Development of a Self Inactivating, Highly Effective TB Vaccine

摘要 结核病仍然是世界范围内发病和死亡的主要原因， 死亡原因是由于单一的传染性病原体，结核分枝杆菌。大多数国家还 为新生儿接种唯一获得许可的结核病疫苗--卡介苗 (BCG)一种减毒的牛分枝杆菌该疫苗是在一个 世纪前，虽然被广泛使用，但功效有限。BCG皮内给药（ID） 确实可以保护婴儿免受结核病最严重的表现，但 可变（0-80%）预防肺结核。我们最近在非人类灵长类动物中的数据 （恒河猴）证明通过静脉内（IV）途径递送的BCG提供 在90%的猕猴中具有灭菌或接近灭菌的保护作用（细菌感染减少> 10，000倍）， 总体负担），而ID BCG在该模型中几乎没有提供保护。然而，即使交付 减毒活疫苗造成了潜在的安全问题，特别是在免疫受损的情况下， 科目在这个提议中，我们的目标是构建自失活的BCG菌株，使用 几种创新的分子方法。这样的菌株只会持续很短的时间， 在体内，可能会通过不同的机制死亡。我们将构建和表征BCG 体外自灭活菌株（目的1），评估在小鼠中的持久性和免疫原性 模型，然后确定卡介苗亚组的持久性，免疫原性和保护性 在易感的非人灵长类动物模型（恒河猴）中的菌株。已发表的数据表明 IV BCG在猕猴中观察到的强有力的保护作用在小鼠中没有重现， 需要在猕猴中进行测试。我们将使用先进的技术来建造 菌株，评估免疫应答和细菌负荷，以及PET CT成像， 跟踪保护。该提案基于Multi-PI团队在分枝杆菌方面的经验 遗传学、免疫学和动物模型，目标是开发一种更安全的结核病疫苗， 交付.

Abstract Tuberculosis remains a major cause of morbidity and mortality worldwide, and is the leading cause of death due to a single infectious agent, Mycobacterium tuberculosis. Most countries still vaccinate newborns with the only licensed vaccine against tuberculosis, Bacille Calmette Guerin (BCG) an attenuated version of Mycobacterium bovis. The vaccine was developed over a century ago and, although widely used, has limited efficacy. BCG delivered intradermally (ID) does provide protection against the worst manifestations of tuberculosis in infants but has variable (0-80%) protection against pulmonary TB. Our recent data in non-human primates (rhesus macaques) demonstrate that BCG delivered by the intravenous (IV) route provides sterilizing or near sterilizing protection in 90% of macaques (>10,000 fold reduction in bacterial burden overall), while ID BCG provides little protection in this model. However, delivery of even an attenuated live vaccine poses potential safety issues, particularly in immune compromised subjects. In this proposal, we aim to construct BCG strains that are self-inactivating, using several innovative molecular approaches. Such strains would persist only for a short time in vivo, and would likely die by different mechanisms. We will construct and characterize the BCG self-inactivating strains in vitro (Aim 1), assess persistence and immunogenicity in a murine model, and then determine persistence, immunogenicity and protection of a subset of BCG strains in a susceptible non-human primate model (rhesus macaques). Published data indicate that the robust protection seen by IV BCG in macaques is not recapitulated in mice, which necessitates testing in macaques. We will use sophisticated technology for construction of strains, assessment of immune responses and bacterial burden, and PET CT imaging for tracking protection. This proposal builds on the experience of the Multi-PI team in mycobacterial genetics, immunology, and animal models, with the goal of developing a safer TB vaccine for IV delivery.