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1.  Heterologous Immunological Effects of Early BCG Vaccination in Low-Birth-Weight Infants in Guinea-Bissau: A Randomized-controlled Trial 
The Journal of Infectious Diseases  2014;211(6):956-967.
Background. Bacillus Calmette–Guérin (BCG) seems to have beneficial nonspecific effects; early BCG vaccination of low-birth-weight (LBW) newborns reduces neonatal mortality by >40% due to prevention of primarily septicemia and pneumonia.
Methods. Within a randomized trial in LBW infants in Guinea-Bissau of early BCG vs the usual postponed BCG, a subgroup was bled 4 weeks after randomization. Levels of interleukin (IL)-1β, IL-5, IL-6, IL-10, IL-17, interferon (IFN)-γ and tumor necrosis factor (TNF)-α were measured from whole-blood assays stimulated with innate agonists to Toll-like receptor (TLR)-2, -4 or -7/8, or purified protein derivative (PPD).
Results. Among 467 infants, BCG significantly increased the in vitro cytokine responses to purified protein derivative of Mycobacterium tuberculosis (PPD), as expected. BCG was also associated with increased responses to heterologous innate stimulation, particularly of the cytokines IL-1β, IL-6, TNF-α, and IFN-γ.
Conclusion. Four weeks after immunization, BCG-vaccinated infants have a significantly increased production of cytokines upon heterologous challenge, particularly T helper cell type 1 polarizing and typically monocyte-derived pro-inflammatory cytokines. BCG may accelerate the development of the neonatal immune system, mediating comprehensive protection against infections and mortality.
PMCID: PMC4340366  PMID: 25210141
BCG; heterologous immunity; nonspecific effects; cytokines; infants; Africa
2.  Neonatal vitamin A supplementation associated with a cluster of deaths and poor early growth in a randomised trial among low-birth-weight boys of vitamin A versus oral polio vaccine at birth 
BMC Pediatrics  2014;14:214.
The effect of oral polio vaccine administered already at birth (OPV0) on child survival was not examined before being recommended in 1985. Observational data suggested that OPV0 was harmful for boys, and trials have shown that neonatal vitamin A supplementation (NVAS) at birth may be beneficial for boys. We set out to test this research question in a randomised trial.
The trial was carried out at the Bandim Health Project, Guinea-Bissau. We planned to enrol 900 low-birth weight (LBW) boys in a randomised trial to investigate whether NVAS instead of OPV0 could lower infant mortality for LBW boys. At birth, the children were randomised to OPV (usual treatment) or VAS (intervention treatment) and followed for 6 months for growth and 12 months for survival. Hazard Ratios (HR) for mortality were calculated using Cox regression. We compared the individual anthropometry measurements to the 2006 WHO growth reference. We compared differences in z-scores by linear regression. Relative risks (RR) of being stunted or underweight were calculated in Poisson regression models with robust standard errors.
In the rainy season we detected a cluster of deaths in the VAS group and the trial was halted immediately with 232 boys enrolled. The VAS group had significantly higher mortality than the OPV0 group in the rainy season (HR: 9.91 (1.23 – 80)). All deaths had had contact with the neonatal nursery; of seven VAS boys enrolled during one week in September, six died within two months of age, whereas only one died among the six boys receiving OPV (p = 0.05). Growth (weight and arm-circumference) in the VAS group was significantly worse until age 3 months.
VAS at birth instead of OPV was not beneficial for the LBW boys in this study. With the premature closure of the trial it was not possible to answer the research question. However, the results of this study call for extra caution when testing the effect of NVAS in the future.
Trial registration NCT00625482. Registered 18 February 2008.
PMCID: PMC4236664  PMID: 25163399
Vitamin A supplementation; Oral polio vaccine; Neonate; Cluster; Mortality; Growth
3.  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.
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.
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.
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.
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 (NCT00168610) (nct00168610)
PMCID: PMC3680237  PMID: 23702185
Neonatal vitamin A supplementation; Low-birth-weight; Growth; Non-specific effects; DTP; BCG
4.  Does the effect of vitamin A supplements depend on vaccination status? An observational study from Guinea-Bissau 
BMJ Open  2012;2(1):e000448.
