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1.  Measles–mumps–rubella vaccination and respiratory syncytial virus-associated hospital contact 
Vaccine  2015;33(1):237-245.
Highlights
•MMR vaccination is given to protect against measles, mumps and rubella.•RSV is an important cause of acute lower respiratory infections in young children.•MMR vaccination was associated with 22% lower rate of RSV hospital contacts.•MMR vaccination may reduce the rate or severity of RSV infection.
Background
The live measles vaccine has been associated with lower non-measles mortality and admissions in low-income countries. The live measles–mumps–rubella vaccine has also been associated with lower rate of admissions with any type of infection in Danish children; the association was strongest for admissions with lower respiratory infections.
Objective
To examine whether measles, mumps, and rubella (MMR) vaccination was associated with reduced rate of hospital contact related to respiratory syncytial virus (RSV) in a high-income country.
Methods
Nationwide cohort study of laboratory-confirmed RSV hospital contacts at age 14–23 months in all children born in Denmark 1997–2002 who had already received the vaccine against diphtheria, tetanus, pertussis (acellular), polio, and Haemophilus influenzae type b (DTaP-IPV-Hib) at the recommended ages of 3, 5, and 12 months.
Results
The study included 888 RSV hospital contacts in 128,588 person years of follow up (rate 6.8/1000 person years). Having MMR as the most recent vaccine was associated with a reduced rate of RSV hospital contacts compared with having DTaP-IPV-Hib as the most recent vaccine (Incidence rate ratio (IRR), 0.75; 95% confidence interval (CI), 0.63–0.89). After adjustment for potential confounders including exact age in days the IRR was 0.78 (95% CI, 0.66–0.93). The adjusted IRR was 0.74 (95% CI, 0.60–0.92) in males and 0.84 (95% CI, 0.66–1.06) in females (P Interaction, 0.42). There was no association in the first month after MMR vaccination (adjusted IRR, 0.97; 95% CI, 0.76–1.24) but the adjusted IRR was 0.70 (95% CI, 0.58–0.85) from one month after MMR vaccination.
Conclusions
MMR vaccination was associated with reduced rate of hospital contacts related to laboratory-confirmed RSV infection. Further research on the association between MMR vaccination and other unrelated pathogens are warranted.
doi:10.1016/j.vaccine.2014.07.110
PMCID: PMC4270443  PMID: 25446818
CI, Confidence interval; DTaP-IPV-Hib, Inactivated vaccine against diphtheria, tetanus, pertussis (acellular), polio, and Haemophilus influenzae type b; GP, general practitioner; IRR, incidence rate ratio; MMR, Live vaccine against measles, mumps, and rubella; OPV, Oral polio vaccine; RSV, Respiratory syncytial virus; Heterologous immunity; Immunization; Non-specific effects; Non-targeted effects; Measles–mumps–rubella vaccination; Respiratory syncytial virus
2.  BCG coverage and barriers to BCG vaccination in Guinea-Bissau: an observational study 
BMC Public Health  2014;14(1):1037.
Background
BCG vaccination is recommended at birth in low-income countries, but vaccination is often delayed. Often 20-dose vials of BCG are not opened unless at least ten children are present for vaccination (“restricted vial-opening policy”). BCG coverage is usually reported as 12-month coverage, not disclosing the delay in vaccination. Several studies show that BCG at birth lowers neonatal mortality. We assessed BCG coverage at different ages and explored reasons for delay in BCG vaccination in rural Guinea-Bissau.
Methods
Bandim Health Project (BHP) runs a health and demographic surveillance system covering women and their children in 182 randomly selected village clusters in rural Guinea-Bissau. BCG coverage was assessed for children born in 2010, when the restricted vial-opening policy was universally implemented, and in 2012–2013, where BHP provided BCG to all children at monthly visits in selected intervention regions. Factors associated with delayed BCG vaccination were evaluated using logistic regression models. Coverage between intervention and control regions were evaluated in log-binomial regression models providing prevalence ratios.
