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，导致人们意识到使用生物武器攻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。土拉菌是一种毒性很强的生物，只要吸入10-100个菌体，就可导致人类患上严重和致命的疾病。它有被几个国家武器化的历史，是一种a类选定剂，是六种最优先开发对策的病原体之一。一种以B型菌株为基础的活疫苗LVS在20世纪60年代被开发和测试，并对暴露于含有毒力强的a型土拉菌的气溶胶具有部分保护作用。虽然提供了土拉菌减毒活疫苗具有保护作用的原理证明，但LVS没有获得FDA的许可，并且存在一些明显的缺陷，使其成为一种次优的土拉菌病疫苗。文献支持A型菌株对A型挑战的优越保护能力。我们设计了一种基于a型菌株SchuS4的候选疫苗，该疫苗在编码微生物代谢过程中关键酶的aroD基因中含有未标记的精确定义缺失。该疫苗在小鼠模型中是高度减毒的，并且对野生型（WT） a型菌株SchuS4的高攻毒剂量（1,000 CFU）具有保护作用。这是首次报道能够抵御如此严重的a型挑战的土拉菌减毒活疫苗。此外，在初步的家兔研究中，SchuS4¿aroD对SchuS4的致命气溶胶攻击提供了部分保护；这种保护水平优于该模型中LVS所赋予的保护水平。事实上，这种疫苗株，SchuS4¿aroD，在小鼠模型中比LVS更弱，更有保护作用，在兔模型中更有保护作用，这支持了它作为人类疫苗成功的潜力。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SchuS4¿aroD的安全性、稳定性和保护能力。在3个机构的合作研究人员的实验室中进行的平行研究将加速进展，这些研究人员在动物模型中具有评估Francisella菌株的专门知识。我们的目标是积累足够的数据来支持该候选药物向高级开发的过渡。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这种候选疫苗作为一种有效的人用疫苗的潜力，这些资源是不合理的。

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.