title: Systematic review and meta-analysis of the current evidence on the duration of protection by bacillus Calmette-Guérin vaccination against tuberculosis.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  The National Institute for Health Research Health Technology Assessment programme.
authors.forename: I
authors.initials: I
authors.lastname: Abubakar
authors.forename: L
authors.initials: L
authors.lastname: Pimpin
authors.forename: C
authors.initials: C
authors.lastname: Ariti
authors.forename: R
authors.initials: R
authors.lastname: Beynon
authors.forename: P
authors.initials: P
authors.lastname: Mangtani
authors.forename: J A C
authors.initials: JA
authors.lastname: Sterne
authors.forename: P E M
authors.initials: PE
authors.lastname: Fine
authors.forename: P G
authors.initials: PG
authors.lastname: Smith
authors.forename: M
authors.initials: M
authors.lastname: Lipman
authors.forename: D
authors.initials: D
authors.lastname: Elliman
authors.forename: J M
authors.initials: JM
authors.lastname: Watson
authors.forename: L N
authors.initials: LN
authors.lastname: Drumright
authors.forename: P F
authors.initials: PF
authors.lastname: Whiting
authors.forename: E
authors.initials: E
authors.lastname: Vynnycky
authors.forename: L C
authors.initials: LC
authors.lastname: Rodrigues
mesh_terms: D000367:Age Factors; D001500:BCG Vaccine / Q000008:administration & dosage* / Q000191:economics / Q000276:immunology*; D015982:Bias; D003362:Cost-Benefit Analysis; D014943:Global Health; D006679:HIV Seropositivity / Q000276:immunology; D006801:Humans; D012111:Residence Characteristics; D012737:Sex Factors; D013997:Time Factors; D014376:Tuberculosis / Q000517:prevention & control*; D006113:United Kingdom
chemical_list: D001500:BCG Vaccine