Results
Among 3951 children born in 2010, vaccination status was assessed for 84%. BCG coverage by 1 week of age was 11%, 38% by 1 month, and 92% by 12 months. If BCG had been given at first contact with the health system, 1-week coverage would have been 35% and 1-month coverage 54%. When monthly visits were introduced in intervention regions, 1-month coverage was higher in intervention regions (88%) than in control regions (51%), the prevalence ratio being 1.74 (1.53-2.00). Several factors, including socioeconomic factors, were associated with delayed BCG vaccination in the 2010-birth cohort. When BCG was available at monthly visits these factors were no longer associated with delayed BCG vaccination, only region of residence was associated with delayed BCG vaccination.
Conclusion
BCG coverage during the first months of life is low in Guinea-Bissau. Providing BCG at monthly vaccination visits removes the risk factors associated with delayed BCG vaccination.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2458-14-1037) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2458-14-1037
PMCID: PMC4195857  PMID: 25282475
BCG; Coverage; Timeliness of vaccines; Implementation of the vaccination programme
3.  Measles Vaccination in the Presence or Absence of Maternal Measles Antibody: Impact on Child Survival 
In 2-dose trials, early measles vaccination at 4–6 months in presence of maternal measles antibody was associated with significantly better survival to age 5 years than vaccination in absence of measles antibody. Confounding factors did not explain the effect.
Background. Measles vaccine (MV) has a greater effect on child survival when administered in early infancy, when maternal antibody may still be present.
Methods. To test whether MV has a greater effect on overall survival if given in the presence of maternal measles antibody, we reanalyzed data from 2 previously published randomized trials of a 2-dose schedule with MV given at 4–6 months and at 9 months of age. In both trials antibody levels had been measured before early measles vaccination.
Results. In trial I (1993–1995), the mortality rate was 0.0 per 1000 person-years among children vaccinated with MV in the presence of maternal antibody and 32.3 per 1000 person-years without maternal antibody (mortality rate ratio [MRR], 0.0; 95% confidence interval [CI], 0–.52). In trial II (2003–2007), the mortality rate was 4.2 per 1000 person-years among children vaccinated in presence of maternal measles antibody and 14.5 per 1000 person-years without measles antibody (MRR, 0.29; 95% CI, .09–.91). Possible confounding factors did not explain the difference. In a combined analysis, children who had measles antibody detected when they received their first dose of MV at 4–6 months of age had lower mortality than children with no maternal antibody, the MRR being 0.22 (95% CI, .07–.64) between 4–6 months and 5 years.
Conclusions. Child mortality in low-income countries may be reduced by vaccinating against measles in the presence of maternal antibody, using a 2-dose schedule with the first dose at 4–6 months (earlier than currently recommended) and a booster dose at 9–12 months of age.
Clinical Trials Registration. NCT00168558.
doi:10.1093/cid/ciu354
PMCID: PMC4111916  PMID: 24829213
maternal measles antibodies; age of measles vaccination; nonspecific beneficial effects of measles vaccine; 2-dose measles vaccination
4.  Both Very Low- and Very High In Vitro Cytokine Responses Were Associated with Infant Death in Low-Birth-Weight Children from Guinea Bissau 
PLoS ONE  2014;9(4):e93562.
Background
The mechanisms behind heterologous immunity and non-specific effects of vaccines on mortality are not well understood. We examined associations between cytokine responses and subsequent mortality in low-birth-weight infants in Guinea-Bissau.
Methods
A low-birth-weight trial randomized children to Bacille Calmette-Guérin (BCG) at birth or later according to local policy. Blood samples were obtained from a sub-group at age 6 weeks. Interleukin (IL)-5, IL-10, IL-13, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α were measured in whole-blood cell cultures stimulated with lipopolysaccharide (LPS), phytohaemagglutinin (PHA), or purified protein derivative (PPD). The outcome was mortality between bleeding and 1 year of age. Non-linear associations between cytokine responses and mortality were examined.
Results
Cytokine measurements were available from 390 children. The mortality rate (MR) was high (6.8/100 person-years-observation (PYO)). Both low and high cytokine responses to LPS and PHA were associated with high mortality (MR up to 25/100 PYO in the lowest 10% and 9.2/100 PYO in the highest 10%). In BCG-vaccinated children, higher IFN-γ responses to PPD were associated with better survival (MR ratio = 0.43 (0.24–0.77)).
