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Review
. 2023 Nov 11;228(10):1467-1478.
doi: 10.1093/infdis/jiad316.

Interpreting the Results of Trials of BCG Vaccination for Protection Against COVID-19

Christie C A Noble  1   2 , Nicole L Messina  1   2 , Laure F Pittet  1   2   3 , Nigel Curtis  1   2   4
Affiliations
Review

Interpreting the Results of Trials of BCG Vaccination for Protection Against COVID-19

Christie C A Noble et al. J Infect Dis. .

Abstract

BCG vaccination has beneficial off-target ("nonspecific") effects on nonmycobacterial infections. On this premise, trials set out to investigate whether BCG provides off-target protection against coronavirus disease 2019 (COVID-19). A literature search identified 11 randomized "BCG COVID-19" trials, with conflicting results. These trials and the differences in their study design are discussed using the PICOT (participants, intervention, control, outcome, and timing) framework to highlight the factors that likely explain their inconsistent findings. These include participant age, sex and comorbid conditions, BCG vaccination strain and dose, outcome measure and duration of follow-up. Understanding how to control these factors to best exploit BCG's off-target effects will be important in designing future trials and intervention strategies.

Keywords: BCG vaccination; COVID-19; SARS-CoV-2; off-target effects.

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Conflict of interest statement

Potential conflicts of interest. N. L. M., L. F. P., and N. C. are investigators on the BRACE trial. C. C. A. N. reports no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Figure 1.
Figure 1.
Features of study design to be considered using the PICOT (participants, intervention, control, outcome, and timing) framework, as applied to the trials of BCG vaccination for protection against coronavirus disease 2019 (COVID-19). Abbreviation: SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
Figure 2.
Figure 2.
Study design of trials of BCG vaccination for protection against coronavirus disease 2019 (COVID-19). A summary of the 11 trials, highlighting the variation in their study design. Ten trials were designed specifically to investigate the effect of BCG on COVID-19. The US trial was a parallel study, using participants in an existing trial investigating the effect of multiple BCG vaccination doses on glycemic control in type 1 diabetes mellitus (depicted by the longer arrowed bar).
Figure 3.
Figure 3.
Incidence of coronavirus disease 2019 (COVID-19) in the trials of BCG vaccination for protection against COVID-19 [16–26]. Bar chart presents the total number of participants enrolled in each trial, along with the total number of reported COVID-19 cases (as defined by each trial). Pie chart presents data from the control group: the percentage of COVID-19 cases in the control group with the absolute number below. aIn the ACTIVATE-2 trial, the rates of COVID-19 at 3 months are presented, as per the primary outcome. bIn the ProBCG trial, the incidence percentage in the control group is as reported by the trial (using person-days of observation). cIn the BRACE trial, the percentage denotes the adjusted estimated probability of symptomatic COVID-19 in the control group at 6 months, as per the primary outcome (adjusted for stratification factors used at randomization: age, geographic location, and comorbid conditions); the extended bar and extra number include the participants recruited to stage 1 of the BRACE trial, who were not included in the primary outcome results.
Figure 4.
Figure 4.
Potential effects of BCG vaccination on coronavirus disease 2019 (COVID-19) incidence. Four scenarios illustrate the potential effects of BCG vaccination on the incidence of symptomatic and severe COVID-19.
See this image and copyright information in PMC

References

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    1. Netea MG, Giamarellos-Bourboulis EJ, Domínguez-Andrés J, et al. Trained immunity: a tool for reducing susceptibility to and the severity of SARS-CoV-2 infection. Cell 2020; 181:969–77. - PMC - PubMed
    1. World Health Organization . BCG vaccines: WHO position paper—February 2018. Wkly Epidemiol Rec 2018; 93:73–96. - PubMed
    1. Fritschi N, Curtis N, Ritz N. Bacille Calmette Guérin (BCG) and new TB vaccines: specific, cross-mycobacterial and off-target effects. Paediatr Respir Rev 2020; 36:57–64. - PMC - PubMed
    1. Pollard AJ, Finn A, Curtis N. Non-specific effects of vaccines: plausible and potentially important, but implications uncertain. Arch Dis Child 2017; 102:1077–81. - PubMed

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