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1.  Decline in measles mortality: nutrition, age at infection, or exposure? 
The mortality from measles was studied in an urban area of Guinea-Bissau one year before and five years after the introduction of a vaccination programme. The years after the introduction of immunisation saw a decline in mortality among unvaccinated children with measles. This decline occurred despite a lower age at infection and an increasing prevalence of malnourished children. State of nutrition (weight for age) did not affect the outcome of measles infection. The incidence of isolated cases, however, increased in the period after the introduction of measles vaccination. As mortality was lower among these cases, diminished clustering explained some of the reduction in mortality. Comparison between the urban district and a rural area inhabited by the same ethnic group showed a lower age at infection, less clustering of cases, and lower case fatality ratios in the urban area.
Endemic transmission of measles in urban districts leads to less clustering of cases, which may help explain the usually lower case fatality ratios in these areas. As measles vaccination increases herd immunity and diminishes clustering of cases, it may reduce mortality even among unvaccinated children who contract the disease.
PMCID: PMC2545704  PMID: 3133023
2.  Testing the hypothesis that diphtheria–tetanus–pertussis vaccine has negative non-specific and sex-differential effects on child survival in high-mortality countries 
BMJ Open  2012;2(3):e000707.
Background
Measles vaccines (MV) have sex-differential effects on mortality not explained by protection against measles infection.
Objective
The authors examined whether whole-cell diphtheria–tetanus–pertussis (DTP) vaccine has sex-differential and non-specific effects.
Data sources and eligibility
Following previous reviews and a new search, the effect of DTP on mortality up to the next vaccination was assessed in all studies where DTP was given after BCG or DTP was given after MV and there was prospective follow-up after ascertainment of vaccination status.
Setting
High-mortality countries in Africa and Asia.
Methods
The initial observation of negative effect of DTP generated six hypotheses, which were examined in all available studies and two randomised trials reducing the time of exposure to DTP.
Main outcome
Consistency between studies.
Results
In the first study, DTP had negative effects on survival in contrast to the beneficial effects of BCG and MV. This pattern was repeated in the six other studies available. Second, the two ‘natural experiments’ found significantly higher mortality for DTP-vaccinated compared with DTP-unvaccinated children. Third, the female–male mortality ratio was increased after DTP in all nine studies; in contrast, the ratio was decreased after BCG and MV in all studies. Fourth, the increased female mortality associated with high-titre measles vaccine was found only among children who had received DTP after high-titre measles vaccine. Fifth, in six randomised trials of early MV, female but not male mortality was increased if DTP was likely to be given after MV. Sixth, the mortality rate declined markedly for girls but not for boys when DTP-vaccinated children received MV. The authors reduced exposure to DTP as most recent vaccination by administering a live vaccine (MV and BCG) shortly after DTP. Both trials reduced child mortality.
Conclusions
These observations are incompatible with DTP merely protecting against the targeted diseases. With herd immunity to whooping cough, DTP is associated with higher mortality for girls. Randomised studies of DTP are warranted to measure the true impact on survival.
Article summary
Article focus
MV has sex-differential non-specific effects for child survival. We examined whether DTP vaccine has negative effects for survival, particularly for girls.
We tested six hypotheses suggesting that DTP may have negative health consequences if found to be true.
Furthermore, we conducted two randomised trials reducing the time of exposure to DTP as most recent vaccination by providing a live vaccine shortly after DTP.
Key messages
All available studies suggest that the effect of DTP on child survival is opposite of the effects of BCG and MV. In the two natural experiments, DTP-vaccinated children had significantly higher mortality than DTP-unvaccinated children.
Among DTP-vaccinated children, girls have higher mortality than boys in all studies, whereas the tendency is the opposite for BCG- and measles-vaccinated children. DTP administered after MV in randomised trials of MV is associated with increased female but not male mortality.
Reducing time of exposure to DTP as the most recent vaccination with BCG or MV reduce child mortality.
Strengths and limitations of this study
Since the healthiest children are vaccinated first, one would expect DTP to be associated with a benefit. However, all the data suggest consistently that DTP is associated with a negative effect for girls.
A randomised trial of the effect of DTP on overall survival could not be conducted. There is a need to conduct such studies now.
doi:10.1136/bmjopen-2011-000707
PMCID: PMC3364456  PMID: 22619263
3.  Effect of revaccination with BCG in early childhood on mortality: randomised trial in Guinea-Bissau 
Objective To determine whether BCG revaccination at 19 months of age reduces overall child mortality.