Conclusions
Data presented a rare opportunity to explore associations between cytokine responses and mortality. Both low and high cytokine responses were associated with high mortality; a balanced response to invading pathogens seems preferable.
doi:10.1371/journal.pone.0093562
PMCID: PMC3979682  PMID: 24714360
5.  The INDEPTH standard population for low- and middle-income countries, 2013 
Global Health Action  2014;7:10.3402/gha.v7.23286.
Crude rates such as the crude death rate are functions of both the age-specific rates and the age composition of a population. However, differences in the age structure between two populations or two time periods can result in specious differences in the corresponding crude rates making direct comparisons between populations or across time inappropriate. Therefore, when comparing crude rates between populations, it is desirable to eliminate or minimize the influence of age composition. This task is accomplished by using a standard age structure yielding an age-standardized rate. This paper proposes an updated International Network for the Demographic Evaluation of Populations and Their Health (INDEPTH) standard for use in low- and middle-income countries (LMICs) based on newly available data from the health and demographic surveillance system site members of the INDEPTH network located throughout Africa and southern Asia. The updated INDEPTH standard should better reflect the age structure of LMICs and result in more accurate health indicators and demographic rates. We demonstrate use of the new INDEPTH standard along with several existing ‘world’ standards and show how resulting age-standardized crude deaths rates differ when using the various standard age compositions.
doi:10.3402/gha.v7.23286
PMCID: PMC3969509  PMID: 24679543
crude death rate; age-specific mortality rate; age-standardized crude death rate; demography; standardized age structure; low- and middle-income countries
6.  A Randomized Trial of a Standard Dose of Edmonston-Zagreb Measles Vaccine Given at 4.5 Months of Age: Effect on Total Hospital Admissions 
The Journal of Infectious Diseases  2014;209(11):1731-1738.
Observational studies and trials from low-income countries indicate that measles vaccine has beneficial nonspecific effects, protecting against non–measles-related mortality. It is not known whether measles vaccine protects against hospital admissions. Between 2003 and 2007, 6417 children who had received the third dose of diphtheria, tetanus, and pertussis vaccine were randomly assigned to receive measles vaccine at 4.5 months or no measles vaccine; all children were offered measles vaccine at 9 months of age. Using hospital admission data from the national pediatric ward in Bissau, Guinea-Bissau, we compared admission rates between enrollment and the 9-month vaccination in Cox models, providing admission hazard rate ratios (HRRs) for measles vaccine versus no measles vaccine. All analyses were conducted stratified by sex and reception of neonatal vitamin A supplementation (NVAS). Before enrollment the 2 groups had similar admission rates. Following enrollment, the measles vaccine group had an admission HRR of 0.70 (95% confidence interval [CI], .52–.95), with a ratio of 0.53 (95% CI, .32–.86) for girls and 0.86 (95% CI, .58–1.26) for boys. For children who had not received NVAS, the admission HRR was 0.53 (95% CI, .34–.84), with an effect of 0.30 (95% CI, .13–.70) for girls and 0.73 (95% CI, .42–1.28) for boys (P = .08, interaction test). The reduction in admissions was separately significant for measles infection (admission HRR, 0 [95% CI, 0–.24]) and respiratory infections (admission HRR, 0.37 [95% CI, .16–.89]). Early measles vaccine may have major benefits for infant morbidity patterns and healthcare costs.
Clinical trials registration
NCT00168558.
doi:10.1093/infdis/jit804
PMCID: PMC4017359  PMID: 24436454
Edmonston-Zagreb; hospital admissions; measles infection; measles vaccination; morbidity reduction; nonspecific effects of vaccine
7.  Trends and determinants of mortality in women of reproductive age in rural Guinea-Bissau, West Africa – a cohort study 
BMC Women's Health  2013;13:48.
Background
There are few studies reporting mortality of women of reproductive age (WRA) in developing countries. The trend and patterns of their mortality may be important for documenting the health status of the population in general.
Methods
We used a prospective open cohort of women aged 12 to 49 years living in the Bandim Health Project’s rural Health and Demographic Surveillance System (HDSS) in 5 regions of Guinea-Bissau from 1996 to 2007. Information on in- and out-migration and deaths were collected through the HDSS routine procedures. We assessed the trends in mortality and the associated determinants using Cox regression models.
