结核病免疫机制及疫苗研究进展

Progress in immunology of tuberculosis and new vaccine development

结核病是一种棘手的重大传染病。虽然存在一些有一定疗效的治疗药物,亦有预防性疫苗———卡介苗(BCG);但结核病仍在世界范围流行,且发病率和病死率居高不下。结核病的免疫病理机制及疫苗研究近年来取得了一定的进展。结核分枝杆菌通过Toll样受体(TLR)等模式识别受体,激活巨噬细胞的天然免疫反应,清除细菌和调节获得性免疫反应。包括主要组织相容性复合物(MHC)限制的CD4+和CD8+T细胞,以及CD1限制的T细胞和γδT细胞参与抗结核获得性免疫反应,其中记忆性T细胞与调节性T细胞具有重要的免疫调节作用。但是,人们对结核病发生机制的认识仍然不足,限制了对结核病治疗药物和新型疫苗的研发。由于BCG对成人缺乏有效的保护力,故研制新型的结核疫苗是预防结核病的当务之急。当前处于实验阶段的候选疫苗包括重组BCG、减毒结核分枝杆菌和可用于加强BCG的亚单位疫苗,后者又包括痘苗病毒载体疫苗、核酸疫苗、新型佐剂辅助的蛋白疫苗。目前可行的疫苗免疫策略主要是使用BCG或其他疫苗初次免疫,然后选择亚单位疫苗加强免疫。然而,疫苗的免疫策略、免疫剂量、免疫途径、强化免疫次数和免疫时机都有待研究。反映疫苗保护力的免疫指标不明确、很难确定哪类疫苗进入临床试验、缺乏临床试验场地、疫苗效果评价需要很长时间及耗资巨大,增加了结核疫苗研究的难度和风险。

Tuberculosis remains a leading infectious cause of morbidity and mortality worldwide despite the availability of the bacille Calmette Guérin（BCG） vaccine and chemotherapy.Progress has been made in understanding immuopathogenesis and vaccine development in recent years.Mycobacterium tuberculosis（Mtb） may activate innate immunity of macrophage by Toll-like receptors（TLRs） and other pattern recognition receptors（PRRs）,which can eliminate the bacteria and regulate the acquired immune responses.Besides major histocompatibility complex（MHC） restricted CD4＋ and CD8＋ T cells,CD1-restricted T cells and γδT cells also take part in immune responses to Mtb infection.Memory T cells and regulatory T cells play a special role in regulating immune responses to mycobacterial infection.In view of poor BCG protective efficacy in adults,improved control of tuberculosis requires development of new and more effective vaccines.Various vaccine candidates including recombinant BCG,live-attenuated Mtb,and booster vaccines,such as recombinant modified vaccinia virus Ankara expressing Mtb antigen,nucleic acid vaccines,and subunit protein vaccines with novel adjuvants,are at different stages of development.One promising vaccine strategy is priming with BCG or BCG replacement vaccine followed by boosting with subunit vaccines.However,the vaccine strategy,optimal dose,route,frequency,and timing of the boost remain to be determined.The challenges facing tuberculosis vaccine development include a lack of immune markers for protection in humans,difficulty in prioritizing which candidates to move to clinical trials,shortage of clinical trial sites,lengthy time required for vaccine evaluation,and high cost.