Bacillus Calmette-Guérin vaccine to reduce COVID-19 infections and hospitalisations in healthcare workers - a living systematic review and prospective ALL-IN meta-analysis of individual participant data from randomised controlled trials

Judith ter Schure, A. Ly, L. Belin, C. S. Benn, M. J. M. Bonten, J. D. Cirillo, J. A. A. Damen, I. Fronteira, K. D. Hendriks, A. P. Junqueira-Kipnis, A. Kipnis, O. Launay, J. E. Mendez-Reyes, J. Moldvay, M. G. Netea, Sebastian Nielsen, C. M. Upton, G. van den Hoogen, J. M. Weehuizen, P. D. GrunwaldH. van Werkhoven

Research output: Working paperPreprintResearch


BACKGROUND The objective is to determine the impact of the Bacillus Calmette-Guérin (BCG) vaccine compared to placebo or no vaccine on COVID-19 infections and hospitalisations in healthcare workers. We are using a living and prospective approach to Individual-Participant-Data (IPD) meta-analysis of ongoing studies based on the Anytime Live and Leading Interim (ALL-IN) meta-analysis statistical methodology.
METHODS Planned and ongoing randomised controlled trials were identified from trial registries and by snowballing (final elicitation: Oct 3 2022). The methodology was specified prospectively - with no trial results available - for trial inclusion as well as statistical analysis. Inclusion decisions were made collaboratively based on a risk-of-bias assessment by an external protocol review committee (Cochrane risk-of-bias tool adjusted for use on protocols), expected homogeneity in treatment effect, and agreement with the predetermined event definitions. The co-primary endpoints were incidence of COVID-19 infection and COVID-19-related hospital admission. Accumulating IPD from included trials was analysed sequentially using the exact e-value logrank test (at level = 0.5% for infections and level = 4.5% for hospitalisations) and anytime-valid 95%-confidence intervals (CIs) for the hazard ratio (HR) for a predetermined fixed-effects approach to meta-analysis (no measures of statistical heterogeneity). Infections were included if demonstrated by PCR tests, antigen tests or suggestive lung CTs. Participants were censored at date of first COVID-19-specific vaccination and two-stage analyses were performed in calendar time, with a stratification factor per trial.
RESULTS Six trials were included in the primary analysis with 4 433 participants in total. The e-values showed no evidence of a favourable effect of minimal clinically relevance (HR < 0.8) in comparison to the null (HR = 1) for COVID-19 infections, nor for COVID-19 hospitalisations (HR < 0.7 vs HR = 1). COVID-19 infection was observed in 251 participants receiving BCG and 244 participants not receiving BCG, HR 1.02 (anytime-valid 95%-CI 0.78-1.35). COVID-19 hospitalisations were observed in 13 participants receiving BCG and 7 not receiving BCG, resulting in an uninformative estimate (HR 1.88; anytime-valid 95%-CI 0.26-13.40).
DISCUSSION It is highly unlikely that BCG has a clinically relevant effect on COVID-19 infections in healthcare workers. With only limited observations, no conclusion could be drawn for COVID-19 related hospitalisation. Due to the nature of ALL-IN meta-analysis, emerging data from new trials can be included without violating type-I error rates or interval coverage. We intend to keep this meta-analysis alive and up-to-date, as more trials report. For COVID-19 related hospitalisations, we do not expect enough future observations for a meaningful analysis. For BCG-mediated protection against COVID-19 infections, on the other hand, more observations could lead to a more precise estimate that concludes the meta-analysis for futility, meaning that the current interval excludes the HR of 0.8 predetermined as effect size of minimal clinical relevance.
OTHER No external funding. Preregistered at PROSPERO: CRD42021213069.
Original languageUndefined/Unknown
Publication statusPublished - 2022


  • infectious diseases

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