Results
We followed 27,185 WRA for 141,693 person-years-at-risk (PYO) among whom 9,093 moved out and 1,006 died. Overall standardized mortality rate was 759 per 100,000 PYO. WRA mortality did not decline, but three periods could be distinguished: a stable mortality between 1996–2000 followed by 14% increase in mortality [Hazard rate ratio (HRR) = 1.14; 95% confidence interval (CI): 0.98-1.32; p = 0.08] between 2001–2003, and then in the last period from 2004–2007 a 25% decline (HRR = 0.75; 95% CI: 0.64-0.87; p < 0.001) in relation to the first period. Compared with the years 1990–1996 mortality increased in the first two periods until 2003; only in the last period did mortality reach the same level as in 1990–1996 (HRR = 0.96; 95% CI: 0.82-1.13; p = 0.62). The level of mortality differed between regions. In the adjusted analysis the eastern regions Bafata (HRR = 1.79; 95% CI: 1.38-2.32; p < 0.001) and Gabu (HRR = 1.70; 95% CI: 1.28-2.26; p < 0.001) had significantly higher mortality, but the hazard rate did not differ by ethnic group. As expected the rate increased with increasing age.
Conclusions
Over the twelve-year period mortality of WRA did not decline. A stable mortality in the beginning was followed by an increase and then a return to the previous levels. Further monitoring of mortality is needed to identify the risk factors for the striking regional differences. Advantage should be taken of the HDSS to monitor progress towards the MDGs and beyond.
doi:10.1186/1472-6874-13-48
PMCID: PMC4235026  PMID: 24304945
Women of reproductive age; Mortality; West Africa
8.  The effect of neonatal vitamin A supplementation on growth in the first year of life among low-birth-weight infants in Guinea-Bissau: two by two factorial randomised controlled trial 
BMC Pediatrics  2013;13:87.
Background
Vitamin A supplementation (VAS) may amplify the effect of vaccines. We therefore investigated if neonatal VAS given with and without Bacille Calmette-Guérin (BCG) vaccine to low-birth-weight (LBW) neonates had an effect on growth in the first year of life. We hypothesised that VAS would be particularly beneficial when provided with BCG.
Methods
We conducted a randomised two-by-two factorial trial in Guinea-Bissau; 1,717 LBW neonates were randomly allocated to VAS or placebo at birth as well as early or the usual postponed BCG vaccination. Anthropometric measurements were obtained at 2, 6, and 12 months after inclusion.
Results
Overall there was no effect of neonatal VAS on growth in the first year of life. By 2 months, VAS tended to have a beneficial effect on weight and head circumference when given with BCG but not when given without BCG (interaction: weight-for-age p = 0.07 and head circumference-for-age: p = 0.06). By 6 months, there was a beneficial effect of VAS on head circumference and weight among children who had not received DTP vaccine 2 months after inclusion (weight: 0.18 (0.00; 0.36) and head circumference 0.27 (0.06; 0.48)), but no beneficial effect among those who had received DTP.
Conclusion
The results support other trials indicating that neonatal VAS does not have consistent effects on childhood growth and if anything the effects seem to be temporary. They also show that the effect may differ by vaccination status, being beneficial when given with BCG at birth and when DTP is delayed.
Trial registration
http://www.ClinicalTrials.gov (NCT00168610) (nct00168610)
doi:10.1186/1471-2431-13-87
PMCID: PMC3680237  PMID: 23702185
Neonatal vitamin A supplementation; Low-birth-weight; Growth; Non-specific effects; DTP; BCG
9.  Determinants of vitamin a deficiency in children between 6 months and 2 years of age in Guinea-Bissau 
BMC Public Health  2013;13:172.
Background
The World Health Organization (WHO) classifies Guinea-Bissau as having severe vitamin A deficiency (VAD). To date, no national survey has been conducted. We assessed vitamin A status among children in rural Guinea-Bissau to assess status and identify risk factors for VAD.
Methods
In a vitamin A supplementation trial in rural Guinea-Bissau, children aged 6 months to 2 years who were missing one or more vaccines were enrolled, vaccinated and randomized to vitamin A or placebo. Provided consent, a dried blood spot (DBS) sample was obtained from a subgroup of participants prior to supplementation. Vitamin A status and current infection was assessed by an ELISA measuring retinol-binding protein (RBP) and C-reactive protein (CRP). VAD was defined as RBP concentrations equivalent to plasma retinol <0.7 μmol/L; infection was defined as CRP >5 ml/L. In Poisson regression models providing prevalence ratios (PR), we investigated putative risk factors for VAD including sex, age, child factors, maternal factors, season (rainy: June-November; dry: December-May), geography, and use of health services.
