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1.  Long-lasting effects of BCG vaccination on both heterologous Th1/Th17 responses and innate trained immunity 
Journal of innate immunity  2013;6(2):152-158.
We have recently shown that BCG vaccination in healthy volunteers induces epigenetic reprogramming of monocytes, leading to increased cytokine production in response to non-related pathogens for up to three months after vaccination. This phenomenon was named ‘trained immunity’. In the present study we assessed whether BCG was able to induce long-lasting effects on both trained immunity and heterologous T-helper 1 (Th1) and Th17 immune responses one year after vaccination. The production of TNFα and IL-1β to mycobacteria or unrelated pathogens was higher after two weeks and three3 months post-vaccination, but these effects were less pronounced one year after vaccination. However, monocytes recovered one year after vaccination had an increased expression of pattern recognition receptors such as CD14, TLR4, and mannose receptor, and this correlated with an increase in pro-inflammatory cytokine production after stimulation with the TLR4 ligand lipopolysaccharide. The heterologous production of Th1 (IFN-gamma) and Th17 (interleukin (IL)-17 and IL-22) immune responses to non-mycobacterial stimulation remained strongly elevated even one year after BCG vaccination. In conclusion, BCG induces sustained changes in the immune system associated with non-specific response to infections both at the level of innate trained immunity, as well as at the level of heterologous Th1/Th17 responses.
doi:10.1159/000355628
PMCID: PMC3944069  PMID: 24192057
Innate immunity; BCG vaccination; trained immunity
2.  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
3.  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
4.  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.
Background
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.
Methods
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.
Results
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.
Conclusion
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
http://www.clinicaltrials.gov NCT00625482. Registered 18 February 2008.
doi:10.1186/1471-2431-14-214
PMCID: PMC4236664  PMID: 25163399
Vitamin A supplementation; Oral polio vaccine; Neonate; Cluster; Mortality; Growth
5.  A Randomized Trial of an Early Measles Vaccine at 4½ Months of Age in Guinea-Bissau: Sex-Differential Immunological Effects 
PLoS ONE  2014;9(5):e97536.
Background
After measles vaccine (MV), all-cause mortality is reduced more than can be explained by the prevention of measles, especially in females.
Objective
We aimed to study the biological mechanisms underlying the observed non-specific and sex-differential effects of MV on mortality.
Methods
Within a large randomised trial of MV at 4.5 months of age blood samples were obtained before and six weeks after randomisation to early MV or no early MV. We measured concentrations of cytokines and soluble receptors from plasma (interleukin-1 receptor agonist (IL-1Ra), IL-6, IL-8, IL-10, tumor necrosis factor (TNF)-α, monocyte chemoattractant protein (MCP)-1, soluble urokinase-type plasminogen activator receptor), and secreted cytokines (interferon-γ, TNF-α, IL-5, IL-10, IL-13, IL-17) after in vitro challenge with innate agonists and recall antigens. We analysed the effect of MV in multiple imputation regression, overall and stratified by sex. The majority of the infants had previously been enrolled in a randomised trial of neonatal vitamin A. Post hoc we explored the potential effect modification by neonatal vitamin A.
Results
Overall, MV versus no MV was associated with higher plasma MCP-1 levels, but the effect was only significant among females. Additionally, MV was associated with increased plasma IL-1Ra. MV had significantly positive effects on plasma IL-1Ra and IL-8 levels in females, but not in males. These effects were strongest in vitamin A supplemented infants. Vitamin A shifted the effect of MV in a pro-inflammatory direction.
Conclusions
In this explorative study we found indications of sex-differential effects of MV on several of the plasma biomarkers investigated; in particular MV increased levels in females, most strongly in vitamin A recipients. The findings support that sex and micronutrient supplementation should be taken into account when analysing vaccine effects.
Trial Registration
clinicaltrials.gov number NCT 00168545
doi:10.1371/journal.pone.0097536
PMCID: PMC4024025  PMID: 24835247
6.  Vitamin A supplementation and risk of atopy: long-term follow-up of a randomized trial of vitamin A supplementation at six and nine months of age 
BMC Pediatrics  2013;13:190.
Background
The World Health Organization recommends high-dose vitamin A supplementation (VAS) for children above six months of age in low-income countries. VAS has been associated with up-regulation of the Th2 response. We aimed to determine if VAS is associated with atopy in childhood.
Methods
Infants in Guinea-Bissau were randomly allocated VAS or placebo, either at six and nine months of age, or only at nine months of age. At six months of age, children were furthermore randomized to measles vaccine or inactivated polio vaccine. At nine months of age all children received measles vaccine. Children were revisited seven years later and skin prick testing was performed. Atopy was defined as a skin prick reaction ≥3 mm.
