Background

SRL172 prevented disease due to Mycobacterium tuberculosis in a Phase 3 trial. DAR-901 represents a scalable manufacturing process for SRL172. We sought to determine if DAR-901 would prevent infection with M. tuberculosis among BCG-primed adolescents age 13–15 years in Tanzania.

Methods

Adolescents with a negative T- SPOT.TB^R interferon gamma release assay (IGRA) were randomized 1:1 to three intradermal injections of DAR-901 or saline placebo at 0, 2 and 4 months. Repeat IGRAs were performed at 2 months, and at 1, 2, and 3 years. The primary efficacy outcome was time to new TB infection (IGRA conversion to positive); the secondary outcome was time to persistent TB infection (IGRA conversion with repeat positive IGRA).

Results

Among 936 participants screened 667 were eligible and randomized to their first dose of vaccine or placebo (safety cohort). At 2 months, 625 participants remained IGRA-negative and were scheduled for the additional two doses (efficacy cohort). DAR-901 was safe and well-tolerated. One DAR-901 recipient developed a vaccine site abscess. Neither the primary nor secondary endpoints differed between the two treatment arms (p = 0.90 and p = 0.20, respectively). DAR-901 IGRA converters had median responses to ESAT-6 of 50.1 spot-forming cells (SFCs) vs. 19.6 SFCs in placebo IGRA converters (p = 0.03).

Conclusions

A three-dose series of 1 mg DAR-901 was safe and well-tolerated but did not prevent initial or persistent IGRA conversion. DAR-901 recipients with IGRA conversion demonstrated enhanced immune responses to ESAT-6. Since protection against disease may require different immunologic responses than protection against infection a trial of DAR-901 to prevent TB disease is warranted.

Trial Registration. The trial is registered at ClinicalTrials.gov as NCT02712424.

中文翻译：

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DAR-901 疫苗用于预防坦桑尼亚卡介苗免疫青少年感染结核分枝杆菌：一项随机对照、双盲 2b 期试验

背景

SRL172 在 3 期试验中预防了结核分枝杆菌引起的疾病。DAR-901 代表 SRL172 的可扩展制造工艺。我们试图确定 DAR-901 是否会在坦桑尼亚 13-15 岁的 BCG 引发的青少年中预防结核分枝杆菌感染。

方法

在 0、2 和 4 个月时，T-SPOT.TB ^{R干扰素 γ 释放试验 (IGRA) 呈阴性的青少年以 1:1 的比例随机分配到 3 次皮内注射 DAR-901 或盐水安慰剂。}在 2 个月和 1、2 和 3 年重复 IGRA。主要疗效结果是新的结核感染时间（IGRA 转为阳性）；次要结果是持续感染结核病的时间（IGRA 转化，IGRA 重复阳性）。

结果

在筛选的 936 名参与者中，有 667 名符合条件并被随机分配到他们的第一剂疫苗或安慰剂组（安全队列）。在 2 个月时，625 名参与者仍然是 IGRA 阴性，并被安排接受额外的两剂（疗效队列）。DAR-901 安全且耐受性良好。一名 DAR-901 接受者出现了疫苗部位脓肿。两个治疗组的主要终点和次要终点均无差异（分别为 p = 0.90 和 p = 0.20）。DAR-901 IGRA 转换器对 ESAT-6 的响应中位数为 50.1 个斑点形成细胞 (SFC)，而安慰剂 IGRA 转换器为 19.6 个 SFC (p = 0.03)。

结论

1 mg DAR-901 的三剂系列安全且耐受性良好，但并未阻止初始或持续的 IGRA 转化。具有 IGRA 转换的 DAR-901 受体表现出对 ESAT-6 的增强免疫反应。由于预防疾病可能需要与预防感染不同的免疫反应，因此有必要进行 DAR-901 试验以预防结核病。

试用注册。该试验在 ClinicalTrials.gov 注册为 NCT02712424。