[Show abstract][Hide abstract] ABSTRACT: Background
In Guinea-Bissau we conducted three trials of neonatal vitamin A supplementation (NVAS) from 2002 to 2008. None of the trials found a beneficial effect on mortality. From 2003 to 2007, an early measles vaccine (MV) trial was ongoing, randomizing children 1:2 to early MV at 4.5 months or no early MV, in addition to the usual MV at 9 months. We have previously found interactions between vitamin A and vaccines.
We investigated whether there were interactions between NVAS and early MV.
We compared the mortality of NVAS and placebo recipients: first, from 4.5 to 8 months for children randomized to early MV or no early MV; and second, from 9 to 17 months in children who had received two MV or one MV. Mortality rates (MR) were compared in Cox models producing mortality rate ratios (MRR).
A total of 5141 children were randomized to NVAS (N = 3015) or placebo (N = 2126) and were later randomized to early MV (N = 1700) or no early MV (N = 3441). Between 4.5 and 8 months, NVAS compared with placebo was associated with higher mortality in early MV recipients (MR = 30 versus MR = 0, p = 0.01), but not in children who did not receive early MV (p for interaction between NVAS and early MV = 0.03). From 9 to 17 months NVAS was not associated with mortality. Overall, from 4.5 to 17 months NVAS was associated with increased mortality in early MV recipients (Mortality rate ratio = 5.39 (95% confidence interval: 1.62, 17.99)).
These observations indicate that NVAS may interact with vaccines given several months later. This may have implications for the planning of future child intervention programs.
[Show abstract][Hide abstract] ABSTRACT: Background
After measles vaccine (MV), all-cause mortality is reduced more than can be explained by the prevention of measles, especially in females.
We aimed to study the biological mechanisms underlying the observed non-specific and sex-differential effects of MV on mortality.
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.
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.
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.
clinicaltrials.gov number NCT 00168545
PLoS ONE 05/2014; 9(5):e97536. DOI:10.1371/journal.pone.0097536 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Measles vaccine (MV) has a greater effect on child survival when administered in early infancy, when maternal antibody may still be present. To test whether MV has a greater effect on overall survival if given in the presence of maternal measles antibody, we reanalysed data from two previously published randomised trials of a two-dose schedule with MV given at 4-6 months and at 9 months of age.
In trial I (1993-95), 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% CI 0-0.52). In trial II (2003-07), 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 (0.09-0.91). 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 (0.07-0.64) between 4-6 months and 5 years.
Child mortality in low-income countries may be reduced by vaccinating against measles in the presence of maternal antibody, using a two-dose schedule with the first dose at 4-6 months (earlier than currently recommended) and a booster dose at 9-12 months of age.
[Show abstract][Hide abstract] ABSTRACT: WHO recommends measles vaccination (MV) at age 9 months in low-income countries. We tested the measles antibody response at 4.5, 9, 18 and 24 months of age for children randomized to standard-titer Edmonston-Zagreb MV at 4.5 and 9 months, at 9 months, or at 9 and 18 months of age. At 4.5 months 75% had non-protective measles antibody levels. Following MV at 4.5 months, 77% (316/408) had protective antibody levels at 9 months of age and after a second dose at 9 months 97% (326/337) had protective levels at 24 months. The response at both 9 and 24 months was inversely correlated with antibodies level at the first MV. The second dose of MV at 9 months provided a significant boost in antibody level to children who had low antibody levels. In the EZ-at-9-months group, 99% (4/318) had protective levels at 24 months after one dose at 9 months or two doses at 9 and 18 months. The geometric mean titre was significantly lower in the early MV group than in the EZ-at-9-month group (p=0.0001). In conclusion, an early two-dose MV schedule was associated with protective measles antibody levels at age 24 months of age in nearly all children.
The Journal of Infectious Diseases 03/2014; DOI:10.1093/infdis/jiu117 · 6.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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
The Journal of Infectious Diseases 01/2014; 209(11). DOI:10.1093/infdis/jit804 · 6.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Standard-titre Schwarz (SW) and Edmonston-Zagreb (EZ) measles vaccines (MV) are both used in the routine immunisation programme. Within a trial of different strains of MV, we examined antibody responses in both one-dose and two-dose schedules when the first dose was administered at 9 months.