Results
40 of 263 children (15%) were atopic. Overall VAS had no significant effect on the risk of atopy (Prevalence Ratio 1.23; 95% CI 0.69-2.18). The Prevalence Ratio was 1.60 (0.66-3.90) for males and 1.00 (0.46-2.15) for females.
Conclusions
There was no significant effect of VAS in infancy on atopy later in childhood. The role of infant VAS in the development of atopy is still unclear.
doi:10.1186/1471-2431-13-190
PMCID: PMC3871024  PMID: 24252418
Atopy; Immunization; Measles vaccine; Vitamin A supplementation
7.  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
8.  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
9.  A prospective study of twinning and perinatal mortality in urban Guinea-Bissau 
Background
Despite twinning being common in Africa, few prospective twin studies have been conducted. We studied twinning rate, perinatal mortality and the clinical characteristics of newborn twins in urban Guinea-Bissau.
Methods
The study was conducted at the Bandim Health Project (BHP), a health and demographic surveillance site in Bissau, the capital of Guinea-Bissau. The cohort included all newborn twins delivered at the National Hospital Simão Mendes and in the BHP study area during the period September 2009 to August 2011 as well as singleton controls from the BHP study area. Data regarding obstetric history and pregnancy were collected at the hospital. Live children were examined clinically. For a subset of twin pairs zygosity was established by using genetic markers.
Results
Out of the 5262 births from mothers included in the BHP study area, 94 were twin births, i.e. a community twinning rate of 18/1000. The monozygotic rate was 3.4/1000. Perinatal mortality among twins vs. singletons was 218/1000 vs. 80/1000 (RR = 2.71, 95% CI: 1.93-3.80). Among the 13783 hospital births 388 were twin births (28/1000). The hospital perinatal twin mortality was 237/1000.
Birth weight < 2000g (RR = 4.24, CI: 2.39-7.51) and caesarean section (RR = 1.78, CI: 1.06-2.99) were significant risk factors for perinatal twin mortality. Male sex (RR = 1.38, CI: 0.97-1.96), unawareness of twin pregnancy (RR = 1.64, CI: 0.97-2.78) and high blood pressure during pregnancy (RR = 1.77, CI: 0.88-3.57) were borderline non-significant. Sixty-five percent (245/375) of the mothers who delivered at the hospital were unaware of their twin pregnancy.
Conclusions
Twins had a very high perinatal mortality, three-fold higher than singletons. A birth weight < 2000g was the strongest risk factor for perinatal death, and unrecognized twin pregnancy was common. Urgent interventions are needed to lower perinatal twin mortality in Guinea-Bissau.
doi:10.1186/1471-2393-12-140
PMCID: PMC3534574  PMID: 23216795
10.  Vaccination coverage and out-of-sequence vaccinations in rural Guinea-Bissau: an observational cohort study 
BMJ Open  2012;2(6):e001509.
Objective
The WHO aims for 90% coverage of the Expanded Program on Immunization (EPI), which in Guinea-Bissau included BCG vaccine at birth, three doses of diphtheria−tetanus−pertussis vaccine (DTP) and oral polio vaccine (OPV) at 6, 10 and 14 weeks and measles vaccine (MV) at 9 months when this study was conducted. The WHO assesses coverage by 12 months of age. The sequence of vaccines may have an effect on child mortality, but is not considered in official statistics or assessments of programme performance. We assessed vaccination coverage and frequency of out-of-sequence vaccinations by 12 and 24 months of age.
Design
Observational cohort study.
Setting and participants
The Bandim Health Project's (BHP) rural Health and Demographic Surveillance site covers 258 randomly selected villages in all regions of Guinea-Bissau. Villages are visited biannually and vaccination cards inspected to ascertain vaccination status. Between 2003 and 2009 vaccination status by 12 months of age was assessed for 5806 children aged 12–23 months; vaccination status by 24 months of age was assessed for 3792 children aged 24–35 months.
Outcome measures
Coverage of EPI vaccinations and frequency of out-of-sequence vaccinations.
Results
Half of 12-month-old children and 65% of 24-month-old children had completed all EPI vaccinations. Many children received vaccines out of sequence: by 12 months of age 54% of BCG-vaccinated children had received DTP with or before BCG and 28% of measles-vaccinated children had received DTP with or after MV. By 24 months of age the proportion of out-of-sequence vaccinations was 58% and 35%, respectively, for BCG and MV.
Conclusions
In rural Guinea-Bissau vaccination coverage by 12 months of age was low, but continued to increase beyond 12 months of age. More than half of all children received vaccinations out of sequence. This highlights the need to improve vaccination services.
doi:10.1136/bmjopen-2012-001509
PMCID: PMC3532986  PMID: 23166127
11.  The Effect of 50 000 IU Vitamin A with BCG Vaccine at Birth on Growth in the First Year of Life 
Journal of Tropical Medicine  2011;2011:570170.
