Timing of Mycobacterium tuberculosis exposure explains variation in BCG effectiveness: a systematic review and meta-analysis

Abstract

Rationale: The 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.

Methods: We 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 results: Of 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.

Conclusions: The 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.

Keywords: clinical epidemiology; respiratory infection; tuberculosis.

Figure 1

Modified PRISMA flow diagram. ^aIncludes two reports of one revaccination trial which observed zero cases of TB during follow-up. ^bTrials in Chicago medical students, Chicago nursing students and New York infants were not included in Mangtani review. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; TB, tuberculosis.

Figure 2

Age distribution (in years) of participants in studies for which these data were provided. Studies with very narrow age inclusion criteria not presented (ie, five neonatal trials and English cities trial of children aged 14–15½ years). All age distributions normalised to the same maximum vertical height.

Figure 3

Distribution of cases of active TB occurring in the vaccinated (red) and unvaccinated (blue) populations in which timing of cases by age can be determined to within a 5-year interval. The area of each marker is set proportional to the number of cases occurring within a certain time/age interval and then linearly scaled by an arbitrary value for visual effect. First six studies assigned to vaccinated and control in a 1:1 ratio, while Chengalpattu assigned in ratio of 2 BCG: 1 control, with the size of the vaccinated circles halved to compensate for this effect. Madanapalle panel presents results for bacteriologically-confirmed cases only. First panel data obtained from table IV of Ferguson 1949, second panel data obtained from figure 1 of Rosenthal 1961, third panel data obtained from table 3 of MRC 1972,, fourth panel data obtained from table 3 of Rosenthal 1963, fifth panel data obtained from tables 1 and 2 of Bettag 1964, sixth panel data obtained from table 5 of Frimodt-Moller 1973, seventh panel presents previously unpublished data. TB, tuberculosis.

Figure 4

Forest plot of TB incidence rate ratios from trials of BCG vaccination by participant demographics and background epidemiology. Pooled effects are from random effects meta-analysis. Pooled estimates with confidence limits when using a restricted maximum likelihood model with Stata 16.1 and Knapp-Hartung adjustments were: all neonatal and young children: 0.27 (0.15, 0.40); Paediatric/adolescent, declining burden, longer follow-up: 0.25 (0.17, 0.33); adult, short follow-up: 0.59 (0.42, 0.77); adult, declining burden, longer follow-up: 0.86 (0.08, 1.64), adult, high-burden, longer follow-up: 1.05 (0.50, 1.61). New York infants trial not included because only the outcome of TB-related deaths was reported from this trial. TB, tuberculosis.