Timing of <i>M. tuberculosis</i> exposure explains variation in BCG effectiveness: A systematic review and meta-analysis

Abstract Background The variable efficacy observed in studies of BCG vaccination is incompletely explained by currently accepted hypotheses, such as latitudinal gradient in non-tuberculous mycobacteria exposure. We investigated heterogeneity in BCG vaccination in the context of participant demography, diagnostic approach and TB-related epidemiological context. Methods We updated previous systematic reviews of the effectiveness of BCG vaccination to 31 st December 2018. We employed an identical search strategy and inclusion/exclusion criteria to past reviews, but reclassified several studies and developed an alternative classification system. Results Of 21 included trials, those recruiting neonates and children aged under five were consistent in demonstrating considerable protection for several years. Trials in high-burden settings with shorter follow-up also showed considerable protection, as did most trials in settings of declining burden with longer follow-up. However, the few trials performed in high-burden settings with longer follow-up showed no protection, sometimes with higher case rates in the vaccinated than the controls in the later follow-up period. Conclusions The most plausible explanatory hypothesis is that BCG protects against TB that results from exposure shortly after vaccination. However, risk is equivalent or increased when exposure occurs later from vaccination, a phenomenon which is predominantly observed in adults in high-burden settings with longer follow-up. In settings of declining burden, most exposure occurs shortly following vaccination and the sustained protection thereafter represents continued protection against this early exposure. By contrast, in settings of continued intense transmission, initial protection subsequently declines due to repeated exposure to M. tuberculosis or other pathogens.