BCG vaccine may reduce overall mortality by increasing resistance to nontuberculosis infections. In 2 randomized trials in Guinea-Bissau of early BCG-Denmark (Statens Serum Institut) given to low-weight (LW) neonates (<2500 g at inclusion) to reduce infant mortality rates, we observed a very beneficial effect in the neonatal period. We therefore conducted the present trial to test whether early BCG-Denmark reduces neonatal mortality by 45%. We also conducted a meta-analysis of the 3 BCG-Denmark trials. In 2008–2013, we randomized LW neonates to “early BCG-Denmark” (intervention group; n = 2083) or “control” (local policy for LW and no BCG-Denmark; n = 2089) at discharge from the maternity ward or at first contact with the health center. The infants were randomized (1:1) without blinding in blocks of 24. Data was analyzed in Cox hazards models providing mortality rate ratios (MRRs). We had prespecified an analysis censoring follow-up at oral poliovirus vaccine campaigns. Early administration of BCG-Denmark was associated with a nonsignificant reduction in neonatal mortality rate (MRR, 0.70; 95% confidence interval [CI], .47–1.04) and a 34% reduction (0.66; .44–1.00) when censoring for oral poliovirus vaccine campaigns. There was no reduction in mortality rate for noninfectious diseases, but a 43% reduction in infectious disease mortality rate (MRR, 0.57; 95% CI, .35–.93). A meta-analysis of 3 BCG trials showed that early BCG-Denmark reduced mortality by 38% (MRR, 0.62; 95% CI, .46–.83) within the neonatal period and 16% (0.84; .71–1.00) by age 12 months. Early administration of BCG-Denmark in LW infants is associated with major reductions in mortality rate. It is important that all LW infants receive early BCG in areas with high neonatal mortality rates. NCT00625482.

Background: A recent WHO review concluded that live BCG and measles vaccine (MV) may have beneficial non-specific effects (NSEs) reducing mortality from non-targeted diseases. NSEs of oral polio vaccine (OPV) were not examined. If OPV vaccination campaigns reduce the mortality rate, it would suggest beneficial NSEs. Setting: Between 2002 and 2014, Guinea-Bissau had 15 general OPV campaigns and other campaigns with OPV plus vitamin A supplementation (VAS), VAS-only, MV, and H1N1 vaccine. In this period, we conducted seven randomized controlled trials (RCTs) with mortality as main outcome. Methods: Within these RCTs, we assessed whether the mortality rate was lower after-campaign than before-campaign. We used Cox models with age as underlying time and further adjusted for low birth-weight, season and time trend in mortality. We calculated the adjusted mortality rate ratio (MRR) for after-campaign vs before-campaign. Results: The mortality rate was lower after OPV-only campaigns than before, the MRR being 0.81 (95% CI = 0.68–0.95). With each additional dose of campaign-OPV the mortality rate declined further (MRR = 0.87 (95% CI: 0.79–0.96) per dose) (test for trend, p = 0.005). No other type of campaign had similar beneficial effects. Depending on initial age and with follow-up to 3 years of age, the number needed to treat with campaign-OPV-only to save one life was between 68 and 230 children. Conclusion: Bissau had no case of polio infection so the results suggest that campaign-OPV has beneficial NSEs. Discontinuation of OPV-campaigns in low-income countries may affect general child mortality levels negatively.

Objective To investigate the effect of vitamin A supplementation and BCG vaccination at birth in low birthweight neonates. Design Randomised, placebo controlled, two by two factorial trial. Setting Bissau, Guinea-Bissau. Participants 1717 low birthweight neonates born at the national hospital. Intervention Neonates who weighed less than 2.5 kg were randomly assigned to 25 000 IU vitamin A or placebo, as well as to early BCG vaccine or the usual late BCG vaccine, and were followed until age 12 months. Main outcome measure Mortality, calculated as mortality rate ratios (MRRs), after follow-up to 12 months of age for infants who received vitamin A supplementation compared with those who received placebo. Results No interaction was observed between vitamin A supplementation and BCG vaccine allocation (P=0.73). Vitamin A supplementation at birth was not significantly associated with mortality: the MRR of vitamin A supplementation compared with placebo, controlled for randomisation to “early BCG” versus “no early BCG” was 1.08 (95% CI 0.79 to 1.47). Stratification by sex revealed a significant interaction between vitamin A supplementation and sex (P=0.046), the MRR of vitamin A supplementation being 0.74 (95% CI 0.45 to 1.22) in boys and 1.42 (95% CI 0.94 to 2.15) in girls. When these data were combined with data from a complementary trial among normal birthweight neonates in Guinea-Bissau, the combined estimate of the effect of neonatal vitamin A supplementation on mortality was 1.08 (95% CI 0.87 to 1.33); 0.80 (95% CI 0.58 to 1.10) in boys and 1.41 (95% CI 1.04 to 1.90) in girls (P=0.01 for interaction between neonatal vitamin A and sex). Conclusions The combined results of this trial and the complementary trial among normal birthweight neonates have now shown that, overall, it would not be beneficial to implement a neonatal vitamin A supplementation policy in Guinea-Bissau. Worryingly, the trials show that vitamin A supplementation at birth can be harmful in girls. Previous studies and future trials should investigate the possibility that vitamin A supplementation has sex differential effects. Trial registration ClinicalTrials.gov NCT00168610.

Objective To investigate the effect of high dose vitamin A supplementation given with BCG vaccine at birth in an African setting with high infant mortality. Design Randomised placebo controlled trial. Setting Bandim Health Project’s demographic surveillance system in Guinea-Bissau, covering approximately 90 000 inhabitants. Participants 4345 infants due to receive BCG. Intervention Infants were randomised to 50 000 IU vitamin A or placebo and followed until age 12 months. Main outcome measure Mortality rate ratios. Results 174 children died during follow-up (mortality=47/1000 person-years). Vitamin A supplementation was not significantly associated with mortality; the mortality rate ratio was 1.07 (95% confidence interval 0.79 to 1.44). The effect was 1.00 (0.65 to 1.56) during the first four months and 1.13 (0.75 to 1.68) from 4 to 12 months of age. The mortality rate ratio in boys was 0.84 (0.55 to 1.27) compared with 1.39 (0.90 to 2.14) in girls (P for interaction=0.10). An explorative analysis revealed a strong interaction between vitamin A and season of administration. Conclusions Vitamin A supplementation given with BCG vaccine at birth had no significant benefit in this African setting. Although little doubt exists that vitamin A supplementation reduces mortality in older children, a global recommendation of supplementation for all newborn infants may not contribute to better survival. Trial registration Clinical trials NCT00168597.