The trial was conducted in an urban area in Guinea-Bissau where we have had a health and demographic surveillance system and studied strategies to prevent measles infection since 1978. In the present study, children were randomised to SW or EZ as the first MV and furthermore randomised to a second dose of the same MV or no vaccine at 18 months of age. We obtained blood samples from 996 children at baseline; post-vaccination blood samples were collected at 18 and 24 months of age to assess measles antibody levels after one or two doses of MV.
At age 18 months all had responded to the first dose and only 1% (8/699) of the children had non-protective antibody levels irrespective of vaccine type. SW was associated with significantly higher levels of measles antibodies (geometric mean titre (GMT)=2114mIU/mL (95%CI 1153-2412)) than EZ (GMT=807mIU/mL (722-908)) (p=0.001). Antibody concentration was significantly higher in girls than in boys after EZ but not after SW. Antibody levels were higher in the rainy than the dry season. There was no clear indication that a booster dose at 18 months increased the antibody level at 24 months of age.
Maternal antibody levels have declined significantly in recent years and 99% had protective levels of measles antibody following primary MV at 9 months of age. It is unlikely that measles prevention and child health will be improved by increasing the age of MV as currently recommended.
[Show abstract][Hide abstract] ABSTRACT: The current policy of measles vaccination at 9 months of age was decided in the mid-1970s. The policy was not tested for impact on child survival but was based on studies of seroconversion after measles vaccination at different ages. The authors examined the empirical evidence for the six underlying assumptions.
These assumptions have not been research issues. Hence, the authors examined case reports to assess the empirical evidence for the original assumptions. The authors used existing reviews, and in December 2011, the authors made a PubMed search for relevant papers. The title and abstract of papers in English, French, Portuguese, Spanish, German and Scandinavian languages were assessed to ascertain whether the paper was potentially relevant. Based on cumulative measles incidence figures, the authors calculated how many measles cases had been prevented assuming everybody was vaccinated at a specific age, how many 'vaccine failures' would occur after the age of vaccination and how many cases would occur before the specific age of vaccination. In the combined analyses of several studies, the authors used the Mantel-Haenszel weighted RR stratifying for study or age groups to estimate common trends.
African community studies of measles infection. PRIMARY AND SECONDARY OUTCOMES: Consistency between assumptions and empirical evidence and the predicted effect on mortality.
In retrospect, the major assumptions were based on false premises. First, in the single study examining this point, seronegative vaccinated children had considerable protection against measles infection. Second, in 18 community studies, vaccinated measles cases ('vaccine failures') had threefold lower case death than unvaccinated cases. Third, in 24 community studies, infants had twofold higher case death than older measles cases. Fourth, the only study examining the assumption that 'vaccine failures' lead to lack of confidence found the opposite because vaccinated children had milder measles infection. Fifth, a one-dose policy was recommended. However, the two randomised trials of early two-dose measles vaccination compared with one-dose vaccination found significantly reduced mortality until 3 years of age. Thus, current evidence suggests that the optimal age for a single dose of measles vaccine should have been 6 or 7 months resulting in fewer severe unvaccinated cases among infants but more mild 'vaccine failures' among older children. Furthermore, the two-dose trials indicate that measles vaccine reduces mortality from other causes than measles infection.
Many lives may have been lost by not determining the optimal age of measles vaccination. Since seroconversion continues to be the basis for policy, the current recommendation is to increase the age of measles vaccination to 12 months in countries with limited measles transmission. This policy may lead to an increase in child mortality.
BMJ Open 07/2012; 2(4). DOI:10.1136/bmjopen-2011-000761 · 2.27 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We examined risk factors for measles infection before measles vaccination at 9 months of age in Guinea-Bissau.
Among 1524 children enrolled in a trial of early measles vaccination at 4.5 months of age, we assessed the relative risk (RR) of measles before enrollment and the incidence rate ratio between 4.5 and 9 months of age for different groups.
The incidence was high, with 4% having measles before 4.5 months and 10% having measles between 4.5 and 9 months of age. The main risk factor was the age of the mother; children of young mothers (age, 15-24 years) had lower antibody titers and higher risk of measles than children of older mothers both before 4.5 months (RR = 1.74 [1.02-2.96]) and between 4.5 and 9 months of age (incidence rate ratio = 1.59 [1.05-2.41]). Having no Bacillus Calmette-Guérin scar was associated with a higher risk of measles before 4.5 months of age (RR = 2.61 [1.54-4.45]). Children who were not breast-fed and had fever or respiratory infection at enrollment had a 2- to 4-fold higher risk of measles between 4.5 and 9 months of age.
