Advancement of a Defined, Protective, Live Attenuated Tularemia Vaccine

描述（由申请人提供）：2001年在美国发生的炭疽生物恐怖袭击使人们认识到生物武器袭击的潜在破坏性影响，并认识到需要为未来可能发生的邪恶事件做好准备。F.土拉热是一种剧毒生物体，在吸入少至10-100种生物体后可在人类中引起严重和致命的疾病。它有几个国家将其武器化的历史，是A类特选物剂，是制定对策的最高优先事项之一。一种基于B型菌株的活疫苗菌株LVS在20世纪60年代被开发和测试，并赋予了对暴露于含有毒力A F型的气溶胶的部分保护。土拉热。同时提供了原理证明，活减毒F。虽然土拉菌疫苗可以保护，但LVS没有获得FDA的许可，并且具有使其成为次优土拉菌疫苗的几个显著缺点。文献支持A型菌株对A型攻毒的上级保护能力。我们已经设计了一种基于A型菌株SchuS 4的候选疫苗，该菌株在编码微生物代谢过程中的关键酶的aroD基因中含有未标记的精确定义的缺失。该疫苗在小鼠模型中高度减毒，并对极高攻毒剂量（1，000 CFU）的野生型（WT）A型菌株SchuS 4具有保护作用。这是首次报道的活的减毒F。土拉热疫苗能够保护免受这种规模的A型攻击。此外，在初步的兔子研究中，SchuS 4？aroD提供了对SchuS 4致死性气溶胶攻击的部分保护;在该模型中，这种保护水平上级LVS所赋予的保护水平。该疫苗株SchuS 4 <$aroD在小鼠模型中比LVS更减毒且更具保护性，在兔模型中更具保护性，这一事实支持其作为人用疫苗的成功潜力。我们建议使用小鼠和家兔模型进行一系列重点研究，以确认候选疫苗SchuS 4 <$aroD的安全性、稳定性和保护能力。在3个机构的合作研究者的实验室中进行的平行研究，具有在动物模型中评估弗朗西斯菌菌株的专门知识，将加快进展。我们的目标是积累足够的数据，以支持该候选产品过渡到高级开发阶段。高级开发将需要大量的资源承诺，如果没有本提案中概述的初步研究来证实该候选疫苗作为有效人用疫苗的潜力，则无法证明这些资源的合理性。

DESCRIPTION (provided by applicant): The anthrax bioterror attacks in the US in 2001, led to an awareness of the potentially devastating effects of attack with a bioweapon and the recognition of the need to prepare against possible future nefarious events. F. tularensis is a highly virulent organism that can cause severe and fatal disease in humans following inhalation of as few as 10-100 organisms. It has a history of weaponization by several countries and is a Category A select agent, one of six pathogens that are of highest priority for countermeasure development. One live vaccine strain, LVS, based on a type B strain, was developed and tested in the 1960's and conferred partial protection against exposure to aerosols containing virulent type A F. tularensis. While providing proof of principle that a live attenuated F. tularensis vaccine can protect, LVS is not licensed by the FDA and suffers from several notable drawbacks that render it a sub-optimal tularemia vaccine. The literature supports the superior protective capacity of type A strains against type A challenge. We have engineered a vaccine candidate based on type A strain SchuS4, that contains an unmarked precisely defined deletion in the aroD gene encoding a critical enzyme in microbial metabolic processes. This vaccine is highly attenuated in the mouse model and was protective against a very high challenge dose (1,000 CFU) of wild type (WT) type A strain SchuS4. This is the first report of a live attenuated F. tularensis vaccine capable of protecting against a type A challenge of this magnitude. Furthermore, in preliminary rabbit studies SchuS4¿aroD provided partial protection against a lethal aerosol challenge with SchuS4; this level of protection was superior to that conferred by LVS in this model. The fact that this vaccine strain, SchuS4¿aroD, is more attenuated and more protective than LVS in the mouse model and more protective in the rabbit model supports its potential for success as a human vaccine. We are proposing to perform a set of focused studies to confirm the safety, stability, and protective capacity of the candidate vaccine, SchuS4¿aroD, using the mouse and rabbit models. Parallel studies in the laboratories of collaborating investigators at 3 institutions, with specific expertise in the evaluation of Francisella strains i animal models, will accelerate progress. Our goal is to accumulate sufficient data to support transition of this candidate to advanced development. Advanced development will require a substantial commitment of resources that cannot be justified without the preliminary studies outlined within this proposal to substantiate the potential of this candidate as an efficacious human vaccine.