Design Randomised trial, with follow-up to age 5.
Setting A health project in Bissau, Guinea-Bissau, which maintains a health and demographic surveillance system in an urban area with 90 000 inhabitants.
Participants 2871 children aged 19 months to 5 years with low or no reactivity to tuberculin and who were not severely sick on the day of enrolment.
Intervention BCG vaccination or no vaccination (control).
Main outcome measure Hazard ratios for mortality.
Results 77 children died during follow-up. Compared with controls, the BCG revaccinated children had a hazard ratio of 1.20 (95% confidence interval 0.77 to 1.89). Two hundred and fifty children were admitted to hospital for the first time between enrolment and the end of the study, with an incidence rate ratio for BCG revaccinated children versus controls of 1.04 (0.81 to 1.33). The trial was stopped prematurely because of a cluster of deaths in the BCG arm of the study. This increase in mortality occurred at a time when many children had received missing vaccinations or vitamin A or iron supplementation; the hazard ratio for BCG revaccinated children compared with controls was 2.69 (1.05 to 6.88) in the period after these campaigns. Throughout the trial, the effect of BCG revaccination on mortality was significantly different (P=0.006) in children who had received diphtheria-tetanus-pertussis (DTP) booster vaccination before enrolment (hazard ratio 0.36, 0.13 to 0.99) and children who had not received the booster before enrolment (1.78, 1.04 to 3.04).
Conclusions There was no overall beneficial effect of being revaccinated with BCG. The effect of BCG revaccination on mortality might depend on other health interventions.
Trial registration Clinical Trials ICA4-CT-2002-10053-REVAC.
doi:10.1136/bmj.c671
PMCID: PMC2839082  PMID: 20231251
4.  Effect of 50 000 IU vitamin A given with BCG vaccine on mortality in infants in Guinea-Bissau: randomised placebo controlled trial 
BMJ : British Medical Journal  2008;336(7658):1416-1420.
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.
doi:10.1136/bmj.39542.509444.AE
PMCID: PMC2432170  PMID: 18558641
5.  Vaccinia Scars Associated with Improved Survival among Adults in Rural Guinea-Bissau 
PLoS ONE  2006;1(1):e101.
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.
doi:10.1371/journal.pone.0000101
PMCID: PMC1762358  PMID: 17183634
6.  Randomised study of effect of different doses of vitamin A on childhood morbidity and mortality 
BMJ : British Medical Journal  2005;331(7530):1428-1432.
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.
doi:10.1136/bmj.38670.639340.55
PMCID: PMC1315642  PMID: 16306060
8.  Early diphtheria-tetanus-pertussis vaccination associated with higher female mortality and no difference in male mortality in a cohort of low birthweight children: an observational study within a randomised trial 
Archives of Disease in Childhood  2012;97(8):685-691.
Background
Studies from low-income countries have suggested that diphtheria-tetanus-pertussis (DTP) vaccine provided after Bacille Calmette-Guerin (BCG) vaccination may have a negative effect on female survival. The authors examined the effect of DTP in a cohort of low birthweight (LBW) infants.
Methods
2320 LBW newborns were visited at 2, 6 and 12 months of age to assess nutritional and vaccination status. The authors examined survival until the 6-month visit for children who were DTP vaccinated and DTP unvaccinated at the 2-month visit.
Results
Two-thirds of the children had received DTP at 2 months and 50 deaths occurred between the 2-month and 6-month visits. DTP vaccinated children had a better anthropometric status for all indices than DTP unvaccinated children. Small mid-upper arm circumference (MUAC) was the strongest predictor of mortality. The death rate ratio (DRR) for DTP vaccinated versus DTP unvaccinated children differed significantly for girls (DRR 2.45; 95% CI 0.93 to 6.45) and boys (DRR 0.53; 95% CI 0.23 to 1.20) (p=0.018, homogeneity test). Adjusting for MUAC, the overall effect for DTP vaccinated children was 2.62 (95% CI 1.34 to 5.09); DRR was 5.68 (95% CI 1.83 to 17.7) for girls and 1.29 (95% CI 0.56 to 2.97) for boys (p=0.023, homogeneity test). While anthropometric indices were a strong predictor of mortality among boys, there was little or no association for girls.
Conclusion
Surprisingly, even though the children with the best nutritional status were vaccinated early, early DTP vaccination was associated with increased mortality for girls.
doi:10.1136/archdischild-2011-300646
PMCID: PMC3409557  PMID: 22331681

Results 1-8 (8)