Kumarasamy Nagalingeswaran, Poongulali Selvamuthu, Bollaerts Anne, Moris Philippe, Beulah Faith Esther, Ayuk Leo Njock, Demoitié Marie-Ange, Jongert Erik, Ofori-Anyinam Opokua
From the YRG CARE Medical Centre, VHS (NK, SP, FEB); and GSK Vaccines, Rixensart/Wavre, Belgium (AB, PM, LNA, M-AD, EJ, OO-A).
Medicine (Baltimore). 2016 Jan;95(3):e2459. doi: 10.1097/MD.0000000000002459.
Human immunodeficiency virus (HIV)-associated tuberculosis is a major public health threat. We evaluated the safety and immunogenicity of the candidate tuberculosis vaccine M72/AS01 in HIV-positive and HIV-negative Indian adults.Randomized, controlled observer-blind trial (NCT01262976).We assigned 240 adults (1:1:1) to antiretroviral therapy (ART)-stable, ART-naive, or HIV-negative cohorts. Cohorts were randomized 1:1 to receive M72/AS01 or placebo following a 0, 1-month schedule and followed for 12 months (time-point M13). HIV-specific and laboratory safety parameters, adverse events (AEs), and M72-specific T-cell-mediated and humoral responses were evaluated.Subjects were predominantly QuantiFERON-negative (60%) and Bacille Calmette-Guérin-vaccinated (73%). Seventy ART-stable, 73 ART-naive, and 60 HIV-negative subjects completed year 1. No vaccine-related serious AEs or ART-regimen adjustments, or clinically relevant effects on laboratory parameters, HIV-1 viral loads or CD4 counts were recorded. Two ART-naive vaccinees died of vaccine-unrelated diseases. M72/AS01 induced polyfunctional M72-specific CD4 T-cell responses (median [interquartile range] at 7 days postdose 2: ART-stable, 0.9% [0.7-1.5]; ART-naive, 0.5% [0.2-1.0]; and HIV-negative, 0.6% [0.4-1.1]), persisting at M13 (0.4% [0.2-0.5], 0.09% [0.04-0.2], and 0.1% [0.09-0.2], respectively). Median responses were higher in the ART-stable cohort versus ART-naive cohort from day 30 onwards (P ≤ 0.015). Among HIV-positive subjects (irrespective of ART-status), median responses were higher in QuantiFERON-positive versus QuantiFERON-negative subjects up to day 30 (P ≤ 0.040), but comparable thereafter. Cytokine-expression profiles were comparable between cohorts after dose 2. At M13, M72-specific IgG responses were higher in ART-stable and HIV-negative vaccinees versus ART-naive vaccinees (P ≤ 0.001).M72/AS01 was well-tolerated and immunogenic in this population of ART-stable and ART-naive HIV-positive adults and HIV-negative adults, supporting further clinical evaluation.
人类免疫缺陷病毒（HIV）相关结核病是一项重大的公共卫生威胁。我们评估了候选结核病疫苗M72/AS01在HIV阳性和HIV阴性印度成年人中的安全性和免疫原性。随机、对照、观察者盲法试验（NCT01262976）。我们将240名成年人（按1:1:1分配）分为抗逆转录病毒疗法（ART）稳定组、未接受ART组或HIV阴性组。各队列按1:1随机分组，按照0、1个月的接种程序接受M72/AS01或安慰剂，并随访12个月（时间点M13）。评估了HIV特异性和实验室安全参数、不良事件（AE）以及M72特异性T细胞介导和体液反应。受试者主要为QuantiFERON阴性（60%）且接种过卡介苗（73%）。70名ART稳定组、73名未接受ART组和60名HIV阴性组的受试者完成了第1年的研究。未记录到与疫苗相关的严重AE或ART治疗方案调整，以及对实验室参数、HIV-1病毒载量或CD4细胞计数的临床相关影响。两名未接受ART的疫苗接种者死于与疫苗无关的疾病。M72/AS01诱导了多功能的M72特异性CD4 T细胞反应（给药后2天7天时的中位数[四分位间距]：ART稳定组，0.9%[0.7 - 1.5]；未接受ART组，0.5%[0.2 - 1.0]；HIV阴性组，0.6%[0.4 - 1.1]），在M13时持续存在（分别为0.4%[0.2 - 0.5]、0.09%[0.04 - 0.2]和0.1%[0.09 - 0.2]）。从第30天起，ART稳定组的中位数反应高于未接受ART组（P≤0.015）。在HIV阳性受试者中（无论ART状态如何），直至第30天，QuantiFERON阳性受试者的中位数反应高于QuantiFERON阴性受试者（P≤0.040），但此后相当。给药后2次剂量后各队列间细胞因子表达谱相当。在M13时，ART稳定组和HIV阴性疫苗接种者的M72特异性IgG反应高于未接受ART的疫苗接种者（P≤0.001）。M72/AS01在这群ART稳定和未接受ART的HIV阳性成年人以及HIV阴性成年人中耐受性良好且具有免疫原性，支持进一步的临床评估。
