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

Abstract

IntroductionReceiving 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.MethodsProspective 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.ResultsThe 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.ConclusionAmong 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 numbersNCT00146302, NCT00168610, NCT00625482, NCT01989026 and NCT02447536.

Parental Bacillus Calmette-Guérin vaccine scars decrease infant mortality in the first six weeks of life: A retrospective cohort study

“…The only difference between parents with and without a scar was age. Older parents were less likely to have a BCG scar, presumably reflecting improved BCG vaccination since it became general policy in the late 1980s as correct vaccination technique is one of the main determinants for developing a BCG scar [ 12 , 13 ]. Parental age in itself did not determine child survival in the first six weeks of life.…”

“…Field assistants were unaware of the hypothesis regarding parental BCG scars. We have previously shown that a BCG scar is an indicator for a correctly applied BCG vaccine[ 10 , 12 , 13 ] and its use, instead of reported BCG vaccination, overcomes possible problems with recall bias.…”

Development of a multiplex real-time PCR assay for BCG and validation in a clinical laboratory

“…Upon switching to the late strain BCG Glaxo in 1978, that rate decreased to 6.4 per 100,000 2, 24 . Conversely, in phase one of a randomized control trial where BCG Danish was compared with BCG Russia, lymphadenitis was reported in 6 out of 582 patients given BCG Danish and one out of 575 patients given BCG Russia 28 . In this study, 6 out of 10 BCG isolates were early strains, presumably BCG Russia.…”

Development of a Multiplex Real-Time PCR Assay for Mycobacterium bovis BCG and Validation in a Clinical Laboratory

“…BCG strains differ from one another by genetic deletions, SNPs, and duplications ( 15 ). It has been suggested that some BCG strains may be associated with a higher rate of adverse events ( 2 , 14 – 16 ). This possibility is of particular interest in India, where both an early and a late BCG strain are currently in use.…”

“…Given the increased data on M. tuberculosis SNPs and the availability of real-time PCR reagents that enable multiplexed analyses, we developed a two-step real-time PCR assay to rapidly identify BCG from a bacterial culture or directly from infected tissue. The two steps were designed to (i) identify BCG from other members of the MTBC and (ii) differentiate between early and late strains of BCG, something of interest in India, where two different BCG strains (BCG Russia and BCG Danish) with potentially different rates of adverse events are in use ( 2 , 14 – 16 ). This assay was validated on 19 clinical isolates previously collected at Christian Medical College in Vellore, India, and our results suggest that the use of this assay may better inform patient management and enable BCG vaccine pharmacovigilance.…”