Optimizing vaccine science to improve the outcome of tuberculosis treatment

优化疫苗科学以改善结核病治疗效果

• 批准号: 10434012
• 负责人: Selvakumar Subbian
• 金额: $ 59.09万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-17 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10434012
• 关键词: Adult; Aerosols; Animal Model; Antibiotics; Antimycobacterial Agents; Attenuated; Attenuated Vaccines; Award; BCG Live; BCG Vaccine; Biological Models; Blood; CD4 Positive T Lymphocytes; Cells; Child; Clinical; Clinical Trials; Communities; Containment; Development; Disease; Functional disorder; Generations; HIV; Health; Human; Immune; Immunity; Immunocompetent; Immunocompromised Host; Immunomodulators; Immunosuppression; Individual; Intervention; Lung; Measures; Memory; Modeling; Morbidity - disease rate; Mucous Membrane; Mus; Mycobacterium bovis; Mycobacterium tuberculosis; Mycobacterium tuberculosis antigens; Natural Immunity; Oryctolagus cuniculus; Pathogenicity; Pathologic; Pathology; Pharmaceutical Preparations; Pharmacotherapy; Population; Pre-Clinical Model; Pulmonary Tuberculosis; Recombinant Vaccines; Recombinants; Recurrence; Regimen; Reproducibility; Rifampin; Role; SDZ RAD; Safety; Science; Source; T cell response; Testing; Therapeutic; Training; Treatment outcome; Tuberculosis; Tuberculosis Vaccines; Vaccination; Vaccines; Virulence; World Health Organization; active control; adaptive immunity; base; co-infection; combat; combinatorial; drug candidate; immunogenic; immunogenicity; improved; improved outcome; isoniazid; latent infection; mTOR Inhibitor; mortality; mouse model; novel; novel vaccines; pathogen; pathogenic bacteria; pre-clinical; prevent; protective efficacy; rBCG; reactivation from latency; recurrent infection; response; therapeutic vaccine; therapy duration; transmission process; tuberculosis drugs; tuberculosis treatment; vaccine candidate; vaccine evaluation; vaccine platform

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.

项目概要 结核病 (TB) 由致病菌结核分枝杆菌 (Mtb) 引起，导致严重的 世界各地人类的发病率和死亡率。活的减毒牛支原体卡介苗 (BCG)， 是目前世界卫生组织许可用于人类的唯一结核病疫苗。虽然卡介苗 它可以预防儿童的严重疾病，但效果参差不齐，但无法预防成人的肺结核。 是社区结核病的主要传播源。此外，卡介苗可能会导致免疫疾病 受影响的个人，例如同时感染艾滋病毒的人。控制活动性疾病的发展和 为了打破结核分枝杆菌传播链，迫切需要一种新的、更安全、更有效的疫苗接种方法 必需的。 “转变范式”的结核病保护措施的制定将得到极大的帮助 优化安全有效的组合平台，例如将新型疫苗与辅助药物相结合 宿主定向治疗（HDT）和/或抗分枝杆菌药物。该策略旨在诱导适当的 先天免疫以及有效且持久的 T 细胞反应，两者都是有效控制所必需的 结核病。迫切需要这种综合方法来控制活动性空洞结核病例和 结核分枝杆菌的传播，以及防止潜伏感染者的重新激活，估计约为 世界人口的四分之一感染了结核分枝杆菌，大多数人没有症状，但可以使疾病重新激活 当免疫抑制时。选择和使用能够概括的相关动物模型 人类空洞结核的病理生理学对于筛选新颖且更好的干预策略至关重要 对抗这种疾病，包括有效的疫苗和候选药物。我们建立了兔子模型 气溶胶结核分枝杆菌感染，模仿人类肺结核的一系列表现，包括空洞 （传染性）疾病到潜伏感染。 Subbian 博士建立了兔子空洞性结核病模型 作为子奖 PI，Kupz 博士开发了一种易于处理且可重复的小鼠模型来研究重新激活 HIV 共感染个体中 CD4+ T 细胞丢失后潜伏 Mtb 感染的动态。 使用这两个模型，我们建议确定新型重组 BCG 菌株（BCG::ESAT- 6-PE25SS（由 Kupz 博士实验室开发），与 mTOR 抑制剂（依维莫司）和/或两种一线药物联合使用 抗生素、异烟肼和利福平，以防止进展为空洞结核（兔）和/或诱导 消除潜伏期的免疫力（小鼠）。为了比较我们的方法，我们将测试这些中的各个组件 模型动物。我们还将定义预测粘膜（肺）和全身（血液）免疫参数 在我们的模型系统中防止 Mtb 挑战。这些研究的结果可以有助于 开发针对除 Mtb 之外的其他细胞内病原体的新一代疫苗平台。