective tularemia vaccine, the goals of this proposal are to test the efficacy and safety of new acellular (subunit) vaccine formulations, derived from bacterial outer membrane vesicles (OMVs), in multiple animal models. In preliminary studies, we have demonstrated that OMVs provide up to 100% protection against Type A F. tularensis pulmonary challenge in mice. As such, this proposal will extend those findings by: (1) Evaluating the ability of OMVs to protect mice and rats from Type A F. tularensis pulmonary infection; (2) Evaluating the safety of OMV immunization in mice and rats; (3) Comparing the protective capacity of OMVs and LVS against Type A F. tularensis pulmonary challenge; (4) Developing and testing new recombinant protein vaccine formulations to protect against Type A F. tularensis pulmonary challenge, based upon recent data defining the components of OMVs; (5) Characterizing the immune responses induced by OMV immunization; (6) Characterizing the immune responses required to protect against and eliminate Type A F. tularensis pulmonary challenge. Taken together, the proposed experiments have enormous potential to advance a lead tularemia vaccine formulation and to test the safety and efficacy of new vaccine formulations against Type A F. tularensis pulmonary challenge. PUBLIC HEALTH RELEVANCE STATEMENT: Francisella tularensis (tularemia) has been classified as a Category A Select Agent, indicating that it could be used as a biological weapon with substantial loss of human life. Because no vaccine is currently licensed for human use, the development of new vaccine formulations should remain a national priority. The projects outlined in this proposal seek to advance a lead tularemia vaccine candidate and test new vaccine formulations for efficacy and safety.