title: Protection by BCG vaccine against tuberculosis: a systematic review of randomized controlled trials.
abstract: BACKGROUND
  Randomized trials assessing BCG vaccine protection against tuberculosis have widely varying results, for reasons that are not well understood.
  
  
  METHODS
  We examined associations of trial setting and design with BCG efficacy against pulmonary and miliary or meningeal tuberculosis by conducting a systematic review, meta-analyses, and meta-regression.
  
  
  RESULTS
  We identified 18 trials reporting pulmonary tuberculosis and 6 reporting miliary or meningeal tuberculosis. Univariable meta-regression indicated efficacy against pulmonary tuberculosis varied according to 3 characteristics. Protection appeared greatest in children stringently tuberculin tested, to try to exclude prior infection with Mycobacterium tuberculosis or sensitization to environmental mycobacteria (rate ratio [RR], 0.26; 95% confidence interval [CI], .18-.37), or infants (RR, 0.41; 95% CI, .29-.58). Protection was weaker in children not stringently tested (RR, 0.59; 95% CI, .35-1.01) and older individuals stringently or not stringently tested (RR, 0.88; 95% CI, .59-1.31 and RR, 0.81; 95% CI, .55-1.22, respectively). Protection was higher in trials further from the equator where environmental mycobacteria are less and with lower risk of diagnostic detection bias. These associations were attenuated in a multivariable model, but each had an independent effect. There was no evidence that efficacy was associated with BCG strain. Protection against meningeal and miliary tuberculosis was also high in infants (RR, 0.1; 95% CI, .01-.77) and children stringently tuberculin tested (RR, 0.08; 95% CI, .03-.25).
  
  
  CONCLUSIONS
  Absence of prior M. tuberculosis infection or sensitization with environmental mycobacteria is associated with higher efficacy of BCG against pulmonary tuberculosis and possibly against miliary and meningeal tuberculosis. Evaluations of new tuberculosis vaccines should account for the possibility that prior infection may mask or block their effects.
authors: Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine.
authors: Punam
authors: P
authors: Mangtani
authors: Ibrahim
authors: I
authors: Abubakar
authors: Cono
authors: C
authors: Ariti
authors: Rebecca
authors: R
authors: Beynon
authors: Laura
authors: L
authors: Pimpin
authors: Paul E M
authors: PE
authors: Fine
authors: Laura C
authors: LC
authors: Rodrigues
authors: Peter G
authors: PG
authors: Smith
authors: Marc
authors: M
authors: Lipman
authors: Penny F
authors: PF
authors: Whiting
authors: Jonathan A
authors: JA
authors: Sterne
mesh_terms: D001500:BCG Vaccine / Q000008:administration & dosage* / Q000276:immunology*; D006801:Humans; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome; D014390:Tuberculosis, Meningeal / Q000453:epidemiology / Q000517:prevention & control*; D014391:Tuberculosis, Miliary / Q000453:epidemiology / Q000517:prevention & control*; D014397:Tuberculosis, Pulmonary / Q000453:epidemiology / Q000517:prevention & control*
chemical_list: D001500:BCG Vaccine
keywords: BCG vaccine; meta-analysis; meta-regression; trials; vaccine efficacy