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
Authors: ter Schure J.A. (Judith) , Ly Alexander , Belin Lisa , Benn Christine S. , Bonten Marc J.M. , Cirillo Jeffrey D. , Damen Johanna A.A. , Fronteira Inês , Hendriks Kelly D. , Junqueira-Kipnis Ana Paula , Kipnis André , Launay Odile , Mendez-Reyes Jose Euberto , Moldvay Judit , Netea Mihai G. , Nielsen Sebastian , Upton Caryn M. , van den Hoogen Gerben , Weehuizen Jesper M. , Grünwald Peter D. , van Werkhoven C.H. (Henri) 
Published: December 2022

AbstractBACKGROUNDThe 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.METHODSPlanned 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 exacte-value logrank test (at level α = 0.5% for infections and level α = 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.RESULTSSix trials were included in the primary analysis with 4 433 participants in total. Thee-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).DISCUSSIONIt 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.OTHERNo external funding. Preregistered at PROSPERO: CRD42021213069.