BCG skin reactions by 2 months of age are associated with better survival in infancy: a prospective observational study from Guinea-Bissau

Abstract

Introduction: Receiving Bacille Calmette-Guérin (BCG)-Denmark vaccine at birth has been associated with ~40% reductions in all-cause neonatal mortality. We evaluated determinants of BCG skin reaction characteristics by age 2 months and tested the association with subsequent mortality.

Methods: Prospective observational study amalgamating five trials providing BCG-at-birth that were conducted between 2002 and 2018 in Guinea-Bissau. The reaction status and size were evaluated at home-visits by 2 months of age among 6012 neonates; mortality from 2 to 12 months was assessed at subsequent visits. Reaction determinants were evaluated by binomial regression providing risk ratios (RRs). In Cox-models providing adjusted mortality rate ratios (aMRRs), we assessed the association between (1) having a 2-month reaction (yes/no) and (2) reaction size tertiles and subsequent all-cause mortality risk. A subgroup had their BCG reaction evaluated and were bled at age 4 weeks; their samples underwent in vitro analysis for specific and non-specific cytokine responses.

Results: The BCG strain was the main determinant for developing a 2-month reaction and the reaction size: the BCG-Russia/BCG-Denmark RR for large-reaction was 0.38 (0.30-0.47) and the BCG-Russia/BCG-Japan RR was 0.61 (0.51-0.72). 5804 infants (96.5%) were reactors by age 2 months; 208 (3.5%) were non-reactors. The 2-12 months mortality risk was 4.8% (10/208) for non-reactors, 2.9% (64/2213) for small reactors, 1.8% (30/1710) for medium reactors and 0.8% (15/1881) for large reactors. The reactor/non-reactor aMRR was 0.49 (0.26-0.95) and there was a linear trend of decreasing mortality with increasing reaction size (p for trend <0.001). BCG reactors had higher 4-week specific and non-specific cytokine responses, responses that were highest among those with large reactions.

Conclusion: Among BCG-vaccinated infants, having a BCG skin reaction by age 2 months was associated with markedly better survival, as was the reaction size. Our findings thus support that BCG has substantial effects on all-cause mortality. Emphasising at-birth vaccination with immunogenic BCG strains and revaccinating non-reactors and small reactors could have major public health benefits.

Trial registration numbers: NCT00146302, NCT00168610, NCT00625482, NCT01989026 and NCT02447536.

Keywords: child health; epidemiology; immunisation; other study design; public health.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Measurement of an infant’s Bacille Calmette-Guérin skin reaction at the vaccine injection site in the left deltoid region during a home-visit within the BCGSTRAIN randomised controlled trial (RCT V).

Figure 2

Study flow chart. BCG, Bacille Calmette-Guérin; RCT, randomised controlled trial.

Figure 3

Kaplan-Meier curve of cumulative deaths up to 1 year of age among infants with a Bacille Calmette-Guérin reaction versus no reaction. The statistical analysis is a reaction/no reaction Cox proportional hazards regression model with non-reactors as baseline, adjusted for maternal mid upper-arm circumference, year and 2-month reaction assessor, stratified by study, providing the adjusted mortality rate ratio (aMRR) estimate.

Figure 4

Kaplan-Meier curve of cumulative deaths up to 1 year of age by Bacille Calmette-Guérin reaction size. All statistical analyses were conducted using Cox proportional hazards regression models with infants with small reactions as baseline, adjusted for maternal mid upper-arm circumference, year and 2-month reaction assessor, stratified by study, providing the aMRR estimate. aMRR, adjusted mortality rate ratio

Figure 5

Mortality risk by BCG reaction size in millimetres. ***P for trend