Schmidt Alexander C, Fairlie Lee, Hellström Elizabeth, Luabeya Kany Kany Angelique, Middelkoop Keren, Naidoo Kogieleum, Nair Gonasagrie, Gela Anele, Nemes Elisa, Scriba Thomas J, Cinar Amy, Frahm Nicole, Mogg Robin, Kaufman David, Dunne Michael W, Hatherill Mark
Gates Medical Research Institute, Cambridge, MA.
Wits Reproductive Health and HIV Institute, University of Witwatersrand, Johannesburg.
N Engl J Med. 2025 May 8;392(18):1789-1800. doi: 10.1056/NEJMoa2412381.
In a previous phase 2 trial, bacille Calmette-Guérin (BCG) revaccination was not shown to provide protection from primary infection but prevented sustained infection, defined by an initial conversion on a QuantiFERON-TB (QFT) test (an interferon- release assay) from negative to positive, followed by two additional positive QFT tests at 3 and 6 months after the initial conversion (a secondary end point). A vaccine efficacy of 45% (95% confidence interval [CI], 6 to 68) was observed.
We performed a phase 2b, double-blind, randomized, placebo-controlled trial to evaluate the efficacy of BCG revaccination, as compared with placebo, for the prevention of sustained QFT test conversion (primary end point) in QFT test-negative, human immunodeficiency virus (HIV)-negative adolescents. Adverse events were assessed in a secondary analysis, and immunogenicity was assessed in an exploratory analysis. Vaccine efficacy was evaluated in the modified intention-to-treat population, which included all the participants who had undergone randomization, received the BCG vaccine or placebo, and had a negative QFT test 10 weeks after receipt of BCG vaccine or placebo; the last criterion was added to exclude participants with infection around the time that the vaccine or placebo was administered. Hazard ratios and 95% confidence intervals were estimated from a stratified Cox proportional-hazards model.
A total of 1836 participants underwent randomization; 918 received the BCG vaccine, and 917 received placebo. After a median 30 months of follow-up, a sustained QFT test conversion was observed in 62 of 871 participants in the BCG-vaccine group and 59 of 849 participants in the placebo group. The hazard ratio for a sustained QFT test conversion (BCG vaccine vs. placebo) was 1.04 (95% CI, 0.73 to 1.48), for a vaccine efficacy point estimate of -3.8% (95% CI, -48.3 to 27.4). Adverse events occurred more frequently in the BCG-vaccine group than in the placebo group, and most were due to injection-site reactions (pain, redness, swelling, and ulceration). BCG revaccination induced cytokine-positive type 1 helper CD4 T cells.
BCG revaccination in QFT-test negative, HIV-negative adolescents did not provide protection from sustained infection. (Funded by the Gates Foundation; ClinicalTrials.gov number NCT04152161.).
在先前的一项2期试验中，未显示卡介苗（BCG）再接种可预防原发性感染，但可预防持续性感染，持续性感染的定义为在定量干扰素释放试验（QFT）中最初从阴性转为阳性，随后在初次转换后3个月和6个月另外两次QFT试验呈阳性（次要终点）。观察到疫苗效力为45%（95%置信区间[CI]，6至68）。
我们进行了一项2b期双盲随机安慰剂对照试验，以评估BCG再接种与安慰剂相比，在预防QFT试验阴性、人类免疫缺陷病毒（HIV）阴性青少年中持续性QFT试验转换（主要终点）方面的效力。在次要分析中评估不良事件，在探索性分析中评估免疫原性。在改良意向性治疗人群中评估疫苗效力，该人群包括所有接受随机分组、接受BCG疫苗或安慰剂且在接受BCG疫苗或安慰剂10周后QFT试验为阴性的参与者；添加最后一项标准以排除在接种疫苗或安慰剂时周围有感染的参与者。通过分层Cox比例风险模型估计风险比和95%置信区间。
共有1836名参与者接受随机分组；918名接受BCG疫苗，917名接受安慰剂。经过中位30个月的随访，BCG疫苗组871名参与者中有62名出现持续性QFT试验转换，安慰剂组849名参与者中有59名出现持续性QFT试验转换。持续性QFT试验转换的风险比（BCG疫苗与安慰剂相比）为1.04（95%CI，0.73至1.48），疫苗效力点估计值为-3.8%（95%CI，-48.3至27.4）。BCG疫苗组不良事件的发生频率高于安慰剂组，且大多数是由于注射部位反应（疼痛、发红、肿胀和溃疡）。BCG再接种诱导了细胞因子阳性的1型辅助性CD4 T细胞。
在QFT试验阴性、HIV阴性青少年中进行BCG再接种并不能预防持续性感染。（由盖茨基金会资助；ClinicalTrials.gov编号NCT04152161。）
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