Munseri Patricia, Said Jamila, Amour Maryam, Magohe Albert, Matee Mecky, Rees Christiaan A, Mackenzie Todd, Tvaroha Susan, Bailey-Kellogg Chris, Maro Isaac, Wieland-Alter Wendy, Adams Lisa V, Horsburgh C Robert, Nakamura Keiko, Arbeit Robert D, Pallangyo Kisali, von Reyn C Fordham
Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania.
Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
Vaccine. 2020 Oct 27;38(46):7239-7245. doi: 10.1016/j.vaccine.2020.09.055. Epub 2020 Sep 29.
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.
Adolescents with a negative T- SPOT.TB 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).
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).
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.
The trial is registered at ClinicalTrials.gov as NCT02712424.
在一项3期试验中，SRL172预防了结核分枝杆菌引起的疾病。DAR - 901代表了一种可扩展的SRL172生产工艺。我们试图确定DAR - 901是否能预防坦桑尼亚13至15岁接种卡介苗的青少年感染结核分枝杆菌。
结核感染T细胞检测（T - SPOT.TB）干扰素γ释放试验（IGRA）结果为阴性的青少年按1:1随机分组，在0、2和4个月时接受三次皮内注射DAR - 901或生理盐水安慰剂。在2个月时以及1、2和3年时重复进行IGRA检测。主要疗效指标是出现新的结核感染的时间（IGRA转为阳性）；次要指标是持续结核感染的时间（IGRA转为阳性且重复检测IGRA仍为阳性）。
在936名筛查的参与者中，667名符合条件并被随机分配接受第一剂疫苗或安慰剂（安全性队列）。在2个月时，625名参与者的IGRA仍为阴性，并计划接受另外两剂（疗效队列）。DAR - 901安全且耐受性良好。一名接受DAR - 901的受试者出现了疫苗接种部位脓肿。两个治疗组之间的主要终点和次要终点均无差异（p分别为0.90和0.20）。DAR - 901组IGRA转为阳性者对早期分泌性抗原靶6（ESAT - 6）的反应中位数为50.1个斑点形成细胞（SFCs），而安慰剂组IGRA转为阳性者为19.6个SFCs（p = 0.03）。
1毫克DAR - 901的三剂系列疫苗安全且耐受性良好，但未能预防初始或持续的IGRA转换。IGRA转换的DAR - 901接受者对ESAT - 6表现出增强的免疫反应。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预防结核病的试验。
该试验已在ClinicalTrials.gov注册，注册号为NCT02712424。
