Hepatitis B vaccination associated with higher female than male mortality in Guinea-bissau: an observational study.

OBJECTIVE: Studies from high mortality areas have suggested that diphtheria-tetanus-pertussis may be associated with an increase in the mortality of girls relative to boys. We therefore examined whether hepatitis B vaccine (HBV) was associated with sex-specific differences in mortality. DESIGN: As part of a randomized trial of measles vaccine, a subcohort of 876 children was offered HBV at 7(1/2), 9 and 10(1/2) months of age. We examined whether this cohort differed in mortality rate and female-male mortality ratio compared with previous and subsequent birth cohort enrolled in the same trial. SETTING: Four districts in Bissau, the capital of Guinea-Bissau. SUBJECTS: Six annual birth cohorts of 8906 children registered in the study area and followed from 1(1/2) to 12 months of age between March 1995 and February 2001. Of these children, 6399 took part in a 2-dose measles vaccination trial; of those born between March 1996 and February 1997, 876 received HBV. MAIN OUTCOME MEASURES: (1) The mortality rate ratio (MR) between 7(1/2) and 12 months and 1(1/2) and 7(1/2) months old children; (2) the female-male MR among trial children having received HBV plus measles vaccine or only measles vaccine. RESULTS: In cohorts not receiving HBV, the MR for children 7(1/2)-12 and 1(1/2)-7(1/2) months of age was 0.97 "95% confidence interval (95% CI), 0.79-1.24", whereas the MR was 1.62 (95% CI 1.09-2.41) in the cohort receiving HBV at 7(1/2) months (test of homogeneity, P = 0.030). Among children enrolled in the measles vaccination trial, HBV-vaccinated children 7(1/2)-12 months of age had higher mortality than both prior and subsequent cohorts who had not received HBV (MR = 1.81; 95% CI 1.19-2.75), the difference being particularly strong for girls (MR=2.27; 95% CI 1.31-3.94). In the cohort who had received both HBV and measles vaccine, the female-male MR between 9 and 24 months of age was 2.20 (95% CI 1.07-4.54) compared with 0.96 (95% CI 0.70-1.32) in trial participants who had received measles vaccine only (test for homogeneity, P = 0.040). With longer follow-up, these tendencies remained the same. CONCLUSIONS: These comparisons suggested changes in the mortality pattern after the introduction of HBV, particularly for girls. Hence in areas with high mortality, HBV may affect girls' and boys' susceptibility to infections differently.

BCG scar and positive tuberculin reaction associated with reduced child mortality in West Africa. A non-specific beneficial effect of BCG?

Previous studies have suggested that the bacille Calmette-Guérin (BCG) vaccine may have a non-specific beneficial effect on childhood survival in areas with high mortality. We examined whether BCG-vaccinated children with a BCG scar or a positive tuberculin reaction had better survival than children without such reactions. As part of an ongoing two-dose measles vaccine trial for which children were recruited at 6 months of age, we examined 1813 children for BCG scar at 6 months of age and 813 BCG-vaccinated children were skin-tested for delayed hypersensitivity to tuberculin, tetanus and diphtheria. We found that BCG-vaccinated children with a BCG scar had significantly lower mortality compared with BCG scar-negative children, the mortality ratio in the first 12 months of follow-up being 0.41 (0.25-0.67). BCG-vaccinated children with a positive tuberculin test had a mortality ratio of 0.45 (0.24-0.85) compared with tuberculin negative children. These results were unchanged by control for potential confounders or using different cut-off points for a tuberculin-positive response. Exclusion of dead children who had HIV antibodies did not modify the estimate (mortality rate (MR)=0.46 (0.23-0.94)). After censoring for tuberculosis (TB) exposure at home, the mortality ratios for having a scar and being tuberculin-positive were 0.46 (0.27-0.79) or 0.42 (0.21-0.84), respectively. Children positive to tetanus or diphtheria in the skin test had the same mortality as children not responding to these vaccine-related antigens. Thus, BCG scar and a positive tuberculin reaction were associated with better survival in early childhood in an area with high mortality. Since nothing similar was found for responders to diphtheria-tetanus-pertussis (DTP) vaccine, and the effect could not be explained by protection against tuberculosis, the effect of BCG vaccination could be due to non-specific immune-stimulation protecting against other infections.