M72/AS01 疫苗预防结核病的 2b 期对照试验。
Phase 2b Controlled Trial of M72/AS01 Vaccine to Prevent Tuberculosis.
机构信息
From GlaxoSmithKline, Wavre, Belgium (O.V.D.M., M.-A.D., T.S., E.J.A., A.K.A., A.B., P.G.); South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and Division of Immunology, Department of Pathology (M.H., T.J.S., M.T.), and Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine (R.J.W., F.T.), University of Cape Town, Task Applied Science (E.V.B., A.D.), Stellenbosch University (A.D.), and Aeras Global TB Vaccine Foundation (D.R.T.) Cape Town, Setshaba Research Centre, Pretoria (M. Malahleha), the Aurum Institute, Klerksdorp and Tembisa Research Centres (J.C.I.), and the Perinatal HIV Research Unit, Chris Hani Baragwanath Hospital, South African Medical Research Council Collaborating Centre for HIV/AIDS and TB, and National Research Foundation Centre of Excellence for Biomedical Tuberculosis Research, University of the Witwatersrand (N.M.), Johannesburg, and Be Part Yoluntu Centre, Paarl (E.H.) - all in South Africa; Kenya Medical Research Institute, Nairobi (V.N.); Francis Crick Institute (R.J.W.), the Department of Medicine, Imperial College London (R.J.W.), and the London School of Hygiene and Tropical Medicine (H.M.A.) - all in London; Centre for Infectious Disease Research in Zambia (M. Muyoyeta, G.H.) and Zambart, University of Zambia (H.M.A.) - both in Lusaka, Zambia; the Department of Internal Medicine, University Hospital of Zurich, Zurich, Switzerland (F.T.); and Aeras, Rockville (G.L.B., A.M.G., T.G.E.), and Johns Hopkins University Center for Tuberculosis Research, Baltimore (N.M.) - both in Maryland.
出版信息
N Engl J Med. 2018 Oct 25;379(17):1621-1634. doi: 10.1056/NEJMoa1803484. Epub 2018 Sep 25.
BACKGROUND
A vaccine to interrupt the transmission of tuberculosis is needed.
METHODS
We conducted a randomized, double-blind, placebo-controlled, phase 2b trial of the M72/AS01 tuberculosis vaccine in Kenya, South Africa, and Zambia. Human immunodeficiency virus (HIV)-negative adults 18 to 50 years of age with latent M. tuberculosis infection (by interferon-γ release assay) were randomly assigned (in a 1:1 ratio) to receive two doses of either M72/AS01 or placebo intramuscularly 1 month apart. Most participants had previously received the bacille Calmette-Guérin vaccine. We assessed the safety of M72/AS01 and its efficacy against progression to bacteriologically confirmed active pulmonary tuberculosis disease. Clinical suspicion of tuberculosis was confirmed with sputum by means of a polymerase-chain-reaction test, mycobacterial culture, or both.
RESULTS
We report the primary analysis (conducted after a mean of 2.3 years of follow-up) of the ongoing trial. A total of 1786 participants received M72/AS01 and 1787 received placebo, and 1623 and 1660 participants in the respective groups were included in the according-to-protocol efficacy cohort. A total of 10 participants in the M72/AS01 group met the primary case definition (bacteriologically confirmed active pulmonary tuberculosis, with confirmation before treatment), as compared with 22 participants in the placebo group (incidence, 0.3 cases vs. 0.6 cases per 100 person-years). The vaccine efficacy was 54.0% (90% confidence interval [CI], 13.9 to 75.4; 95% CI, 2.9 to 78.2; P=0.04). Results for the total vaccinated efficacy cohort were similar (vaccine efficacy, 57.0%; 90% CI, 19.9 to 76.9; 95% CI, 9.7 to 79.5; P=0.03). There were more unsolicited reports of adverse events in the M72/AS01 group (67.4%) than in the placebo group (45.4%) within 30 days after injection, with the difference attributed mainly to injection-site reactions and influenza-like symptoms. Serious adverse events, potential immune-mediated diseases, and deaths occurred with similar frequencies in the two groups.
CONCLUSIONS
M72/AS01 provided 54.0% protection for M. tuberculosis-infected adults against active pulmonary tuberculosis disease, without evident safety concerns. (Funded by GlaxoSmithKline Biologicals and Aeras; ClinicalTrials.gov number, NCT01755598 .).
背景
需要一种疫苗来阻断结核病的传播。
方法
我们在肯尼亚、南非和赞比亚开展了一项 M72/AS01 结核疫苗的随机、双盲、安慰剂对照、2b 期临床试验。18 至 50 岁、潜伏性结核分枝杆菌感染（通过干扰素-γ释放试验）的人类免疫缺陷病毒（HIV）阴性成年人以 1:1 的比例随机分配（接受）接受两剂 M72/AS01 或安慰剂肌肉内注射，间隔 1 个月。大多数参与者以前都接种过卡介苗。我们评估了 M72/AS01 的安全性及其对进展为经细菌学证实的活动性肺结核病的疗效。通过聚合酶链反应试验、分枝杆菌培养或两者结合来确认对结核的临床怀疑。
结果
我们报告了正在进行的试验的主要分析（在平均 2.3 年的随访后进行）。1786 名参与者接受了 M72/AS01 治疗，1787 名参与者接受了安慰剂治疗，1623 名和 1660 名参与者分别纳入了符合方案的疗效队列。M72/AS01 组共有 10 名参与者符合主要病例定义（经细菌学证实的活动性肺结核，治疗前得到证实），而安慰剂组有 22 名参与者（发病率为 0.3 例/100 人年）。疫苗效力为 54.0%（90%置信区间[CI]，13.9 至 75.4；95%CI，2.9 至 78.2；P=0.04）。全接种疫苗疗效队列的结果相似（疫苗效力为 57.0%；90%CI，19.9 至 76.9；95%CI，9.7 至 79.5；P=0.03）。在注射后 30 天内，M72/AS01 组（67.4%）比安慰剂组（45.4%）报告的不良事件更多，差异主要归因于注射部位反应和流感样症状。两组不良事件、潜在免疫介导疾病和死亡的发生率相似。
结论
M72/AS01 为潜伏性结核分枝杆菌感染的成年人提供了 54.0%的保护，防止活动性肺结核病，且无明显安全性问题。（由葛兰素史克生物制品公司和 Aeras 资助；临床试验.gov 编号，NCT01755598 ）。
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