Development of Vaccines to Prevent Tuberculosis

结核分枝杆菌（Mtb）是全世界感染死亡的主要原因。卡介苗皮内（ID）接种对肺结核（死亡和疾病传播的主要原因）具有不同的疗效。我们发现，BCG疫苗接种的途径和剂量改变了循环和肺驻留T细胞，并随后保护非人灵长类动物（NHP）免受Mtb攻击。与通过ID或气溶胶（AE）途径施用相同剂量的BCG相比，通过静脉内（IV）途径用BCG免疫的NHP在血液、脾、支气管肺泡灌洗（BAL）和肺淋巴结中诱导显著更高的抗原特异性CD4（Th1或Th17）和CD8应答。此外，IV免疫是在肺实质中诱导高频率的抗原特异性组织驻留T细胞的唯一途径。接种卡介苗后6个月，用Mtb强毒攻击NHP。引人注目的是，接受BCG IV的10个NHP中有9个受到高度保护，其中6个NHP显示通过PET CT成像、分枝杆菌生长、病理学、肉芽肿形成或对Mtb特异性抗原的从头免疫应答确定没有可检测的感染。BCG IV预防或显著限制NHP中Mtb感染的发现对疫苗开发具有重要意义，并提供了用于确定免疫相关性和针对Mtb的保护机制的模型。

Mycobacterium tuberculosis (Mtb) is the leading cause of death from infection worldwide. Intradermal (ID) vaccination with BCG has variable efficacy against pulmonary tuberculosis, the major cause of mortality and disease transmission. We showed that the route and dose of BCG vaccination alters circulating and lung resident T cells and subsequent protection against Mtb challenge in nonhuman primates (NHP). NHP immunized with BCG by the intravenous (IV) route induced substantially higher antigen-specific CD4 (Th1 or Th17) and CD8 responses in blood, spleen, bronchoalveolar lavage (BAL), and lung lymph nodes compared to the same BCG dose administered by ID or aerosol (AE) routes. Moreover, IV immunization was the only route that induced a high frequency of antigen-specific tissue resident T cells in lung parenchyma. Six months after BCG vaccination, NHP were challenged with virulent Mtb. Strikingly, 9 of 10 NHP that received BCG IV were highly protected, with 6 NHP showing no detectable infection as determined by PET CT imaging, mycobacterial growth, pathology, granuloma formation, or de novo immune responses to Mtb-specific antigens. The finding that BCG IV prevents or significantly limits Mtb infection in NHP has important implications for vaccine development and provides a model for determining immune correlates and mechanisms of protection against Mtb.