Young mothers transmit lower titers of antibodies to their children and an increasing proportion of infants become susceptible to measles before the age of measles vaccination.
[Show abstract][Hide abstract] ABSTRACT: Vitamin A treatment reduces mortality during acute measles infection, and vitamin A supplementation (VAS) to children above 6 months of age may reduce the incidence of measles infection. The effect of VAS at birth on measles incidence is unknown. In a randomised placebo-controlled trial in Guinea-Bissau, normal-birth-weight newborns were randomised to 50 000 IU (15 mg) VAS or placebo. During the trial, a measles epidemic occurred. We linked data from the trial with data from the measles infection surveillance and studied the effect of VAS on the measles incidence before 12 months of age in both sexes. A total of 165 measles cases were identified among the 4183 children followed from 28 d of age. Up to 6 months of age, the incidence rate ratio of measles for VAS compared with placebo was 0·54 (95 % CI 0·25, 1·15) among boys and 1·57 (95 % CI 0·80, 3·08) among girls (test of interaction, P = 0·04). The corresponding figures at 12 months were 0·67 (95 % CI 0·43, 1·05) and 1·17 (95 % CI 0·76, 1·79) (test of interaction, P = 0·08). VAS compared with placebo tended to be associated with less measles hospitalisation or death during the first 6 months of life in boys (P = 0·06), but not in girls. VAS at birth may affect the susceptibility to measles infection during the first 6 months of life in a sex-differential manner.
The British journal of nutrition 02/2011; 1(12):1-4. DOI:10.1017/S0007114510005532 · 3.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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).
Randomised controlled trial.
The Bandim Health Project, Guinea-Bissau, which maintains a health and demographic surveillance system in an urban area.
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.
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.
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).
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.
Clinical trials NCT00168558.
[Show abstract][Hide abstract] ABSTRACT: Routine immunizations have non-specific and sex-differential effects on childhood mortality and morbidity in low-income countries; BCG and measles vaccine (MV) may reduce and diphtheria-tetanus-pertussis vaccine (DTP) may increase the mortality of girls relative to boys.
Urban area in Guinea-Bissau, with a demographic surveillance system and registration of all pediatric hospitalizations. Guinea-Bissau experienced a large outbreak of measles infection in 2003-2004.
We used hospital and community data to examine the impact of other vaccines on the risk of hospitalizations for measles infection. Vaccine efficacy (VE) against hospitalization for children aged 6 to 59 months of age was examined. We assessed whether VE depended on vaccination status for other vaccines and whether the pattern differed for boys and girls.
Sex-specific vaccine efficacy against hospitalization for children aged 6 to 59 months of age.
The VE depended on sex and the sequence of vaccinations. The VE of MV against hospitalization for measles was better for girls than for boys. Among children who had received MV as the most recent vaccine VE against hospitalization was as high as 96% for girls, but only 81% for boys (P = 0.002). Among children who had received DTP simultaneously with MV or DTP after MV, VE declined for girls (91%) and increased for boys (90%). Compared with having received MV as most recent vaccination, DTP simultaneously with MV or DTP after MV improved the efficacy significantly for boys and the effect was significantly different for boys and girls (P = 0.023). The female-male risk ratio of hospitalization varied significantly, depending on the most recent vaccination (P = 0.014); it was 0.28 (0.11-0.68) for MV alone, but 1.21 (0.82-1.77) for DTP but no MV, and 1.13 (0.58-2.18) for DTP simultaneously with MV or after MV. Among MV-unvaccinated children, BCG-vaccinated girls had a lower risk of measles hospitalization than DTP-vaccinated girls (RR=0.0 (0.0-0.99), exact test).
[Show abstract][Hide abstract] ABSTRACT: Previous studies have suggested that girls may have lower maternal measles antibody levels than boys. Girls might therefore be more likely to contract measles infection before the normal age of measles vaccination at 9 months of age.
In connection with a clinical trial of different measles vaccination strategies, we collected pre-measles vaccination blood samples at 4.5 months of age from two subgroups of children. Samples from these children were used to assess possible differences in maternal antibody levels for boys and girls. At 9 months of age another subgroup of children was sampled before the normal measles vaccination; these samples were used to assess the frequency of subclinical measles infection among boys and girls.
