Maternal BCG scars and mortality risk for male and female newborns: observational study from Guinea-Bissau.

BACKGROUND: Maternal priming with Bacille Calmette-Guérin (BCG) has been associated with reduced mortality in male offspring. We investigated this association in a cohort of healthy BCG-vaccinated neonates. METHODS: Observational study within a randomized controlled trial comparing different BCG strains conducted in Guinea-Bissau from 2017-2020. As part of trial inclusion procedures, on the day of discharge from the maternity ward, maternal BCG scar status was evaluated by visual inspection, followed by offspring BCG and polio vaccination. Through mortality data collected at telephone interviews at six weeks and six months of age, we assessed all-cause mortality risk in Cox Proportional Hazards models adjusted for maternal schooling and BCG strain, providing adjusted Mortality Rate Ratios (aMRRs). RESULTS: 64% (11,070/17,275) of mothers had a BCG scar, which for females and overall was not associated with neither admission risk, admission severity nor all-cause mortality. By six months of age, the mortality rate (MR) was 4.1 (200 deaths/4,919 person-years) for the maternal BCG scar cohort and 5.2 (139 deaths/2,661 person-years) for no maternal scar, aMRR=0.86 (0.69-1.06). In males, six-month MRs were 4.3 (109/2,531) for maternal BCG scar vs 6.3 (87/1,376) for no scar, the maternal scar/no scar aMRR being 0.74 (0.56-0.99). In females, six-month MRs were 3.8 (91/2,388) vs 4.0 (52(1,286), the aMRR being 1.04 (0.74-1.47), p for interaction with sex=0.16. CONCLUSION: While we cannot rule out an association in females, being born to a mother with a BCG scar reduced the risk of death during early infancy for BCG-vaccinated males, reproducing findings from previous studies.

Effects of Neonatal BCG-Japan Versus BCG-Russia Vaccination on Overall Mortality and Morbidity: Randomized Controlled Trial From Guinea-Bissau (BCGSTRAIN II).

Background: Vaccination with the Danish strain of bacille Calmette-Guérin (BCG) has been associated with pronounced reductions in all-cause neonatal mortality and morbidity. Developing a skin reaction postvaccination is associated with markedly reduced mortality risk. It is unknown whether the beneficial nonspecific effects are maintained across different BCG strains. Methods: This was an open-label randomized controlled trial in Guinea-Bissau, comparing BCG-Japan (n = 8754) versus BCG-Russia (n = 8752) for all-cause hospital admission risk by 6 weeks of age (primary outcome) and 6 months of age. Additional secondary outcomes were in-hospital case-fatality risk (CFR), all-cause mortality, and BCG skin reaction prevalence. Participants were followed through telephone calls at 6 weeks and 6 months, with a subgroup also visited at home. We assessed admission and mortality risk in Cox models providing incidence rate ratios (IRRs) and mortality rate ratios. CFR and skin reactions were assessed by binomial regression providing risk ratios. Analyses were done overall and stratified by sex. Results: BCG strain was not associated with admission risk, the BCG-Japan/BCG-Russia IRR being 0.92 (95% confidence interval [CI], .81-1.05) by 6 weeks and 0.92 (95% CI, .82-1.02) by 6 months. By 6 months of age, there were significantly fewer BCG-Japan infants with no skin reaction (1%) than for BCG-Russia (2%), the risk ratio being 0.36 (95% CI, .16-.81). BCG-Japan skin reactions were also larger. Conclusions: Both vaccines induced a skin reaction in almost all participants. The BCG strains had comparable effects on morbidity and mortality, but BCG-Japan was associated with more and larger skin reactions that are indicators of lower mortality risk. Clinical Trials Registration: NCT03400878.

Maternal BCG primes for enhanced health benefits in the newborn.

