Non-Specific Effects of Bacillus Calmette-Guérin: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Abstract

Background: Vaccines induce antigen-specific immunity, which provides long-lived protection from the target pathogen. Trials from areas with high incidence rates for infectious diseases indicated that the tuberculosis vaccine Bacillus Calmette-Guérin (BCG) induces in addition non-specific immunity against various pathogens and thereby reduces overall mortality more than would have been expected by just protecting from tuberculosis. Although recent trials produced conflicting results, it was suggested that BCG might protect from non-tuberculosis respiratory infections and could be used to bridge the time until a specific vaccine against novel respiratory diseases like COVID-19 is available.

Methods: We performed a systematic search for randomized controlled trials (RCTs) published between 2011 and December 9^th, 2022, providing evidence about non-specific effects after BCG vaccination, assessed their potential for bias, and meta-analyzed relevant clinical outcomes. We excluded RCTs investigating vaccination with an additional vaccine unless outcomes from a follow-up period before the second vaccination were reported.

Results: Our search identified 16 RCTs including 34,197 participants. Vaccination with BCG caused an estimated 44% decrease in risk for respiratory infections (hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.39-0.82) with substantial heterogeneity between trials (I² = 77%). There was evidence for a protective effect on all-cause mortality of 21% if follow-up was restricted to one year (HR 0.79, 95% CI 0.64-0.99). We did not find evidence for an effect when we considered longer follow-up (HR 0.88, 95% CI 0.75-1.03). Infection-related mortality after BCG vaccination was reduced by 33% (HR 0.67; 95% CI 0.46-0.99), mortality for sepsis by 38% (HR 0.62, 95% CI 0.41-0.93). There was no evidence for a protective effect of BCG vaccination on infections of any origin (HR 0.84, 95% CI 0.71-1.00), COVID-19 (HR 0.88, 95% CI 0.68-1.14), sepsis (HR 0.78, 95% CI 0.55-1.10) or hospitalization (HR 1.01, 95% CI 0.91-1.11).

Conclusions: According to these results, depending on the setting, vaccination with BCG provides time-limited partial protection against non-tuberculosis respiratory infections and may reduce mortality. These findings underline BCG's potential (1) in pandemic preparedness against novel pathogens especially in developing countries with established BCG vaccination programs but limited access to specific vaccines; (2) in reducing microbial infections, antimicrobial prescriptions and thus the development of antimicrobial resistance. There is a need for additional RCTs to clarify the circumstances under which BCG's non-specific protective effects are mediated.

Keywords: BCG; COVID-19; non-specific effects; pandemic preparedness; respiratory infection; trained immunity; vaccine.

Figure 1

Identification and selection of eligible trials for inclusion in meta-analysis.

Figure 2

Forest plots of random-effects meta-analysis of BCG trials for (A) respiratory infections, (B) COVID-19, and (C) infections of any origin. Solid squares represent hazard ratio estimates for the single studies. The size of the squares represents the weight assigned to the individual study in the meta-analysis and is proportional to the inverse variance (IV) of the estimate. Horizontal lines indicate 95% confidence intervals (CI). The diamond shows the 95% CI for the pooled hazard ratios. Values smaller than 1.0 indicate hazard ratios that favor BCG. BCG = Bacillus Calmette-Guérin, SE = standard error.

Figure 3

Forest plots of random-effects meta-analysis of BCG trials for (A) all-cause mortality, (B) all-cause mortality with one year follow-up, (C) mortality for infections, and (D) mortality for sepsis. Solid squares represent hazard ratio estimates for the single studies. The size of the squares represents the weight assigned to the individual study in the meta-analysis and is proportional to the inverse variance (IV) of the estimate. Horizontal lines indicate 95% confidence intervals (CI). The diamond shows the 95% CI for the pooled hazard ratios. Values smaller than 1.0 indicate hazard ratios that favor BCG. BCG = Bacillus Calmette-Guérin, SE = standard error.