Preclinical Development of a Tularemia Vaccine

描述(申请人提供)：图拉方济氏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身疾病(图拉热症)。这种细菌被广泛认为是已知的最危险的细菌病原体之一，因为它易于气雾化，感染量低(ID50和lt；10个生物体)，感染途径多，发病快，发病率和死亡率高(如果不治疗，人类死亡率为33%)，以及对BSL3实验室操作的要求。尽管人们对故意使用图拉氏丝虫作为生物武器感到担忧，但目前还没有获得许可的图拉热病疫苗，对保护性免疫的相关性也知之甚少。尽管目前正在计划对图拉氏丝虫活疫苗株(LVS)进行第二阶段临床试验，但人们对LVS回复到野生型毒力、对免疫受损个体的安全性以及对气雾剂暴露的有效性的担忧已经得到了充分的记录。鉴于对安全有效的兔热病疫苗的明确需求，这项提案的目标是在多种动物模型中测试新的脱细胞(亚单位)疫苗配方的有效性和安全性，这些疫苗来自细菌外膜泡囊(OMV)。在初步研究中，我们已经证明OMV对小鼠的A型图拉氏丝虫肺攻击提供了高达100%的保护。因此，这项建议将通过以下方式扩展这些发现：(1)评估OMVs保护小鼠和大鼠免受A型图拉氏丝虫肺部感染的能力；(2)评估OMV免疫在小鼠和大鼠中的安全性；(3)比较OMVs和LVS对A型图拉氏丝虫肺部感染的保护能力；(4)基于定义OMVs成分的最新数据，开发和测试新的重组蛋白疫苗配方，以保护A型土拉氏丝虫肺部感染；(5)表征OMV免疫诱导的免疫反应；(6)表征保护和消除A型图拉氏肺吸虫攻击所需的免疫反应。综上所述，拟议的实验在推进主导图拉热病疫苗配方和测试新疫苗配方对抗A型图拉氏菌肺炎的安全性和有效性方面具有巨大的潜力。 公共卫生相关声明：图拉氏方济氏菌(图拉热病)已被列为A类选择剂，表明它可能被用作生物武器，造成大量生命损失。由于目前没有疫苗被批准供人类使用，开发新的疫苗配方应该仍然是国家的优先事项。该提案中概述的项目寻求推进一种主要的兔热病候选疫苗，并测试新的疫苗配方的有效性和安全性。

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.