Genetically Defined Attenuated Living Vaccine for Francisella

描述（由申请人提供）：土拉菌病是由土拉菌感染引起的严重且有时致命的疾病。这些细菌是已知的一些最致命的病原体，只需接种或吸入10种微生物即可引起疾病。感染可通过多种途径获得：被节肢动物媒介叮咬、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土拉菌被一些国家的武器计划发展为生物武器。由于它对国家安全构成严重威胁，美国疾病控制中心（CDC）将土拉菌杆菌列为a类精选病原体。尽管有这些标准，目前还没有批准的土拉菌病疫苗。本研究的目的是构建一种合理的兔热病减毒活疫苗。我们将建立在之前发现的土拉菌毒力所需基因的基础上，这些基因的突变衍生物可以保护小鼠免受野生型的攻击。这些基因将在最毒的细菌亚种中被单独或组合地删除，从而产生减毒的、不恢复的、没有特定抗生素耐药性的确定菌株。在确认这些菌株保护小鼠免受野生型攻击后，我们建议在非人类灵长类动物模型中测试疫苗，这是获得FDA批准的必要步骤。土拉菌病是一种由土拉菌感染引起的严重且有时致命的疾病。它的低感染剂量和相对容易的空气传播导致土拉菌被一些国家的武器计划发展为生物武器。由于没有批准的土拉菌病疫苗，我们寻求开发一种土拉菌病减毒活疫苗。

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.