Advancement of F. tularensis live attenuated typed A vaccine strains

图拉氏丝孢子菌是一种A类选择因子，如果 吸入含有10-100个CPU的气雾剂。事实上，在过去的几年里，有几个国家将F。 作为一种可能的生物武器。出于这些原因，它现在被认为是一个潜在的 生物恐怖毒剂，是制定对策的优先事项。一种活疫苗株LVS，基于 生物型B型毒株是在1950年的S和1960年的S期间培育和测试的，并对 暴露在含有野生型A型毒力图拉氏菌的气雾剂中。在提供原则证据的同时， 一种图拉氏弗氏杆菌减毒活疫苗可以保护，LVS没有得到FDA的许可，并患有几种 显著的缺点使其成为次优的图拉热病疫苗。最佳的活疫苗将基于 将精确定义的减毒突变引入A型毒力亲本菌株，并将赋予强大的 防止暴露于A型图拉氏菌的雾化毒力。在目前的Marce资金范围内 在这个周期中，我们开发了基因工具来产生A型和B型土拉氏菌的特异性靶向突变。 确定了多个独立的基因座，当灭活时呈现A型原型菌株SchuS4， 在小鼠模型中是无毒的。在本次拨款申请中，我们将完成一系列双人楼的建设 突变菌株，每个都包含两个独立的减毒突变。与Dr合作。 Stefan ie Vogel的实验室将对疫苗株诱导先天和适应性反应进行评估 巨噬细胞感染后，为了筛选出最有希望的菌株进入动物体内 学习。最佳候选疫苗将通过一系列系统的临床前兔子研究取得进展 评估它们的安全性、免疫原性和抵御野生型气雾剂攻击的能力 与SchuS4合作(与UMB和匹兹堡大学RBL的研究人员合作)。 这些工作的完成将导致确定一种活的减毒Ft疫苗候选者(S)准备好 人类临床安全性和免疫原性研究及非人类灵长类动物疗效研究进展 对抗恶毒的挑战。

F. tularensis is a Category A select agent that can cause severe and fatal disease in humans if an aerosol containing as few as 10-100 CPU is inhaled. Indeed, in years past several countries weaponized F. tularensis for use as a possible biological weapon. For these reasons, it is now considered a potential bioterror agent and is a priority for countermeasure development. One live vaccine strain LVS, based on a biotype B strain, was developed and tested in the 1950's and 1960's and conferred partial protection against exposure to aerosols containing wild type 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. An optimal live vaccine will be based on introducing precisely defined attenuating mutations into a virulent Type A parent strain and will confer strong protection against exposure to aerosolized virulent Type A F. tularensis. Within the current MARCE funding cycle, we developed genetic tools to produce specifically targeted mutations in Type A and B F. tularensis. Multiple separate loci were identified that when inactivated render the prototype Type A strain, SchuS4, avirulent in a mouse model. In this grant application we will complete the construction of a series of double mutant strains, each containing two independently attenuating mutations. Working in collaboration with Dr. Stefanie Vogel's lab the vaccine strains will be evaluated for induction of innate and adaptive responses following infection of macrophages, in order to downselect the most promising strains to advance to animal studies. The optimal vaccine candidates will progress through a series of systematic preclinical rabbit studies to assess their safety, immunogenicity and capacity to protect against a against wild type aerosol challenge with SchuS4 (in collaboration with investigators at UMB and the University of Pittsburgh RBL). Completion of these will result in the identification of a live attenuated Ft vaccine candidate(s) ready to advance to human clinical studies of safety and immunogencity and non human primate studies of efficacy against virulent challenge.