South African Tuberculosis Vaccine Initiative and School of Child and Adolescent Health, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, South Africa.
Am J Respir Crit Care Med. 2013 Aug 15;188(4):492-502. doi: 10.1164/rccm.201208-1385OC.
Tuberculosis (TB) is a major cause of morbidity and mortality worldwide, thus there is an urgent need for novel TB vaccines.
We investigated a novel TB vaccine candidate, M72/AS01, in a phase IIa trial of bacille Calmette-Guérin-vaccinated, HIV-uninfected, and Mycobacterium tuberculosis (Mtb)-infected and -uninfected adults in South Africa.
Two doses of M72/AS01 were administered to healthy adults, with and without latent Mtb infection. Participants were monitored for 7 months after the first dose; cytokine production profiles, cell cycling, and regulatory phenotypes of vaccine-induced T cells were measured by flow cytometry.
The vaccine had a clinically acceptable safety profile, and induced robust, long-lived M72-specific T-cell and antibody responses. M72-specific CD4 T cells produced multiple combinations of Th1 cytokines. Analysis of T-cell Ki67 expression showed that most vaccination-induced T cells did not express Th1 cytokines or IL-17; these cytokine-negative Ki67(+) T cells included subsets of CD4 T cells with regulatory phenotypes. PD-1, a negative regulator of activated T cells, was transiently expressed on M72-specific CD4 T cells after vaccination. Specific T-cell subsets were present at significantly higher frequencies after vaccination of Mtb-infected versus -uninfected participants.
M72/AS01 is clinically well tolerated in Mtb-infected and -uninfected adults, induces high frequencies of multifunctional T cells, and boosts distinct T-cell responses primed by natural Mtb infection. Moreover, these results provide important novel insights into how this immunity may be appropriately regulated after novel TB vaccination of Mtb-infected and -uninfected individuals.
Clinical trial registered with www.clinicaltrials.gov (NCT 00600782).
结核病（TB）是全球发病率和死亡率的主要原因，因此急需新型结核疫苗。
我们在南非的卡介苗（BCG）接种的、HIV 阴性和结核分枝杆菌（Mtb）感染和未感染的成年人中进行了一项 IIa 期试验，研究了一种新型结核候选疫苗 M72/AS01。
给健康成年人接种两剂 M72/AS01，包括潜伏性 Mtb 感染者和非感染者。在第一剂后监测参与者 7 个月；通过流式细胞术测量疫苗诱导的 T 细胞的细胞因子产生谱、细胞周期和调节表型。
该疫苗具有临床可接受的安全性，可诱导强烈、持久的 M72 特异性 T 细胞和抗体反应。M72 特异性 CD4 T 细胞产生多种 Th1 细胞因子组合。T 细胞 Ki67 表达分析表明，大多数疫苗诱导的 T 细胞不表达 Th1 细胞因子或 IL-17；这些无细胞因子的 Ki67(+)T 细胞包括具有调节表型的 CD4 T 细胞亚群。PD-1 是激活 T 细胞的负调节剂，在接种疫苗后短暂表达于 M72 特异性 CD4 T 细胞上。与未感染者相比，Mtb 感染者接种疫苗后，特异性 T 细胞亚群的频率显著更高。
M72/AS01 在 Mtb 感染者和未感染者中具有良好的临床耐受性，可诱导高频率的多功能 T 细胞，并增强由天然 Mtb 感染引发的独特 T 细胞反应。此外，这些结果为新型结核疫苗接种 Mtb 感染者和未感染者后如何适当调节这种免疫提供了重要的新见解。
该临床试验已在 www.clinicaltrials.gov 上注册（NCT 00600782）。
