Timing ofMycobacterium tuberculosisexposure explains variation in BCG effectiveness: a systematic review and meta-analysis

Abstract

RationaleThe heterogeneity in efficacy observed in studies of BCG vaccination is not fully explained by currently accepted hypotheses, such as latitudinal gradient in non-tuberculous mycobacteria exposure.MethodsWe updated previous systematic reviews of the effectiveness of BCG vaccination to 31 December 2020. We employed an identical search strategy and inclusion/exclusion criteria to these earlier reviews, but reclassified several studies, developed an alternative classification system and considered study demography, diagnostic approach and tuberculosis (TB)-related epidemiological context.Main resultsOf 21 included trials, those recruiting neonates and children aged under 5 were consistent in demonstrating considerable protection against TB 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.ConclusionsThe most plausible explanatory hypothesis for these results is that BCG protects against TB that results from exposure shortly after vaccination. However, we found no evidence of protection when exposure occurs later from vaccination, which would be of greater importance in trials in high-burden settings with longer follow-up. In settings of declining burden, most exposure occurs shortly following vaccination and the sustained protection observed for many years thereafter represents continued protection against this early exposure. By contrast, in settings of continued intense transmission, initial protection subsequently declines with repeated exposure to Mycobacterium tuberculosis or other pathogens.

A prospective cross-sectional study of tuberculosis in elderly Hispanics reveals that BCG vaccination at birth is protective whereas diabetes is not a risk factor

“…A recent meta-analysis concluded that BCG confers protection against TB shortly after vaccination, and hence, its effect is most notable in children but not in adults in high burden settings. Their results in adults do not support our findings, but there is limited data in individuals beyond 60 years of age [47]. Confirmation of our findings in other elderly cohorts would open the possibilities for considering a booster BCG in the elderly.…”

Assessing vaccine-mediated protection in an ultra-low doseMycobacterium tuberculosismurine model

“…Our results are consistent with findings that BCG can sometimes provide long-term protection against human TB, and are consistent with studies showing BCG-mediated protection in individuals without prior Mtb exposure (tuberculin skin test-negative or IGRA-negative individuals) or in low Mtb transmission settings 1-4 . The low overall observed efficacy (∼13%) in preventing detectable infection also reflects the suboptimal nature of BCG-mediated immunity.…”

“…New and effective tuberculosis (TB) vaccines are urgently needed. Although BCG vaccination can provide protection in infants and older children in some clinical settings [1][2][3][4] , it has proven to be inadequate to combat the global pandemic. There are numerous TB vaccine candidates in the developmental pipeline 5 , but it will not be feasible to conduct human efficacy trials for most of them.…”

Protection against tuberculosis by Bacillus Calmette-Guérin (BCG) vaccination: A historical perspective

“…In a systematic review of trial data on BCG effectiveness, the variation in background intensity of Mtb transmission seems to be able to explain the considerable heterogeneity of BCG vaccination, with sustained protection more evident in settings with lower transmission rates. 30 In line with this hypothesis, in a study among household contacts of individuals with sputum-smear-positive pulmonary TB disease in Indonesia, protection of BCG against infection was found to be stronger in individuals with lower levels of exposure. These data support the hypothesis that higher exposure to Mtb, which is more common in areas with high TB prevalence, may overcome protection induced by BCG and explain variation between geographical areas.…”