Prevention of M. tuberculosis Infection with H4:IC31 Vaccine or BCG Revaccination.
Prevention of M. tuberculosis Infection with H4:IC31 Vaccine or BCG Revaccination.
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DOI：
10.1056/nejmoa1714021
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发表时间：
2018-07-12
期刊：
影响因子：
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通讯作者：
C-040-404 Study Team
中科院分区：
文献类型：
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作者：
Nemes E;Geldenhuys H;Rozot V;Rutkowski KT;Ratangee F;Bilek N;Mabwe S;Makhethe L;Erasmus M;Toefy A;Mulenga H;Hanekom WA;Self SG;Bekker LG;Ryall R;Gurunathan S;DiazGranados CA;Andersen P;Kromann I;Evans T;Ellis RD;Landry B;Hokey DA;Hopkins R;Ginsberg AM;Scriba TJ;Hatherill M;C-040-404 Study Team
最近的结核分枝杆菌(M.tb)感染易患结核病，结核病是全球主要的传染病杀手。我们测试了H4：IC31®疫苗或卡介苗(BCG)复种预防结核分枝杆菌感染的安全性和有效性。Quantiferon-TB金试管(QFT)阴性、艾滋病毒未感染、远程接种卡介苗的青少年被随机分为3组，分别接受安慰剂、H4：IC31®或卡介苗复种(NCT02075203)。主要结果是安全性和获得结核分枝杆菌感染，定义为两年内每6个月测试一次的初始QFT转换。次要结果是免疫原性和持续的结核分枝杆菌感染，定义为持续的QFT转换，在转换后三个月和六个月没有逆转。疗效概念验证的统计学意义设为单侧p<；0.10。990名参与者参加了调查。这两种疫苗都具有可接受的安全性，并具有免疫原性。134例患者发生QFT转换，82例患者持续转换。H4：IC31®和BCG均不能阻止QFT的初始转换，有效点估计分别为9.4%(95%可信区间：-36.2，39.7；单侧p=0.32)和20.1%(-21.0，47.2；单侧p=0.14)。但卡介苗有效率为45.4%(6.468.1；单侧p=0.013)；H4：IC31R有效率为30.5%(-15.858.3；单侧p=0.08)。卡介苗组、H4：IC31组和安慰剂组QFT转阴率分别为46%、40%和25%。这项首次概念验证、预防结核分枝杆菌感染的试验表明，在高传播环境下接种疫苗可以预防持续感染，并确认了这一策略的可行性，为临床开发新的候选疫苗提供了信息。在未感染结核分枝杆菌的人群中，有必要评估卡介苗复种预防结核病的效果。
Recent Mycobacterium tuberculosis (M.tb) infection predisposes to tuberculosis disease, the leading global infectious disease killer. We tested safety andefficacy of H4:IC31® vaccination or Bacille Calmette-Guerin (BCG) revaccination for prevention of M.tb infection. QuantiFERON-TB Gold In-tube (QFT) negative, HIV-uninfected, remotely BCG-vaccinated adolescents were randomized 1:1:1 to placebo, H4:IC31® or BCG revaccination (NCT02075203). Primary outcomes were safety and acquisition of M.tb infection, defined by initial QFT conversion tested 6-monthly over two years. Secondary outcomes were immunogenicity and sustained M.tb infection, defined by sustained QFT conversion without reversion three and six months post-conversion. Statistical significance for efficacy proof-of-concept was set at 1-sided p<0.10. 990 participants were enrolled. Both vaccines had acceptable safety profiles and were immunogenic. QFT conversion occurred in 134 and sustained conversion in 82 participants. Neither H4:IC31® nor BCG prevented initial QFT conversion, with efficacy point estimates of 9.4% (95% confidence interval: -36.2, 39.7; one-sided p=0.32) and 20.1% (-21.0, 47.2; one-sided p=0.14), respectively. However, BCG did prevent sustained QFT conversion with an efficacy of 45.4% (6.4, 68.1; one-sided p=0.013); H4:IC31® efficacy was 30.5% (-15.8, 58.3; one-sided p=0.08). QFT reversion rate from positive to negative was 46% in BCG, 40% in H4:IC31 and 25% in placebo recipients. This first proof-of-concept, prevention of M.tb infection trial showed that sustained infection can be prevented by vaccination in a high-transmission setting and confirmed feasibility of this strategy to inform clinical development of new vaccine candidates. Evaluation of BCG revaccination to prevent tuberculosis disease in M.tb- uninfected populations is warranted.