Durability of systemic and lung immune correlates of BCG-induced protection against M. tuberculosis infection

项目摘要 结核分枝杆菌（M.tb）在全世界造成的死亡人数比任何其他传染性病原体都多， 越来越多地表现为抗菌素耐药性。有效的疫苗接种策略，以防止建立 预防结核分枝杆菌感染并发展为结核病是实现全球结核病快速控制的优先事项。 结核病流行，但新疫苗的开发和临床试验因缺乏免疫相关因素而受到阻碍 保护。青少年重新接种唯一获得许可的结核病疫苗，卡介苗 (BCG)，部分预防已确定的结核分枝杆菌感染，为新型结核病提供了第一个疗效信号 高风险人群的疫苗接种策略。有一个一次性的机会来利用这个现有的队列，因为 以及一项更大规模的确证性2b期临床试验中新招募的参与者，以确定和测试 免疫相关的保护对建立结核分枝杆菌感染的肺，这可能是关键的港口 与外周血不同的免疫反应。 将采集血液和支气管肺泡灌洗标本，以鉴定和确定疫苗的寿命- 诱导的全身和肺部免疫应答与针对持续的结核分枝杆菌的保护相关 感染疫苗诱导的抗感染保护作用在接种后约6年的持久性也将 探讨了 新的和强大的技术，如多色流式细胞术，质谱仪和系统血清学将 应用于研究参加两项BCG疗效试验的参与者的适应性和先天性免疫反应， 接种疫苗后6个月和6年，以及原发性结核分枝杆菌感染后1个月和4-5年。的 总体假设是卡介苗接种诱导免疫系统的多臂， Th 1/Th 17和伊加应答的组合与建立的结核分枝杆菌感染的较低风险相关。 该方法将：1）鉴定和评估BCG介导的全身和肺部免疫应答的持久性。 结核分枝杆菌未感染个体的免疫应答; 2）确定结核分枝杆菌感染后的全身和肺部免疫相关性。 在经历短暂性（受保护）的受试者中，结核分枝杆菌暴露保护免受结核分枝杆菌感染 或持续（无保护）结核分枝杆菌感染。确定疫苗诱导的免疫应答对于 预防结核分枝杆菌感染将提高我们对结核分枝杆菌早期控制的认识， 可以告知免疫相关物对结核病的保护。 通过延长第一次卡介苗再接种试验的随访时间并比较参与者的结核分枝杆菌感染率， 从BCG和安慰剂组，我们还将3）测量疫苗介导的预防的持久性， 接种疫苗后至少6年内持续感染结核分枝杆菌，如果感染显著， 开展更大规模的试验，检验在地方性人群中预防结核病的有效性。

Project summary Mycobacterium tuberculosis (M.tb) causes more deaths worldwide than any other infectious agent and is increasingly characterized by antimicrobial resistance. An effective vaccination strategy to prevent establishment of M.tb infection and progression to tuberculosis (TB) disease is a priority to achieve rapid control of the global TB epidemic, but development and clinical testing of new vaccines is hampered by the lack of immune correlates of protection. Revaccination of adolescents with the only licenced vaccine against TB, Bacille Calmette-Guerin (BCG), partially protected against established M.tb infection, providing the first efficacy signal for a novel TB vaccination strategy in a high-risk population. There is a one-time opportunity to leverage this existing cohort, as well as newly enrolled participants in a larger confirmatory phase 2b clinical trial, to identify and test the durability of immune correlates of protection against established M.tb infection in the lung, which could harbour critically different immune responses compared to peripheral blood. Blood and bronchoalveaolar lavage specimens will be collected to identify and determine longevity of vaccine- induced systemic and pulmonary immune responses that correlate with protection against sustained M.tb infection. The durability of vaccine-induced protection against infection ~6 years after vaccination will also be explored. Novel and robust technologies, such as polychromatic flow cytometry, mass cytometry and systems serology will be applied to study adaptive and innate immune responses in participants enrolled in two BCG efficacy trials at 6 months and ~6 years after vaccination as well as 1 month and 4-5 years after primary M.tb infection. The overarching hypothesis is that BCG vaccination induced multiple arms of the immune system and that a combination of Th1/Th17 and IgA responses is associated with lower risk of established M.tb infection. This approach will: 1) Identify and assess durability of BCG-mediated systemic and pulmonary immune responses in M.tb-uninfected individuals; 2) Define systemic and pulmonary immune correlates of post- M.tb exposure protection against established M.tb infection in participants experiencing transient (protected) or sustained (unprotected) M.tb infection. Identification of vaccine-induced immune responses important for protection against established M.tb infection would enhance our understanding of early containment of M.tb and could inform immune correlates of protection against TB disease. By extending the follow-up of the first BCG revaccination trial and comparing rates of M.tb infection in participants from the BCG and placebo arms, we will also 3) Measure the durability of vaccine-mediated prevention of sustained M.tb infection for at least 6 years post-vaccination, which, if significant, would provide impetus to conduct larger trials testing for efficacy to prevent TB disease in endemic populations.