South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, Western Cape, South Africa.
Department of Statistical Sciences, University of Cape Town, Cape Town, Western Cape, South Africa.
PLoS Pathog. 2019 Mar 4;15(3):e1007643. doi: 10.1371/journal.ppat.1007643. eCollection 2019 Mar.
Eradication of tuberculosis (TB), the world's leading cause of death due to infectious disease, requires a highly efficacious TB vaccine. Many TB vaccine candidates are in pre-clinical and clinical development but only a few can be advanced to large-scale efficacy trials due to limited global resources. We aimed to perform a statistically rigorous comparison of the antigen-specific T cell responses induced by six novel TB vaccine candidates and the only licensed TB vaccine, Bacillus Calmette-Guérin (BCG). We propose that the antigen-specific immune response induced by such vaccines provides an objective, data-driven basis for prioritisation of vaccine candidates for efficacy testing. We analyzed frequencies of antigen-specific CD4 and CD8 T cells expressing IFNγ, IL-2, TNF and/or IL-17 from adolescents or adults, with or without Mycobacterium tuberculosis (M.tb) infection, who received MVA85A, AERAS-402, H1:IC31, H56:IC31, M72/AS01E, ID93+GLA-SE or BCG. Two key response characteristics were analyzed, namely response magnitude and cytokine co-expression profile of the memory T cell response that persisted above the pre-vaccination response to the final study visit in each trial. All vaccines preferentially induced antigen-specific CD4 T cell responses expressing Th1 cytokines; levels of IL-17-expressing cells were low or not detected. In M.tb-uninfected and -infected individuals, M72/AS01E induced higher memory Th1 cytokine-expressing CD4 T cell responses than other novel vaccine candidates. Cytokine co-expression profiles of memory CD4 T cells induced by different novel vaccine candidates were alike. Our study suggests that the T cell response feature which most differentiated between the TB vaccine candidates was response magnitude, whilst functional profiles suggested a lack of response diversity. Since M72/AS01E induced the highest memory CD4 T cell response it demonstrated the best vaccine take. In the absence of immunological correlates of protection, the likelihood of finding a protective vaccine by empirical testing of candidates may be increased by the addition of candidates that induce distinct immune characteristics.
消灭结核病（TB）是全球因传染病导致死亡的首要原因，这需要一种高效的结核病疫苗。有许多结核病候选疫苗正在进行临床前和临床开发，但由于全球资源有限，只有少数疫苗能够推进到大规模疗效试验。我们旨在对六种新型结核病候选疫苗和唯一获得许可的结核病疫苗卡介苗（BCG）诱导的抗原特异性 T 细胞反应进行统计学上严格的比较。我们提出，此类疫苗诱导的抗原特异性免疫反应为候选疫苗进行疗效测试提供了一个客观、数据驱动的优先排序基础。我们分析了接受 MVA85A、AERAS-402、H1:IC31、H56:IC31、M72/AS01E、ID93+GLA-SE 或 BCG 的青少年或成年人中有无结核分枝杆菌（M.tb）感染，分析了表达 IFNγ、IL-2、TNF 和/或 IL-17 的抗原特异性 CD4 和 CD8 T 细胞的频率，这些人接受了疫苗接种。在每个试验中，分析了两个关键的反应特征，即反应幅度和记忆 T 细胞反应的细胞因子共表达谱，该反应在最后一次研究访问时持续高于疫苗接种前对 M.tb 的反应。所有疫苗都优先诱导表达 Th1 细胞因子的抗原特异性 CD4 T 细胞反应；IL-17 表达细胞的水平较低或未检测到。在 M.tb 未感染和感染个体中，M72/AS01E 诱导的记忆 Th1 细胞因子表达 CD4 T 细胞反应高于其他新型疫苗候选物。不同新型疫苗候选物诱导的记忆 CD4 T 细胞的细胞因子共表达谱相似。我们的研究表明，区分候选结核病疫苗的最重要的 T 细胞反应特征是反应幅度，而功能谱表明缺乏反应多样性。由于 M72/AS01E 诱导了最高的记忆 CD4 T 细胞反应，因此它表现出了最好的疫苗效果。在缺乏保护免疫相关性的情况下，通过对候选疫苗进行经验性测试，增加诱导不同免疫特征的候选疫苗，可能会增加找到保护性疫苗的可能性。