OBJECTIVES: Bacille Calmette-Guérin (BCG) vaccination lowers the risk of severe infection; we tested whether effects are modulated by maternal BCG in a large cohort of BCG-vaccinated newborns from Guinea-Bissau. METHODS: Maternal BCG scar status were inspected at enrolment in a BCG trial conducted from 2014 to 17 in Bissau, Guinea-Bissau. We tested associations with background factors for potential confounding; maternal age affected effect estimates >5% and accordingly, all analyses were adjusted for maternal age. Hospitalization data was collected prospectively and assessed in Cox-models providing adjusted Incidence Rate Ratios (aIRRs). In-hospital risk of death (case-fatality) risk was assessed using binomial regression providing adjusted Risk Ratios (aRRs). RESULTS: 60% (6,309/10,598) of mothers had a scar. The maternal-scar/no-scar admission aIRR was 0.96 (0.81-1.14) from 0 to 6 weeks and 1.12 (0.97-1.28) for 6 weeks-3 years. The 6-week in-hospital case-fatality infection aRR was 0.59 (0.34-1.05); 0.40 (0.17-0.91) for males and 0.86 (0.38-1.94) for females. Protection was especially evident against sepsis, the overall 6-week aRR=0.49 (0.26-0.91); no effect was observed for non-infectious deaths or after 6 weeks of age. Effects were similar across BCG strains and multivariate models adjusted for socioeconomic status did not affect estimates. CONCLUSION: Among BCG-vaccinated newborns, there was a trend for fewer in-hospital deaths from infection associated with maternal BCG priming, especially for males. Providing BCG to adults without a vaccination scar might enhance their offspring's capacity to handle severe infections. Brief 40-word summary: Within a trial comparing BCG strains for their overall effects on morbidity and mortality in Guinea-Bissau, vertical priming with BCG (represented by the maternal BCG scar) was associated with beneficial sex-differential effects on offspring survival.

Early Vaccination With Bacille Calmette-Guérin-Denmark or BCG-Japan Versus BCG-Russia to Healthy Newborns in Guinea-Bissau: A Randomized Controlled Trial.

BACKGROUND: Bacille Calmette-Guérin (BCG) vaccination remains a cornerstone against tuberculosis. Randomized controlled trials (RCTs) have demonstrated that BCG-Denmark lowers all-cause mortality, but a recent RCT found no effect of BCG-Russia. Observational studies indicate that the genetically divergent BCG strains have different effects. METHODS: This was a parallel-group, open-label RCT conducted at the National Hospital in Guinea-Bissau. Healthy neonates were randomized 1:1 to BCG-Denmark (2851 randomized, 2840 analyzed) vs BCG-Russia (2845 randomized, 2837 analyzed). We hypothesized that BCG-Denmark would reduce morbidity (primary outcome) and mortality while inducing more BCG reactions and purified protein derivative (PPD) responses (secondary outcomes). Halfway through the trial, production of BCG-Denmark was halted, and the trial continued comparing BCG-Japan (3191 neonates randomized, 3184 analyzed) with BCG-Russia (3170 randomized, 3160 analyzed). Mortality and morbidity data were collected by telephone, at home visits, and at the National Hospital and assessed in Cox models providing 6-week mortality rate ratios (MRRs) and hospitalization incidence rate ratios (IRRs). RESULTS: By age 6 weeks, there were 140 and 130 admissions among neonates vaccinated with BCG-Denmark and BCG-Russia, respectively (IRR, 1.08 [95% confidence interval {CI}, .84-1.37]). For BCG-Japan, there were 185 admissions vs 161 admissions for BCG-Russia (IRR, 1.15 [95% CI, .93-1.43]). The 6-week mortality did not differ: BCG-Denmark/BCG-Russia (MRR, 1.15 [95% CI, .74-1.80]); BCG-Japan/BCG-Russia (MRR, 0.71 [95% CI, .43-1.19]). BCG-Denmark and BCG-Japan induced more BCG scars and PPD reactions than BCG-Russia. CONCLUSIONS: BCG strains did not affect morbidity. BCG-Denmark and BCG-Japan were more immunogenic than BCG-Russia by the measures traditionally viewed as surrogates for successful immunization. The implications of strain differences for tuberculosis protection and overall health warrant further study. CLINICAL TRIALS REGISTRATION: NCT02447536.