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.

项目摘要 致病细菌结核病（MTB）引起的结核病（TB）正在引起显着 全世界人类的发病率和死亡率。活着的，减弱的M. bovis bacillus calmette-guérin（BCG）， 是世界卫生组织目前唯一的结核病疫苗用于人类使用。虽然BCG 防止效率可变的儿童的严重疾病，它无法预防成年人中的肺结核 是MTB在社区中传播的主要来源。此外，BCG可能导致免疫中的疾病 受损的个体，例如与艾滋病毒共同感染的人。控制主动疾病的发展和 为了打破MTB传输的链，一种新的，更安全，更有效的疫苗方法是紧急的 必需的。针对结核病的“范式移动”保护措施的发展将大大帮助 优化安全有效的组合平台，例如将新型疫苗与辅助疫苗相结合 宿主定向治疗（HDT）和/或抗菌药物。该策略旨在适当 先天免疫以及潜在耐用的T细胞反应，这两者都是有效控制的必要条件 结核病。迫切需要这种综合方法来控制主动的，腔TB病例的病理和 MTB的传播，以及防止受到潜在感染个体的重新激活，估计是 在全球的四分之一人口中，他们受到了MTB感染，主要是不对称的，但可以重新激活该疾病 免疫抑制。选择和使用相关的动物模型，该模型概括了 如人类中所见，穴位结核病的病理生理对于筛选小说和更好的干预策略至关重要 对抗该疾病，包括有效的疫苗和候选药物。我们已经建立了一个兔子模型 气溶胶MTB感染模仿了肺结核的人类表现范围 （可传染的）疾病对潜在感染。 Subbian博士已经建立了一个兔子结核的兔子模型和 亚雄性PI，Kupz博士开发了一种可拖动且可再现的小鼠模型来研究重新激活 在HIV共感染的个体中，CD4+ T细胞丧失后，潜在MTB感染的动力学。 使用这两个模型，我们建议确定新型重组BCG菌株的能力（BCG :: ESAT-- 6-PE25S在Kupz博士实验室中开发），结合MTOR抑制剂（依维莫司）和/或两条第一线 抗生素，异念珠菌和利福平，以防止进展为穴居结核（兔子）和/或影响 在潜伏期（小鼠）中对免疫进行灭菌。为了比较我们的方法，我们将在这些方法中测试单个组件 模型动物。我们还将定义粘膜（肺）和全身性（血液）免疫参数，以预测 在我们的模型系统中保护MTB挑战。这些研究的结果可能有助于 除MTB外，还开发了针对其他细胞内病原体的新一代疫苗平台。