Neonatal Bacillus Calmette‐Guérin Vaccination Decreases Eczema Incidence at 5 years: The MIS BAIR Randomised Controlled Trial

Eczema significantly impacts the health and quality of life of children and their families. We previously reported that neonatal vaccination with Bacille Calmette-Guérin (BCG) reduces the incidence of eczema by 12% (95% confidence intervals (CI) −0.4 to 26%) in the first year of life [1]. We now report the five-year follow-up results. The Melbourne Infant Study: BCG for Allergy and Infection Reduction (MIS BAIR) trial was designed to investigate whether neonatal BCG vaccination reduces the incidence of eczema, allergy, asthma, and infections in the first 5 years of life [2]. In this phase 3, multicentre, randomised controlled trial, 1272 infants were randomised at birth to the BCG vaccination or control (no BCG) group in Victoria, Australia. Infants randomised to the intervention group received 0.05 mL of the BCG-Denmark vaccine (Statens Serum Institute; Mycobacterium bovis, Danish strain 1331) intradermally in the left deltoid region before 10 days of age. Participants were followed up for 5 years with online questionnaires and clinic visits. ClinicalTrial.gov: NCT01906853. The primary analysis was the cumulative incidence of eczema by 5 years, using William's UK diagnostic criteria from questionnaire data [3]. Binary regression adjusted for stratification factors was used to calculate adjusted risk differences (aRD) with 95% CI. Multiple imputation models were used to handle missing data. Outcome definitions, analyses, and subgroup analyses are detailed in the statistical analysis plan (available on request). Stata v.18.0 was used for all analyses. Between August 2013 and September 2016, 637 infants were allocated to the BCG group and 635 to the control group (Figure E1, Table E1). By 5 years of age, 37.1% of children in the BCG group developed eczema compared to 45.3% in the control group (adjusted risk difference [aRD] −8.2%, 95% CI −14.1% to −2.2%; 18.1% relative risk reduction; number-needed-to-treat 12; Figure 1). The protective effect of BCG was found with different definitions of eczema (Table E2), including reported use of topical steroid (aRD −8.0%, 95% CI −14.9% to −1.2%; 11% relative risk reduction). Subgroup analyses revealed no evidence of interaction (Figure E2). Children born to two atopic parents were more likely to have eczema. In this high-risk group, the cumulative incidence of eczema was lower in the BCG group (43%) compared with the control group (54%; aRD −11.6 percentage points, 95% CI −22.7 to −0.5; 21.3% relative risk reduction; number-needed-to-treat 9). Further details are provided in the Appendix S1. These results provide strong evidence that neonatal vaccination with BCG-Denmark offers a clinically significant protective effect against eczema that persists into childhood. These findings add to previous research suggesting that BCG vaccination has protective effects against atopic diseases [4], particularly eczema [5]. In a meta-analysis involving over 5600 children in three RCTs (including the MIS BAIR trial), early-life BCG vaccination reduced the risk of eczema by 11% in the first 13 to 18 months of life [5]. However, at 1 year of age, it is difficult to predict which participants will have transient versus persisting eczema. Our trial found an even greater relative reduction (18%) in eczema over an extended five-year follow-up. This further supports the hypothesis that early microbial exposure, represented by the live-attenuated BCG vaccine, modulates the immune system to reduce susceptibility to atopic diseases [6]. Early-life immunomodulators should be further investigated as a preventive strategy for atopic diseases, as they may have important implications for public health strategies to reduce the social and economic burden of atopic diseases. Further research is also needed to elucidate the immunological mechanisms by which BCG vaccination confers protection against atopic diseases and to explore its effects on other atopic outcomes. N.C. was the lead investigator and responsible for study conception, design, and funding acquisition. N.C. and S.D. developed the final scientific protocol and ethics application, and all other authors provided critical evaluation and revision. K.G. coordinated, and N.C., D.C., N.L.M., and P.V. were involved in implementation. L.F.P. developed, and N.C., R.P., K.G., N.L.M., A.L.P., S.D., F.S., R.R.-B., K.L.Fr., and K.L.Fl. contributed to the statistical analysis plan. K.L.Fr. led, and L.F.P. and S.D. contributed to statistical analysis. L.F.P. drafted the manuscript, coordinated manuscript preparation, and revision. All authors provided critical evaluation and revision of the manuscript. The authors would like to thank the MIS BAIR participants and their families for their involvement in the trial. We also thank our recruitment and follow-up teams, as well as the members of the MIS BAIR data and safety monitoring committee. The MIS BAIR trial is funded by research grants from the National Health and Medical Research Council of Australia (GNT1051228 and GNT1099676), The University of Melbourne, The Royal Children’s Hospital Foundation, and the Murdoch Children’s Research Institute. Dr. Laure Pittet is supported by the Swiss National Science Foundation (Early Postdoc Mobility Grant number P2GEP3_178155 and Ambizione Grant number PZ00P3-209050). N.C. is supported by a National Health and Medical Research Council (NHMRC) Investigator Grant (GNT1197117). Open access publishing facilitated by The University of Melbourne, as part of the Wiley - The University of Melbourne agreement via the Council of Australian University Librarians. Open access publishing facilitated by The University of Melbourne, as part of the Wiley - The University of Melbourne agreement via the Council of Australian University Librarians. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request. Appendix S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.