Development of a Self Inactivating, Highly Effective TB Vaccine

摘要 结核病仍然是全世界发病率和死亡率的主要原因，并且是主要原因。 死因是一种单一的传染病，结核分枝杆菌。大多数国家仍然 给新生儿接种唯一获得许可的结核病疫苗--卡介苗 (卡介苗)牛分枝杆菌的减毒版本。这种疫苗是在一年多的时间里开发出来的 虽然广泛使用，但疗效有限。卡介苗皮内注射(ID) 确实对婴儿中最严重的结核病表现提供了保护，但 对肺结核的可变(0-80%)保护。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(IV)途径递送的卡介苗提供 对90%的猕猴进行灭菌或接近灭菌保护(细菌减少10,000倍 整体负担)，而ID BCG在这一模型中提供的保护很少。然而，Even的交付 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 研究对象。在这项建议中，我们的目标是构建自灭活的卡介苗菌株，使用 几种创新的分子方法。这样的压力只会持续很短的时间 活体，很可能会因不同的机制而死亡。我们将构建和表征卡介苗 体外自灭活菌株(AIM 1)，评估小鼠的持久性和免疫原性 模型，然后确定卡介苗子集的持久性、免疫原性和保护性 敏感的非人类灵长类动物模型(恒河猴)中的菌株。公布的数据表明 静脉注射卡介苗在猕猴身上看到的强大保护作用并没有在小鼠身上重现，这 有必要在猕猴身上进行测试。我们将使用尖端技术建造 菌株，免疫反应和细菌负荷的评估，以及PET CT成像 跟踪保护。这项建议建立在多PI团队在分枝杆菌方面的经验基础上 遗传学、免疫学和动物模型，目标是开发一种更安全的IV结核病疫苗 送货。

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.