Results
Based on DBS from 1102 children, the VAD prevalence was 65.7% (95% confidence interval 62.9-68.5), 11% higher than the WHO estimate of 54.7% (9.9-93.0). If children with infection were excluded, the prevalence was 60.2% (56.7-63.7). In the age group 9–11 months, there was no difference in prevalence of VAD among children who had received previous vaccines in a timely fashion and those who had not. Controlled for infection and other determinants of VAD, the prevalence of VAD was 1.64 (1.49-1.81) times higher in the rainy season compared to the dry, and varied up to 2-fold between ethnic groups and regions. Compared with having an inactivated vaccine as the most recent vaccine, having a live vaccine as the most recent vaccination was associated with lower prevalence of VAD (PR=0.84 (0.74-0.96)).
Conclusions
The prevalence of VAD was high in rural Guinea-Bissau. VAD varied significantly with season, ethnicity, region, and vaccination status.
Trial registration
Clinicaltrials.gov NCT00514891
doi:10.1186/1471-2458-13-172
PMCID: PMC3599523  PMID: 23442248
Vitamin A deficiency; Children; Guinea-Bissau; Risk factors; Retinol-binding protein
10.  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
11.  Non-specific effects of standard measles vaccine at 4.5 and 9 months of age on childhood mortality: randomised controlled trial 
Objective To examine in a randomised trial whether a 25% difference in mortality exists between 4.5 months and 3 years of age for children given two standard doses of Edmonston-Zagreb measles vaccines at 4.5 and 9 months of age compared with those given one dose of measles vaccine at 9 months of age (current policy).
Design Randomised controlled trial.
Setting The Bandim Health Project, Guinea-Bissau, which maintains a health and demographic surveillance system in an urban area.
Participants 6648 children aged 4.5 months of age who had received three doses of diphtheria-tetanus-pertussis vaccine at least four weeks before enrolment. A large proportion of the children (80%) had previously taken part in randomised trials of neonatal vitamin A supplementation.
Intervention Children were randomised to receive Edmonston-Zagreb measles vaccine at 4.5 and 9 months of age (group A), no vaccine at 4.5 months and Edmonston-Zagreb measles vaccine at 9 months of age (group B), or no vaccine at 4.5 months and Schwarz measles vaccine at 9 months of age (group C).
Main outcome measure Mortality rate ratio between 4.5 and 36 months of age for group A compared with groups B and C. Secondary outcomes tested the hypothesis that the beneficial effect was stronger in the 4.5 to 9 months age group, in girls, and in the dry season, but the study was not powered to test whether effects differed significantly between subgroups.
Results In the intention to treat analysis of mortality between 4.5 and 36 months of age the mortality rate ratio of children who received two doses of Edmonston-Zagreb vaccine at 4.5 and 9 months of age compared with those who received a single dose of Edmonston-Zagreb vaccine or Schwarz vaccine at 9 months of age was 0.78 (95% confidence interval 0.59 to 1.05). In the analyses of secondary outcomes, the intention to treat mortality rate ratio was 0.67 (0.38 to 1.19) between 4.5 and 9 months and 0.83 (0.83 to 1.16) between 9 and 36 months of age. The effect on mortality between 4.5 and 36 months of age was significant for girls (intention to treat mortality rate ratio 0.64 (0.42 to 0.98)), although this was not significantly different from the effect in boys (0.95 (0.64 to 1.42)) (interaction test, P=0.18). The effect did not differ between the dry season and the rainy season. As neonatal vitamin A supplementation is not WHO policy, the analyses were done separately for the 3402 children who did not receive neonatal vitamin A. In these children, the two dose Edmonston-Zagreb measles vaccine schedule was associated with a significantly lower mortality between 4.5 and 36 months of age (intention to treat mortality rate ratio 0.59 (0.39 to 0.89)). The effect was again significant for girls but not statistically significant from the effect in boys. When measles cases were censored, the intention to treat mortality rate ratio was 0.65 (0.43 to 0.99).
