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

项目总结 结核分枝杆菌(M.tb)在全球范围内造成的死亡人数比任何其他感染性因素都多，而且 越来越具有抗菌素耐药性的特点。预防感染的有效疫苗接种策略 控制结核分枝杆菌感染和发展为结核病是实现全球快速控制的一个优先事项。 结核病流行，但由于缺乏免疫相关因素，新疫苗的开发和临床测试受到阻碍 是一种保护。用唯一获得许可的结核病疫苗--卡介苗重新接种青少年 (卡介苗)，对已建立的结核分枝杆菌感染有部分保护作用，为新型结核病提供了第一个疗效信号 高危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群体，因为 以及新登记的更大的确证阶段2b临床试验的参与者，以确定和测试耐用性 对已建立的肺部结核分枝杆菌感染的免疫相关保护作用，这种感染可能是严重的 与外周血相比，免疫反应不同。 将收集血液和支气管肺泡灌洗样本，以鉴定和确定疫苗的寿命- 诱导的系统和肺免疫反应与对持续结核分枝杆菌的保护相关 感染。在接种疫苗后约6年，疫苗诱导的感染保护的持久性也将是 探索过了。 新的和强大的技术，如多色流式细胞术、质量细胞术和系统血清学将 用于研究参加两项卡介苗疗效试验的参与者的适应性和先天免疫反应 接种后6个月和6年，以及初次感染结核分枝杆菌后1个月和4~5年。这个 最重要的假设是，卡介苗接种诱导了免疫系统的多个手臂，并且 Th1/Th17和IgA反应的组合与确定的结核分枝杆菌感染风险较低相关。 这种方法将：1)识别和评估卡介苗介导的系统和肺免疫的持久性 未感染结核分枝杆菌的个体的反应；2)确定结核分枝杆菌感染后的系统和肺免疫相关性 在经历一过性(保护)的参与者中，结核分枝杆菌暴露对已建立的结核分枝杆菌感染的保护 或持续(无保护)结核分枝杆菌感染。识别疫苗诱导的免疫反应对 对已确定的结核分枝杆菌感染的预防将加强我们对及早遏制结核分枝杆菌和 可以告知免疫相关者对结核病的预防措施。 通过延长第一次卡介苗复种试验的随访时间和比较参与者中结核分枝杆菌的感染率 从卡介苗和安慰剂的角度来看，我们还将测量疫苗介导的预防措施的持久性。 在接种疫苗后持续感染结核分枝杆菌至少6年，如果显著，将推动 开展更大规模的试验，测试在流行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.