Oral Polio Vaccine Influences the Immune Response to BCG Vaccination. A Natural Experiment

Background: Oral polio vaccine (OPV) is recommended to be given at birth together with BCG vaccine. While we were conducting two trials including low-birth-weight (LBW) and normal-birth-weight (NBW) infants in Guinea-Bissau, OPV was not available during some periods and therefore some infants did not receive OPV at birth, but only BCG. We investigated the effect of OPV given simultaneously with BCG at birth on the immune response to BCG vaccine. Methods and Findings: We compared the in vitro and the in vivo response to PPD in the infants who received OPV and BCG with that of infants who received BCG only. At age 6 weeks, the in vitro cytokine response to purified protein derivate (PPD) of M. Tuberculosis was reduced in LBW and NBW infants who had received OPV with BCG. In a pooled analysis receiving OPV with BCG at birth was associated with significantly lower IL-13 (p = 0.041) and IFN-gamma (p = 0.004) and a tendency for lower IL-10 (p = 0.054) in response to PPD. Furthermore, OPV was associated with reduced in vivo response to PPD at age 2 months, the prevalence ratio (PR) of having a PPD reaction being 0.75 (0.58-0.98), p = 0.033, and with a tendency for reduced likelihood of having a BCG scar (0.95 (0.91-1.00), p = 0.057)). Among children with a scar, OPV was associated with reduced scar size, the regression coefficient being -0.24 (-0.43-0.05), p = 0.012. Conclusions: This study is the first to address the consequences for the immune response to BCG of simultaneous administration with OPV. Worryingly, the results indicate that the common practice in low-income countries of administering OPV together with BCG at birth may down-regulate the response to BCG vaccine

Vaccinia Scars Associated with Improved Survival among Adults in Rural Guinea-Bissau

BACKGROUND: In urban Guinea-Bissau, adults with a vaccinia scar had better survival but also a higher prevalence of HIV-2 infection. We therefore investigated the association between vaccinia scar and survival and HIV infection in a rural area of Guinea-Bissau. METHODOLOGY/PRINCIPAL FINDINGS: In connection with a study of HIV in rural Guinea-Bissau, we assessed vaccinia and BCG scars in 193 HIV-1 or HIV-2 infected and 174 uninfected participants. Mortality was assessed after 2½–3 years of follow-up. The analyses were adjusted for age, sex, village, and HIV status. The prevalence of vaccinia scar was associated with age, village, and HIV-2 status but not with sex and schooling. Compared with individuals without any scar, individuals with a vaccinia scar had better survival (mortality rate ratio (MR) = 0.22 (95% CI 0.08–0.61)), the MR being 0.19 (95% CI 0.06–0.57) for women and 0.40 (95% CI 0.04–3.74) for men. Estimates were similar for HIV-2 infected and HIV-1 and HIV-2 uninfected individuals. The HIV-2 prevalence was higher among individuals with a vaccinia scar compared to individuals without a vaccinia scar (RR = 1.57 (95% CI 1.02–2.36)). CONCLUSION: The present study supports the hypothesis that vaccinia vaccination may have a non-specific beneficial effect on adult survival

Randomised study of effect of different doses of vitamin A on childhood morbidity and mortality.

OBJECTIVES: To determine whether the dose of vitamin A currently recommended by the World Health Organization or half this dose gives better protection against childhood morbidity and mortality. DESIGN: Randomised study. SETTING: A combined oral polio vaccine and vitamin A supplementation campaign in Guinea-Bissau, Africa. PARTICIPANTS: 4983 children aged 6 months to 5 years. INTERVENTIONS: One of two doses of vitamin A (recommended and half); oral polio vaccine. MAIN OUTCOME MEASURES: Mortality and morbidity at six and nine months. RESULTS: Mortality was lower in the children who took half the recommended dose of vitamin A compared with the full dose at both six months (mortality rate ratio 0.69, 95% confidence interval 0.36 to 1.35) and nine months (0.62, 0.36 to 1.06) of follow-up. There was a significant interaction between sex and dose, the lower dose being associated with significantly reduced mortality in girls (0.19, 0.06 to 0.66) but not in boys (1.98, 0.74 to 5.29). The lower dose of vitamin A was consistently associated with lower hospital case fatality in girls (0.19, 0.02 to 1.45). Paradoxically, in children aged 6-18 months, the low dose was associated with slightly higher morbidity. CONCLUSIONS: Half the dose of vitamin A currently recommended by WHO may provide equally good or better protection against mortality but not against morbidity

DTP vaccination and child survival in observational studies with incomplete vaccination data.

BACKGROUND: Observational studies of diphtheria-tetanus-pertussis (DTP) vaccine from longitudinal study sites have reported divergent effects on child survival, ranging from 10-fold reduction to threefold increased mortality. None of these studies had complete information on DTP vaccinations from both survivors and children who died. We reviewed the data analysis methodology to assess whether methodological differences could explain the divergent results. DESIGN: Studies have used case-control design, survival analysis with interval-fixed vaccination status (landmark approach), and survival analysis with retrospective updating of vaccination status. RESULTS: Seven studies using a case-control design or a landmark approach found a negative effect of DTP on child survival. Eight of nine survival analyses with retrospective updating of vaccination status reported a beneficial effect. This beneficial effect of DTP increased with the length of the interval between data collection visits. Studies with long interval between visits had very high mortality rates among unvaccinated children, low mortality rate ratios for vaccinated compared with unvaccinated children, and strongly beneficial estimates of DTP. CONCLUSION: The divergent results in observational studies of the impact of DTP on child survival are partly because of methodological differences. To assess the impact on mortality of routine vaccinations, observational study designs which minimize the effect of bias are warranted. Randomized trials should be considered

Survival bias in observational studies of the impact of routine immunizations on childhood survival.