Vitamin A supplementation (VAS) is estimated to reduce all-cause mortality by 24%. Previous studies indicate that the effect of VAS may vary with vaccination status. The authors evaluated the effect of VAS provided in campaigns on child survival overall and by sex and vaccination status at the time of supplementation.
Observational cohort study.
Setting and participants
The study was conducted in the urban study area of the Bandim Health Project in Guinea-Bissau. The authors documented participation or non-participation in two national vitamin A campaigns in December 2007 and July 2008 for children between 6 and 35 months of age. Vaccination status was ascertained by inspection of vaccination cards. All children were followed prospectively.
Outcome measures
Mortality rates for supplemented and non-supplemented children were compared in Cox models providing mortality rate ratios (MRRs).
The authors obtained information from 93% of 5567 children in 2007 and 90% of 5799 children in 2008. The VAS coverage was 58% in 2007 and 68% in 2008. Mortality in the supplemented group was 1.5% (44 deaths/2873 person-years) and 1.6% (20 deaths/1260 person-years) in the non-supplemented group (adjusted MRR=0.78 (0.46; 1.34)). The effect was similar in boys and girls. Vaccination cards were seen for 86% in 2007 and 84% in 2008. The effect of VAS in children who had measles vaccine as their last vaccine (2814 children, adjusted MRR=0.34 (0.14; 0.85)) differed from the effect in children who had diphtheria–tetanus–pertussis vaccine as their last vaccine (3680 children, adjusted MRR=1.29 (0.52; 3.22), p=0.04 for interaction).
The effect of VAS differed by most recent vaccination, being beneficial after measles vaccine but not after diphtheria–tetanus–pertussis vaccine.
Article summary
Article focus
Vitamin A supplementation (VAS) is estimated to reduce all-cause mortality by 24%.
The effect of VAS may vary with vaccination status, being beneficial with or after measles vaccine (MV) but not after diphtheria–tetanus–pertussis (DTP) vaccine.
Key messages
The effect of VAS is heterogeneous.
The effect of VAS varied with vaccination status: supplemented children had lower mortality than non-supplemented children when MV was the most recent vaccine but not when DTP was the most recent vaccine.
The effect of VAS tended to differ by season of supplementation.
Strengths and limitations of this study
Information was collected on the individual level, and the children were followed prospectively.
Due to the observational nature of the study, the comparison of supplemented and non-supplemented children should be interpreted with caution.
However, a selection bias is unlikely to have worked in different directions for children who had DTP and MV as the most recent vaccine.
PMCID: PMC3278485  PMID: 22240648
5.  Non-participation in preventive child health examinations at the general practitioner in Denmark: A register-based study 
To examine demographic and socioeconomic characteristics of parents and children in families not participating in preventive child health examinations at the general practitioner in a society with free and easy access to healthcare.
Population-covering register linkage study.
Denmark, 2002–2004.
Two cohorts comprising all children born in Denmark between 1 July 1998 and 30 June 1999 (n =70 891) and in 2002 (n =65 995), respectively. The demographic and socioeconomic characteristics of these children and the adults living in the same household as these were identified through register linkage.
Main outcome measures
Crude and mutually adjusted odds ratios for non-participation in scheduled preventive child health examinations at the GP (age 5 weeks, 5 months, 12 months, 4 years, and 5 years) according to child characteristics (sex, number of hospitalizations, and older siblings) and parental characteristics (age, educational level, attachment to labour market, ethnicity, household income, and number of adults in the household).
Children of young and single parents were less likely to receive a preventive child health examination. Increased odds ratios for non-participation were found for children of parents outside the labour market, with low educational level, and especially for the combination of these. Non-participation increased with decreasing household income and with the number of older siblings.
Despite the fact that Denmark has free and easy access to the GP, the utilization of preventive child health examinations is lower among the more deprived part of the population.
PMCID: PMC3406629  PMID: 18297556
Child public health; family; family practice; general practice; prevention; socioeconomic gradient
6.  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.
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.
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.
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.
Surprisingly, even though the children with the best nutritional status were vaccinated early, early DTP vaccination was associated with increased mortality for girls.
PMCID: PMC3409557  PMID: 22331681

Results 1-6 (6)