Optimizing vaccine science to improve the outcome of tuberculosis treatment

项目摘要 由致病菌结核分枝杆菌（Mycobacterium tuberculosis，Mtb）引起的结核病（tuberculosis，TB）正在引起严重的结核病。 发病率和死亡率。减毒活M.牛卡介苗（BCG）， 是目前世界卫生组织批准用于人类的唯一结核病疫苗。虽然BCG 预防儿童的严重疾病，但疗效不一，不能预防成人的肺结核， 是结核病在社区传播的主要来源。此外，BCG还可引起免疫系统疾病- 受感染的个体，如合并感染艾滋病毒的个体。控制活动性疾病的发展， 为了打破结核病的传播链，迫切需要一种新的、更安全和更有效的疫苗接种方法。 必需的. "范式转变"结核病保护措施的发展将得到以下方面的极大帮助： 安全有效的组合平台的优化，例如将新型疫苗与辅助物整合 宿主导向疗法（HDT）和/或抗分枝杆菌药物。这一战略旨在诱导适当的 先天免疫沿着强有力和持久的T细胞反应，这两者对于有效控制是必要的 结核病迫切需要这种综合方法来控制活动性空洞性结核病例的病理学， Mtb的传播，以及防止潜伏感染个体的重新激活，估计大约 世界人口的四分之一，他们感染了结核病，大多数没有症状，但可以重新激活疾病 免疫抑制后。相关动物模型的选择和使用， 在人类中观察到的空洞性结核病的病理生理学对于筛选新的和更好的干预策略至关重要， 包括强效疫苗和候选药物。我们建立了一个兔子模型， 气溶胶结核分枝杆菌感染，模仿肺结核的人类表现的范围，从空洞 （传染性）疾病潜伏感染。Subbian博士建立了一个空洞结核病的兔子模型， 作为副奖PI，Kupz博士开发了一种易于处理和可重复的小鼠模型来研究 在HIV共感染个体中发生的CD4 + T细胞损失后潜伏性Mtb感染的动力学。 使用这两个模型，我们建议确定一种新的重组BCG菌株（BCG：：ESAT-1）的能力。 Kupz博士实验室开发的6-PE25SS），与mTOR抑制剂（依维莫司）和/或两种一线 抗生素，异烟肼和利福平，以防止进展为空洞性TB（兔）和/或诱导 潜伏期杀菌免疫（小鼠）。为了比较我们的方法，我们将在这些 模型动物我们还将定义粘膜（肺）和全身（血液）免疫参数， 在我们的模型系统中针对Mtb挑战的保护。这些研究的结果有助于 开发新一代疫苗平台，用于靶向除Mtb之外的其他细胞内病原体。

Project Summary Tuberculosis (TB), caused by pathogenic bacteria Mycobacterium tuberculosis (Mtb), is causing significant morbidity and mortality to humans across the world. Live, attenuated M. bovis Bacillus Calmette-Guérin (BCG), is the only TB vaccine currently licensed by the World Health Organization for use in humans. Although BCG prevents severe disease in children with variable efficacy, it fails to protect against pulmonary TB in adults, who are the primary source of transmission of Mtb in the community. Moreover, BCG may cause disease in immune- compromised individuals, such as those co-infected with HIV. To control the development of active disease and to break the chain of Mtb transmission, a new, safer and more effective vaccination approach is urgently required. The development of “paradigm-shifting” protective measures against TB will significantly be aided by the optimization of safe and effective combinatorial platforms, such as integrating novel vaccines with adjunct host-directed therapy (HDT) and/or antimycobacterial drugs. This strategy is aimed at inducing appropriate innate immunity along with potent and durable T cell responses, both of which are necessary for effective control of TB. Such an integrated approach is urgently needed to control the pathology of active, cavitary TB cases and transmission of Mtb, as well as to prevent reactivation of latently infected individuals, estimated to be about a quarter of the world population, who are Mtb-infected and mostly asymptomatic but can reactivate the disease upon immune suppression. Selection and usage of a relevant animal model that recapitulates the pathophysiology of cavitary TB, as seen in humans is vital to screen novel and better intervention strategies to combat the disease, including potent vaccine and drug candidates. We have established a rabbit model of aerosol Mtb infection that mimics the range of human manifestations of pulmonary TB, from cavitary (transmissible) disease to latent infection. Dr. Subbian has established a rabbit model of cavitary TB and the sub-award PI, Dr. Kupz has developed a tractable and reproducible mouse model to study the reactivation dynamics of latent Mtb infection following the loss of CD4+ T cells as it occurs in HIV co-infected individuals. Using these two models, we propose to determine the ability of a novel recombinant BCG strain (BCG::ESAT- 6-PE25SS developed in Dr. Kupz lab), in combination with mTOR inhibitor (everolimus) and/or two first-line antibiotics, isoniazid and rifampicin, to protect against progression to cavitary TB (rabbit) and/or induce sterilizing immunity in latency (mice). To compare our approach, we will test individual components in these model animals. We will also define mucosal (lung) and systemic (blood) immune parameters that predict protection against Mtb challenge in our model system. The results of these studies can contribute towards the development of new generation vaccine platforms for targeting other intracellular pathogens, in addition to Mtb.