Conclusions Although the overall effect did not reach statistical significance, the results may indicate that a two dose schedule with Edmonston-Zagreb measles vaccine given at 4.5 and 9 months of age has beneficial non-specific effects on children’s survival, particularly for girls and for children who have not received neonatal vitamin A. This should be tested in future studies in different locations.
Trial registration Clinical trials NCT00168558.
doi:10.1136/bmj.c6495
PMCID: PMC2994348  PMID: 21118875
12.  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
13.  Vitamin A supplementation and BCG vaccination at birth in low birthweight neonates: two by two factorial randomised controlled trial 
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.
doi:10.1136/bmj.c1101
PMCID: PMC2835853  PMID: 20215360
14.  Sex-Differential Effect on Infant Mortality of Oral Polio Vaccine Administered with BCG at Birth in Guinea-Bissau. A Natural Experiment 
PLoS ONE  2008;3(12):e4056.
Background
The policy to provide oral polio vaccine (OPV) at birth was introduced in low-income countries to increase coverage. The effect of OPV at birth on overall child mortality was never studied. During a trial of vitamin A supplementation (VAS) at birth in Guinea-Bissau, OPV was not available during several periods. We took advantage of this “natural experiment” to test the effect on mortality of receiving OPV at birth.
Methodology
Between 2002 and 2004, the VAS trial randomised normal-birth-weight infants to 50,000 IU VAS or placebo administered with BCG. Provision of OPV at birth was not part of the trial, but we noted whether the infants received OPV or not. OPV was missing during several periods in 2004. We used Cox proportional hazards models to compute mortality rate ratios (MRR) of children who had received or not received OPV at birth.
Principal Findings
A total of 962 (22.1%) of the 4345 enrolled children did not receive OPV at birth; 179 children died within the first year of life. Missing OPV at birth was associated with a tendency for decreased mortality (adjusted MRR = 0.69 (95% CI = 0.46–1.03)), the effect being similar among recipients of VAS and placebo. There was a highly significant interaction between OPV at birth and sex (p = 0.006). Not receiving OPV at birth was associated with a weak tendency for increased mortality in girls (1.14 (0.70–1.89)) but significantly decreased mortality in boys (0.35 (0.18–0.71)).
Conclusions
In our study OPV at birth had a sex-differential effect on mortality. Poliovirus is almost eradicated and OPV at birth contributes little to herd immunity. A randomised study of the effect of OPV at birth on overall mortality in both sexes is warranted.
doi:10.1371/journal.pone.0004056
PMCID: PMC2605256  PMID: 19112511
15.  The effect of vitamin A supplementation administered with missing vaccines during national immunization days in Guinea-Bissau 
Background WHO recommends high-dose Vitamin A supplementation (VAS) at vaccination contacts after 6 months of age. It has not been studied whether the effect of VAS on mortality depends on the type of vaccine. We have hypothesized that VAS administered with measles vaccine (MV) is more beneficial than VAS with diphtheria–tetanus–pertussis (DTP) vaccine. We assessed the effect of VAS administered with different vaccines during national immunization days (NIDs).
Methods In 2003, VAS was distributed during NIDs in Guinea-Bissau. Children 6 months or older were given VAS, and if they were missing vaccines, these were often given as well. We compared survival between children who had received VAS alone, VAS with DTP or DTP + MV, or VAS with MV. We also compared the survival between participants and non-participants. We followed 6- to 17-month old children until 18 months of age and analysed survival in Cox models.
Results Twenty of 982 VAS-recipients died during follow-up. The mortality rate ratio (MRR) for VAS with DTP + MV or VAS with DTP was 3.43 (1.36–8.61) compared with VAS only. There were no deaths among those who received VAS with MV alone (P = 0.0005 for homogeneity of VAS effects). Children who received VAS with DTP had higher mortality than non-participants who did not receive VAS [MRR = 3.04 (1.31–7.07)].
Conclusion The study design does not allow for definite conclusions. However, the results are compatible with our a priori hypothesis that VAS is more beneficial when given with MV and potentially harmful when given with DTP. Randomized trials testing the impact on mortality of the current WHO policy seem warranted.
doi:10.1093/ije/dyn195
PMCID: PMC2639368  PMID: 18796481
Vitamin A; diphtheria–tetanus–pertussis vaccine; measles vaccine; child mortality; low income populations
16.  Protective efficacy of standard Edmonston-Zagreb measles vaccination in infants aged 4.5 months: interim analysis of a randomised clinical trial 
Objective To examine the protective efficacy of measles vaccination in infants in a low income country before 9 months of age.