OBJECTIVES: In situations with vaccination coverage high enough to control pertussis, observational studies have reported divergent effects of diphtheria-tetanus-pertussis (DTP) vaccination on childhood survival. We examined whether this could be because of methodological differences. METHODS: Some studies of the impact of DTP updated information on vaccination retrospectively (retrospective updating approach) while others kept vaccination status fixed for the time between follow-up visits (landmark approach). First, we conducted simulations with these approaches to investigate the impact of different mortality levels, vaccination incidence rates, intervals between data collection visits, and the proportion of children whose vaccination card had not been seen after death. Second, we re-analysed data from Guinea-Bissau using the retrospective updating approach. RESULTS: In simulations, the retrospective updating approach produced rate ratio (vaccinated/unvaccinated) estimates biased towards zero because of a differential misclassification which created survival bias as risk-free observation time was allocated to the vaccinated group. The landmark approach produced rate ratio estimates biased towards one. Biases increased with interval between data collection visits and incidence of vaccination, but were unaffected by the underlying mortality level. Survival bias increased with the proportion of dead children whose vaccination status could not be updated. The re-analysis of data from Guinea-Bissau changed the estimated impact of DTP from an 84% higher mortality using the landmark approach to a 37% lower mortality using the retrospective updating approach. CONCLUSIONS: The apparent contradiction between DTP studies could be because of methodological differences. To assess child survival associated with routine vaccinations, studies minimizing the effect of biases are warranted

Divergent female-male mortality ratios associated with different routine vaccinations among female-male twin pairs.

BACKGROUND: Observational studies have suggested that vaccinations have non-specific effects that differ by sex. In the absence of randomized trials, studies of female-male twin pairs would allow us to investigate whether an intervention had sex-specific effects on survival. We therefore examined mortality patterns among female-male twin pairs according to vaccination status. Design We identified female-male twin pairs using the population registers from one urban district and three rural studies from Guinea-Bissau and Senegal and examined the female-male mortality ratio (MR) according to the last vaccine received among pairs in which a death occurred before 18 months of age. As background information, we examined sex- and age-specific mortality patterns in the pre-vaccination era. Subjects In all, 626 female-male twin pairs identified between 1978 and 2000. RESULTS: There was no sex difference in mortality for boys and girls in the pre-vaccination era. In the combined analysis of all studies, the female-male MR was 0.25 (95% CI: 0.05, 0.93) for pairs having received Bacille Calmette-Guerin (BCG) as the last vaccine, 7.33 (95% CI: 2.20, 38.3) for pairs having received diphtheria, tetanus, pertussis (DTP) as the last vaccine, and 0.40 (95% CI: 0.04, 2.44) for pairs having received measles vaccine as the last vaccine. The female-male MR varied significantly for BCG compared with DTP (exact test of homogeneity, P < 0.001) and for DTP compared with measles vaccine (exact test of homogeneity, P = 0.001). CONCLUSION: Non-specific effects of routine vaccinations are likely to be important and influence sex-specific mortality patterns in areas with high mortality. The effects of vaccines need to be considered in the planning of immunization programmes for low-income countries

Differences in female-male mortality after high-titre measles vaccine and association with subsequent vaccination with diphtheria-tetanus-pertussis and inactivated poliovirus: reanalysis of West African studies.

BACKGROUND: Females given high-titre measles vaccine (HTMV) have high mortality; diphtheria-tetanus-pertussis (DTP) vaccination might be associated with increased female mortality. We aimed to assess whether DTP or inactivated poliovirus (IPV) administered after HTMV was associated with increased female-male mortality ratio. METHODS: In three trials from West Africa, 2000 children were randomised to HTMV or control vaccine at 4-5 months of age; a second vaccination was given at age 9-10 months (standard measles vaccine). Children in high-titre groups were given IPV or DTP-IPV. Another 944 children received HTMV as routine vaccination in Senegal. FINDINGS: When we compared high-titre and control groups, no difference in mortality between the first and the second vaccination was noted. After the second vaccination, the female-male mortality ratio was 1.84 (95% CI 1.19-2.84) in children in the high-titre groups who received DTP-IPV or IPV, and 0.59 (0.34-1.04) in controls who received standard measles vaccine (p=0.007). Children who received HTMV but no additional DTP-IPV or IPV had a female-male mortality ratio of 0.83 (0.41-1.67). This ratio was 2.22 (1.04-4.71) for children who received DTP-IPV after routine HTMV and 1.00 (0.68-1.47) for those who did not. When we combined the results from all trials, the female-male mortality ratio was 1.93 (1.33-2.81) for those who received DTP or IPV after HTMV, and 0.96 (0.69-1.34) for those who did not (p=0.006). INTERPRETATION: A change in sequence of vaccinations, rather than HTMV itself, may have been the cause of increased female mortality in these trials