Vitamin A supplements may interact with diphtheria-tetanus-pertussis (DTP) vaccine causing increased female mortality. In a randomised trial of neonatal vitamin A supplementation (VAS), we examined growth during the first year of life in 808 children, pursuing the hypothesis that a negative interaction between VAS and DTP in girls would be reflected in growth. Length and weight were measured at 6 weekly visits and WHO-growth-reference z-scores derived. Neonatal VAS had no effect on anthropometric measures at 12 months, but may interact sex differentially with routine vaccines. While BCG was the most recent vaccine, neonatal VAS benefitted growth (difference in weight-for-length z-score (dWFL: 0.31(95% CI: 0.03–0.59)). While DTP was the most recent vaccine, VAS tended to affect growth adversely in girls (dWFL = −0.21 (−0.48–0.06)). After measles vaccine (MV) there was no overall effect of neonatal VAS. The VAS effect differed significantly between the BCG and DTP windows (P = 0.03), and the difference was borderline significant between the DTP and MV windows for girls (P = 0.09).
doi:10.1155/2011/570170
PMCID: PMC3170791  PMID: 21912559
12.  Vitamin A Supplementation at Birth Might Prime the Response to Subsequent Vitamin A Supplements in Girls. Three Year Follow-Up of a Randomized Trial 
PLoS ONE  2011;6(8):e23265.
Objectives
Within a randomised trial of neonatal vitamin A supplementation (VAS) in Guinea-Bissau, neonatal VAS did not affect overall infant mortality. We conducted a post-hoc analysis to test the hypothesis that neonatal VAS primes the response to subsequent vitamin A.
Methods
All trial children were offered VAS after follow-up ended at 1 year of age (FU-VAS). We compared mortality between 1 and 3 years of age according to initial randomization to neonatal VAS or placebo in Cox-regression models; we expected that children randomized to neonatal VAS compared with those randomized to placebo would have lower mortality after reception of FU-VAS.
Results
Of 4345 infants enrolled in the original trial, 3646 lived in the study area at 1 year of age and 2958 received FU-VAS. Between 1 and 3 years of age, 112 children died. After FU-VAS, neonatal VAS was associated with lower mortality than placebo: Mortality Rate Ratio (MRR) = 0.54 (95%CI: 0.31–0.94). The effect was more pronounced in girls (MRR = 0.37 (0.16–0.89)) than boys (MRR = 0.73 (0.35–1.51)). The beneficial effect of neonatal VAS may have been particularly strong for girls who received both VAS in a campaign and FU-VAS (MRR = 0.15 (0.03–0.67)). Among children who had not received FU-VAS, mortality in the second and third year of life did not differ according to reception of neonatal VAS or placebo. Hence, in the second and third year of life the effect of neonatal VAS versus placebo was different in girls who had or had not received FU-VAS (p for homogeneity = 0.01).
Conclusions
The present results suggest that neonatal VAS primes the response in girls such that they get a beneficial effect after a subsequent dose of VAS.
Trial Registration
Clinicaltrials.gov NCT00168597
doi:10.1371/journal.pone.0023265
PMCID: PMC3154934  PMID: 21853099
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.  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
17.  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
18.  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
20.  Cohort study of sibling effect, infectious diseases, and risk of atopic dermatitis during first 18 months of life 
BMJ : British Medical Journal  2004;328(7450):1223.
Objectives To determine whether early infectious diseases could explain the association between number of siblings and other markers of microbial exposure and the development of atopic dermatitis before the age of 18 months.
Design Cohort study. Information on atopic dermatitis, infectious diseases occurring before 6 months of age, number of siblings, early day care, pet keeping, farm residence, and background factors was collected in telephone interviews.
Setting Danish national birth cohort.
Participants 24 341 mother-child pairs.
Main outcome measures Incidence rate ratios of atopic dermatitis.
Results 13 070 children (54%) had at least one clinically apparent infectious disease before 6 months of age. At age 18 months, 2638 (10.8%) of the children had had atopic dermatitis. The risk of atopic dermatitis increased with each infectious disease before 6 months of age (incidence rate ratio 1.08, 95% confidence interval 1.04 to 1.13). The risk of atopic dermatitis decreased with each additional exposure to three or more siblings, day care, pet ownership, and farm residence (0.86, 0.81 to 0.93).
Conclusions Early infections do not seem to protect against allergic diseases. The protective effect of number of siblings, day care, pet ownership, and farm residence remained after adjustment for clinically apparent infectious diseases, suggesting that the effect is established independently early in life.
doi:10.1136/bmj.38069.512245.FE
PMCID: PMC416593  PMID: 15121716
21.  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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