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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.
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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.
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BACKGROUND: The Bacillus Calmette-Guérin vaccine (BCG) against tuberculosis (TB) shows beneficial nonspecific effects, which are likely related to innate immune training. Until 2016, a single BCG dose was administered to all newborns in Portugal. In July 2016, a clinical guideline established that only children under 6 years belonging to high-risk groups should receive BCG. This might have prevented nonvaccinated children from developing trained immunological responses as effectively as BCG-vaccinated children. OBJECTIVE: This study aims to investigate if there is variation in TB-related and all-cause mortality, and severe, moderate, or mild morbidity in children under 5 years of age, and whether such variation might be explained by the BCG vaccination policy change in 2016. METHODS: This population-based historical birth cohort study includes children under 5 years of age born in Portugal between July 1, 2010, and June 30, 2021. Newborns with low birth weight, premature status, or known or suspected HIV infection are excluded. The follow-up period is until the completion of 5 years of age or the end of follow-up (June 30, 2021). The study will use secondary data from the National Health Service user registry, death certificate database, vaccination registry, communicable diseases surveillance system, TB surveillance system, diagnosis-related group information system for hospital admissions and emergency department visits, and primary health care information system. The data will be linked. Primary outcomes include person-time incidence rates of death (all causes and TB), TB diagnosis, and all causes and some specific causes of severe, moderate, or mild morbidity, and the incidence rate ratio of nonvaccinated to BCG-vaccinated children. We will compare the probability of surviving the first and fifth years of life or of not having severe, moderate, or mild morbidity during the follow-up period according to exposure (BCG vaccinated or nonvaccinated, number of doses, and time from birth until the first dose), using the log-rank test for assessing differences in survival rates between exposed and nonexposed children and hazard ratios for quantifying the differences. Moreover, we will perform a proportional hazards regression analysis. RESULTS: Ethics approval has been obtained. In March 2022, database owners were contacted to present the project and discuss the request for data. A unique identifier will be used. In July 2023, a process of redefinition of the variables per database was initiated. Data were received in October and November 2023. In November 2023, further work was conducted. By April 2024, we expect to start analyzing the full data set. CONCLUSIONS: The results will contribute to the accumulating body of knowledge and might have relevance to guide global BCG vaccination policy. Data linkage can contribute to a swifter mechanism to use available health data to conduct population-based studies and inform policy decision-making. TRIAL REGISTRATION: ClinicalTrials.gov NCT05471167; https://clinicaltrials.gov/study/NCT05471167. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/55332.
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INTRODUCTION: The live-attenuated vaccines Bacillus Calmette-Guérin (BCG) and Vaccinia have been associated with beneficial non-specific effects. We assessed the prevalence of BCG and Vaccinia vaccine scars in a cohort of Danish health care workers and investigated the association between the presence of vaccine scars and self-reported chronic diseases. METHODS: Cross-sectional study utilizing baseline data collected during 2020-2021 at enrollment in a BCG trial aiming to assess the effect of BCG vaccination on absenteeism and infectious disease morbidity during the SARS-COV-2 pandemic. In Denmark, Vaccinia was discontinued in 1977, and BCG was phased out in the early 1980s. We used logistic regression analysis (adjusted for sex, birth year, and smoking status) to estimate the association between scar status and chronic diseases, providing adjusted Odds Ratios (aORs) with 95 % Confidence Intervals, for participants born before 1977, and born from 1965 to 1976. RESULTS: The cohort consisted of 1218 participants (206 males; 1012 females) with a median age of 47 years (Q1-Q3: 36-56). Among participants born 1965-1976 (n = 403), who experienced the phase-outs, having BCG and/or Vaccinia scar(s) vs. having no vaccine scars yielded an aOR of 0.51 (0.29-0.90) of self-reported chronic disease; an effect primarily driven by BCG. In the same birth cohort, having vaccine scar(s) was most strongly associated with a lower prevalence of chronic respiratory and allergic diseases; the aORs being 0.39 (0.16-0.97) and 0.39 (0.16-0.91), respectively. CONCLUSION: Having a BCG scar was associated with a lower prevalence of self-reported chronic disease.