Preclinical Development of a Tularemia Vaccine

描述（由申请人提供）：土拉菌弗朗西斯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命的全系统疾病（土拉菌病）。该细菌被广泛认为是已知最危险的细菌性病原体之一，因为它易于雾化，感染剂量低（ID50 < 10个生物体），感染途径多，发病迅速，发病率和死亡率高（如果不及时治疗，人类死亡率为33%），并且需要BSL3实验室操作。尽管人们对故意使用土拉菌病作为生物武器感到担忧，但目前还没有获得许可的土拉菌病疫苗，而且对保护性免疫的相关性知之甚少。尽管目前正在计划对土拉菌病活疫苗株（LVS）进行2期临床试验，但有充分证据表明，人们担心LVS的毒力会恢复到野生型，对免疫功能低下个体的安全性以及对气溶胶暴露的有效性。鉴于对安全有效的兔热病疫苗的明确需求，本提案的目标是在多种动物模型中测试来自细菌外膜囊泡（omv）的新型脱细胞（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对小鼠的A型土拉菌肺攻击提供高达100%的保护。因此，本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型土拉菌肺部感染的能力；(2)评价OMV免疫小鼠和大鼠的安全性；(3)比较omv和LVS对A型土拉菌肺攻击的保护能力；(4)根据最近确定omv成分的数据，开发和测试新的重组蛋白疫苗配方，以防止A型土拉菌肺攻击；(5) OMV免疫诱导的免疫应答特征；(6)表征保护和消除A型土拉菌肺攻击所需的免疫反应。总的来说，拟议的实验具有巨大的潜力，可以推进一种铅土拉菌病疫苗制剂，并测试针对a型土拉菌肺攻击的新疫苗制剂的安全性和有效性。

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.