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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

基本信息

批准号：
10629347
负责人：
Selvakumar Subbian
金额：
$ 58.02万
依托单位：
RUTGERS BIOMEDICAL AND HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-17 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10629347
关键词：
Adult Aerosols Animal Model Antibiotics Antimycobacterial Agents Attenuated Attenuated Vaccines BCG Live 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 Licensing 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 Recurrent disease 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 co-infection combat combinatorial drug candidate immune modulating agents immunogenic immunogenicity improved improved outcome isoniazid latent infection mTOR Inhibitor mortality mouse model novel novel vaccines pathogen pathogenic bacteria pre-clinical prevent protective efficacy reactivation from latency recurrent infection response therapeutic vaccine therapy duration transmission process tuberculosis drugs tuberculosis treatment vaccine candidate vaccine evaluation vaccine platform

项目摘要

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.

项目摘要由致病细菌结核分枝杆菌(Mtb)引起的结核病(TB)正在造成严重的世界各地对人类的发病率和死亡率。活的，减毒的牛卡介苗(BCG)，是目前唯一获得世界卫生组织许可用于人类的结核病疫苗。虽然卡介苗在儿童中预防严重疾病的效果各不相同，但它无法预防成人的肺结核病，是该社区结核分枝杆菌的主要传播源。此外，卡介苗可能会导致免疫性疾病- 受感染的个人，例如那些共同感染艾滋病毒的人。控制活动性疾病的发展，为了打破结核分枝杆菌的传播链条，迫切需要一种新的、更安全和更有效的疫苗接种方法。必填项。针对结核病的“范式转换”保护措施的发展将得到以下重大帮助优化安全有效的组合平台，如将新型疫苗与辅助物整合宿主导向治疗(HDT)和/或抗分枝杆菌药物。这一战略的目的是诱导适当的先天免疫以及强大和持久的T细胞反应，这两者都是有效控制所必需的结核病的风险。迫切需要这样一种综合办法来控制活动性空洞性结核病病例的病理。传播结核分枝杆菌，以及防止潜伏感染的人重新激活，估计约为世界上四分之一的人口，他们感染了结核分枝杆菌，大多数人没有症状，但可以重新引发疾病在免疫抑制上。相关动物模型的选择和使用人类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是至关重要的抗击这种疾病，包括有效的疫苗和候选药物。我们已经建立了兔的动物模型。气溶胶结核分枝杆菌感染，与人类肺结核病的表现范围相似，从空洞性 (可传播的)疾病到潜伏感染。Subbian博士已经建立了一个空洞性结核病的兔模型， Kupz博士开发了一种易于处理和可重现的小鼠模型来研究再激活 HIV混合感染者中发生的CD4+T细胞丢失后潜伏的结核分枝杆菌感染的动态变化。利用这两个模型，我们提出了一种新的重组卡介苗菌株(BCG：：ESAT-)的能力。 6-PE25SS由Kupz博士实验室开发)，与mTOR抑制剂(依维莫司)和/或两个一线药物联合使用抗生素、异烟肼和利福平，以防止进展为空洞性结核病(兔)和/或诱导潜伏期(小鼠)的绝育免疫力。为了比较我们的方法，我们将测试这些组件中的各个组件模范动物。我们还将定义粘膜(肺)和系统(血液)免疫参数，以预测在我们的模型系统中针对Mtb挑战的保护。这些研究的结果可以有助于开发针对除结核分枝杆菌外的其他细胞内病原体的新一代疫苗平台。