Design Randomised clinical trial.
Participants 1333 infants aged 4.5 months: 441 in treatment group and 892 in control group.
Setting Urban area in Guinea-Bissau.
Intervention Measles vaccination using standard titre Edmonston-Zagreb vaccine at 4.5 months of age.
Main outcome measures Vaccine efficacy against measles infection, admission to hospital for measles, and measles mortality before standard vaccination at 9 months of age.
Results 28% of the children tested at 4.5 months of age had protective levels of maternal antibodies against measles at enrolment. After early vaccination against measles 92% had measles antibodies at 9 months of age. A measles outbreak offered a unique situation for testing the efficacy of early measles vaccination. During the outbreak, 96 children developed measles; 19% of unvaccinated children had measles before 9 months of age. The monthly incidence of measles among the 441 children enrolled in the treatment arm was 0.7% and among the 892 enrolled in the control arm was 3.1%. Early vaccination with the Edmonston-Zagreb measles vaccine prevented infection; vaccine efficacy for children with serologically confirmed measles and definite clinical measles was 94% (95% confidence interval 77% to 99%), for admissions to hospital for measles was 100% (46% to 100%), and for measles mortality was 100% (−42% to 100%). The number needed to treat to prevent one case of measles between ages 4.5 months and 9 months during the epidemic was 7.2 (6.8 to 9.2). The treatment group tended to have lower overall mortality (mortality rate ratio 0.18, 0.02 to 1.36) although this was not significant.
Conclusions In low income countries, maternal antibody levels against measles may be low and severe outbreaks of measles can occur in infants before the recommended age of vaccination at 9 months. Outbreaks of measles may be curtailed by measles vaccination using the Edmonston-Zagreb vaccine as early as 4.5 months of age.
Trial registration Clinical Trials NCT00168558 [ClinicalTrials.gov].
doi:10.1136/bmj.a661
PMCID: PMC2500198  PMID: 18653640
17.  Mortality associated with HIV-1, HIV-2, and HTLV-I single and dual infections in a middle-aged and older population in Guinea-Bissau 
Retrovirology  2007;4:85.
Background
In Guinea-Bissau HIV-1, HIV-2, and HTLV-I are prevalent in the general population. The natural history of HIV/HTLV-I single and dual infections has not been fully elucidated in this population. Previous studies have shown that combinations of these infections are more common in older women than in men. The present study compares mortality associated with HIV-1, HIV-2, and HTLV-I single and dual infections in individuals over 35 years of age within an urban community-based cohort in Guinea-Bissau.
Results
A total of 2,839 and 1,075 individuals were included in the HIV and HTLV-I mortality analyses respectively. Compared with HIV-negative individuals, adjusted mortality rate ratios (MRRs) were 4.9 (95% confidence interval (CI): 2.3, 10.4) for HIV-1, 1.8 (95%CI: 1.5, 2.3) for HIV-2, and 5.9 (2.4, 14.3) for HIV-1/HIV-2 dual infections. MRR for HTLV-I-positive compared with HTLV-I-negative individuals was 1.7 (1.1, 2.7). Excluding all HIV-positive individuals from the analysis, the HTLV-I MRR was 2.3 (1.3, 3.8). The MRR of HTLV-I/HIV-2 dually infected individuals was 1.7 (0.7, 4.3), compared with HIV/HTLV-I-negative individuals. No statistically significant differences were found in retrovirus-associated mortality between men and women.
Conclusion
HIV-1-associated excess mortality was low compared with community studies from other parts of Africa, presumably because this population was older and the introduction of HIV-1 into the community recent. HIV-2 and HTLV-I-associated mortality was 2-fold higher than the mortality in uninfected individuals. We found no significant differences between the mortality risk for HIV-2 and HTLV-I single infection, respectively, and HIV-2/HTLV-I dual infection. The higher prevalence of retroviral dual infections in older women is not explained by differential retrovirus-associated mortality for men and women.
doi:10.1186/1742-4690-4-85
PMCID: PMC2222662  PMID: 18042276
18.  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
19.  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

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