Genetically Defined Attenuated Living Vaccine for Francisella

描述（由申请人提供）：土拉菌病是一种严重的，有时是致命的疾病，由土拉弗朗西斯菌感染引起。这些细菌是一些已知的最致命的病原体，需要接种或吸入少至10个生物体才能引起疾病。感染可以通过多种方式获得：节肢动物媒介叮咬、皮肤损伤、摄入受污染的食物或水，或吸入雾化颗粒。它的低感染剂量和相对容易的空气传播导致了F。土拉热病毒被几个国家的武器计划用作生物武器。因为它对国家安全构成严重威胁，疾病控制中心（CDC）将F。土拉菌作为A类选择剂。尽管有这些标准，但没有批准的兔热病疫苗。本文所述研究的目的是构建针对兔热病的合理减毒活疫苗。我们将建立在我们以前发现的F.兔热病，其突变衍生物在小鼠中提供针对野生型攻击的保护。这些基因将在最毒力的微生物亚种中单独或组合缺失，从而产生减毒、非回复性、确定的菌株，这些菌株不指定抗生素耐药性。在确认这些菌株保护小鼠免受野生型攻击后，我们建议在非人灵长类动物模型中测试疫苗，这是获得FDA批准的必要步骤。土拉菌病是一种严重的，有时是致命的疾病，由土拉弗朗西斯菌感染引起。它的低感染剂量和相对容易的空气传播导致了F。土拉热病毒被几个国家的武器计划用作生物武器。由于没有批准的兔热病疫苗，我们寻求开发一种兔热病减毒活疫苗。

DESCRIPTION (provided by applicant): Tularemia is the severe and sometimes fatal disease caused by infection with Francisella tularensis. These bacteria are some of the most virulent pathogens known, requiring inoculation or inhalation with as few as 10 organisms to cause disease. Infections can be acquired in a variety of ways: bites from an arthropod vector, skin lesions, ingestion of contaminated food or water, or inhalation of aerosolized particles. Its low infectious dose and relative ease of airborne transmission led to the development of F. tularensis as a biological weapon by several national weapons programs. Because it presents a serious threat to national security, the Centers for Disease Control (CDC) classify F. tularensis as a category A select agent. Despite these criteria, there is no approved tularemia vaccine. The goal of the research described herein is to construct a rationally attenuated living vaccine against tularemia. We will build upon our previous discovery of genes required for virulence in F. tularemia, mutant derivatives of which provide protection against wild-type challenge in mice. These genes will be deleted, individually and in combinations, in the most virulent subspecies of the organism, resulting in attenuated, non-reverting, defined strains that do not specify antibiotic resistance. After confirming that these strains protect mice against wild-type challenge, we propose to test the vaccines in a non-human primate model, a necessary step to achieving FDA approval. Tularemia is the severe and sometimes fatal disease caused by infection with Francisella tularensis. Its low infectious dose and relative ease of airborne transmission led to the development of F. tularensis as a biological weapon by several national weapons programs. As there is no approved tularemia vaccine, we seek to develop a live attenuated tularemia vaccine.