Health Technol Assess. 2013 Sep;17(37):1-372, v-vi. doi: 10.3310/hta17370.
Recent evidence suggests that the duration of protection by bacillus Calmette-Guérin (BCG) may exceed previous estimates with potential implications for estimating clinical and cost-efficacy.
To estimate the protection and duration of protection provided by BCG vaccination against tuberculosis, explore how this protection changes with time since vaccination, and examine the reasons behind the variation in protection and the rate of waning of protection.
Electronic databases including MEDLINE, Excerpta Medica Database (EMBASE), Cochrane Databases, NHS Economic Evaluation Database (NHS EED), Database of Abstracts of Reviews of Effects (DARE), Web of Knowledge, Biosciences Information Service (BIOSIS), Latin American and Caribbean Health Sciences Literature (LILACs), MEDCARIB Database, Cumulative Index to Nursing and Allied Health Literature (CINAHL) were searched from inception to May 2009. Index to Theses, System for Information on Grey Literature in Europe (SIGLE), Centre for Agricultural Bioscience International (CABI) Abstracts, Scopus, Article First, Academic Complete, Africa-Wide Information, Google Scholar, Global Health, British National Bibliography for Report Literature, and clinical trial registration websites were searched from inception to October 2009.
Electronic databases searches, screening of identified studies, data extraction and analysis were undertaken. Meta-analysis was used to present numerical and graphical summaries of clinical efficacy and efficacy by time since vaccination. Evidence of heterogeneity was assessed using the tau-squared statistic. Meta-regression allowed the investigation of observed heterogeneity. Factors investigated included BCG strain, latitude, stringency of pre-BCG vaccination tuberculin testing, age at vaccination, site of disease, study design and vulnerability to biases. Rate of waning of protection was estimated using the ratio of the measure of efficacy after 10 years compared with the efficacy in the first 10 years of a study.
Study selection. A total of 21,030 references were identified, providing data on 132 studies after abstract and full-text review. Efficacy. Protection against pulmonary tuberculosis in adults is variable, ranging from substantial protection in the UK MRC trial {rate ratio 0.22 [95% confidence interval (CI) 0.16 to 0.31]}, to absence of clinically important benefit, as in the large Chingleput trial [rate ratio 1.05 (95% CI 0.88 to 1.25)] and greater in latitudes further away from the equator. BCG vaccination efficacy was usually high, and varied little by form of disease (with higher protection against meningeal and miliary tuberculosis) or study design when BCG vaccination was given only to infants or to children after strict screening for tuberculin sensitivity. High levels of protection against death were observed from both trials and observational studies. The observed protective effect of BCG vaccination did not differ by the strain of BCG vaccine used in trials.
Reviewed studies showed that BCG vaccination protects against pulmonary and extrapulmonary tuberculosis for up to 10 years. Most studies either did not follow up participants for long enough or had very few cases after 15 years. This should not be taken to indicate an absence of effect: five studies (one trial and four observational studies) provided evidence of measurable protection at least 15 years after vaccination. Efficacy declined with time. The rate of decline was variable, with faster decline in latitudes further from the equator and in situations where BCG vaccination was given to tuberculin-sensitive participants after stringent tuberculin testing.
The main limitation of this review relates to quality of included trials, most of which were conducted before current standards for reporting were formulated. In addition, data were lacking in some areas and the review had to rely on evidence from observational studies.
BCG vaccination protection against tuberculosis varies between populations, to an extent that cannot be attributed to chance alone. Failure to exclude those already sensitised to mycobacteria and study latitude closer to the equator were associated with lower efficacy. These factors explained most of the observed variation. There is good evidence that BCG vaccination protection declines with time and that protection can last for up to 10 years. Data on protection beyond 15 years are limited; however, a small number of trials and observational studies suggest that BCG vaccination may protect for longer. Further studies are required to investigate the duration of protection by BCG vaccination.
The National Institute for Health Research Health Technology Assessment programme.
最近的证据表明，卡介苗（BCG）的保护期可能超过之前的估计，这对估计临床和成本效益有潜在影响。
评估卡介苗接种预防结核病的保护作用及其持续时间，探讨这种保护作用随时间的变化，并研究保护作用变化的原因和保护作用衰减的速度。
电子数据库包括 MEDLINE、Excerpta Medica Database (EMBASE)、Cochrane 数据库、NHS Economic Evaluation Database (NHS EED)、Database of Abstracts of Reviews of Effects (DARE)、Web of Knowledge、 Biosciences Information Service (BIOSIS)、拉丁美洲和加勒比健康科学文献 (LILACs)、MEDCARIB 数据库、Cumulative Index to Nursing and Allied Health Literature (CINAHL)，从成立到 2009 年 5 月进行了检索。索引到论文、欧洲信息系统灰色文献 (SIGLE)、农业生物科学国际中心 (CABI) 摘要、Scopus、Article First、Academic Complete、Africa-Wide Information、Google Scholar、全球健康、英国国家书目报告文献和临床试验注册网站从成立到 2009 年 10 月进行了检索。
进行电子数据库检索、识别研究的筛选、数据提取和分析。采用荟萃分析对临床疗效和接种后时间的疗效进行数值和图形总结。使用 tau-squared 统计量评估异质性的存在。荟萃回归允许调查观察到的异质性。调查的因素包括 BCG 菌株、纬度、接种前结核菌素检测的严格程度、接种年龄、疾病部位、研究设计和易受偏倚的影响。通过比较研究前 10 年和后 10 年的保护效果来估计保护作用衰减的速度。
研究选择。共识别出 21030 篇参考文献，经过摘要和全文审查后，提供了 132 项研究的数据。疗效。成人肺结核的保护作用是可变的，范围从英国 MRC 试验中的显著保护（比率比 0.22 [95%置信区间 0.16 至 0.31]）到不存在临床重要益处，如在 Chingleput 大型试验中（比率比 1.05 [95%置信区间 0.88 至 1.25]），并且在离赤道更远的纬度保护作用更大。卡介苗接种的疗效通常较高，当卡介苗接种仅用于婴儿或在严格筛查结核菌素敏感性后用于儿童时，其形式的疾病或研究设计差异不大。从试验和观察性研究中都观察到了对死亡的高度保护作用。观察到的卡介苗接种保护作用不因试验中使用的卡介苗菌株而不同。
综述研究表明，卡介苗接种可预防 10 年内的肺和肺外结核病。大多数研究要么没有足够长的时间进行随访，要么在 15 年后很少有病例。这不应被视为缺乏效果：五项研究（一项试验和四项观察性研究）提供了至少 15 年后接种疫苗仍有可衡量的保护作用的证据。疗效随时间下降。下降速度是可变的，离赤道越远的纬度和在严格的结核菌素检测后对结核菌素敏感的参与者中接种卡介苗的情况下，下降速度越快。
本综述的主要限制与试验的质量有关，大多数试验都是在当前报告标准制定之前进行的。此外，在某些领域缺乏数据，综述不得不依赖于观察性研究的证据。
卡介苗接种预防结核病的保护作用在不同人群之间存在差异，这种差异不能仅归因于偶然因素。未能排除已对分枝杆菌敏感的人和接近赤道的研究纬度与较低的疗效有关。这些因素解释了大部分观察到的差异。有很好的证据表明卡介苗接种的保护作用随时间衰减，并且保护作用可持续长达 10 年。关于 15 年以上保护作用的数据有限；然而，少数试验和观察性研究表明，卡介苗接种可能持续更长时间。需要进一步研究以调查卡介苗接种的保护作用持续时间。
英国国家卫生研究院卫生技术评估计划。