We determined measles-specific antibody levels for 812 children at 4.5 months of age and for 896 children at 9 months of age. At 4.5 months of age girls were less likely to have protective maternal antibody levels, the male-female ratio for protective antibody level being 1.23 (1.00-1.51). Among children sampled at 9 months of age, girls were more likely to have protective levels, the female-male ratio for having protective antibody levels being 1.65 (0.98-2.78) (p=0.054) and the geometric mean titre was significantly higher for girls (p=0.007). Children who lived in houses with known measles cases were more likely to have protective levels at 9 months of age even though they had not reported measles infection. Since we had excluded children with known measles infection, girls may have been more likely to have had subclinical measles infection. Combining clinical and possible subclinical measles infection, girls tended to be more likely than boys to contract measles infection before 9 months of age, the RR being 1.36 (0.97-1.90).
Girls lost maternal measles antibodies more rapidly than boys and well before 9 months of age. They may be more likely to contract subclinical measles infection before the current age of measles vaccination.
[Show abstract][Hide abstract] ABSTRACT: To examine the protective efficacy of measles vaccination in infants in a low income country before 9 months of age.
Randomised clinical trial.
1333 infants aged 4.5 months: 441 in treatment group and 892 in control group.
Urban area in Guinea-Bissau.
Measles vaccination using standard titre Edmonston-Zagreb vaccine at 4.5 months of age.
Vaccine efficacy against measles infection, admission to hospital for measles, and measles mortality before standard vaccination at 9 months of age.
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.
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].
[Show abstract][Hide abstract] ABSTRACT: To examine determinants of thymus size at age 6 months and investigate whether thymus size at this age is a determinant of subsequent mortality.
Thymus size was measured by transsternal sonography in 923 6-month-old children participating in a measles vaccination trial in Guinea-Bissau.
Thymus size was strongly associated with anthropometric measurements. Boys had larger thymuses than girls, controlling for anthropometry. Crying during sonography made the thymus appear smaller. Children who were not vaccinated with Bacille Calmette-Guérin (BCG) or were vaccinated with BCG in the preceding 4 weeks before inclusion into the study had larger thymuses. Children who had malaria or had been treated with chloroquine or Quinimax in the previous week before inclusion had smaller thymuses. Controlled for background factors associated with thymus size and mortality, small thymus size remained a strong and independent risk factor for mortality (hazard ratio = 0.31; 95% confidence interval = 0.18 to 0.52).
Small thymus size at age 6 months is a strong risk factor for mortality. To prevent unnecessary deaths, it is important to identify preventable factors predisposing to small thymus size.
The Journal of pediatrics 07/2008; 153(5):683-8, 688.e1-3. DOI:10.1016/j.jpeds.2008.04.069 · 3.79 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Community studies in West Africa have suggested that routine vaccinations may have sex-differential non-targeted effects, the female-male mortality ratios being increased after receiving diphtheria-tetanus-pertussis (DTP) vaccination and reduced after administration of BCG or measles vaccine (MV). Using an existing data set, we examined whether vaccinations were associated with gender-differential incidences of Cryptosporidium parvum infection.
Two hundred children had been recruited shortly after birth and followed until 2 years of age or until follow-up was interrupted by a war. We performed weekly morbidity interviews and collected stool specimens, irrespective of whether the children had diarrhoea. Vaccination status for each child was classified according to the most recent vaccination with BCG, DTP, or MV.
The female-male incidence rate ratio (IRR) for Cryptosporidium infection among children who had received BCG as their last vaccine was 0.0 (95% CI: 0-3.49). However, among those who had received DTP as their last vaccine, the female-male IRR was 6.25 (2.06-18.9) for Cryptosporidium infection and 3.60 (0.91-14.2) for Cryptosporidium-associated diarrhoea. The female-male IRRs for Cryptosporidium infection differed significantly among BCG and DTP recipients (p=0.01). Among children who had received measles as their last routine vaccine, the female-male IRR was 1.57 (0.60-4.11) for Cryptosporidium infection and 0.98 (0.28-3.52) for Cryptosporidium-associated diarrhoea. The female-male IRRs for Cryptosporidium infection differed among DTP and MV recipients (p=0.02). For girls, early DTP vaccination compared with late or no DTP vaccination was associated with increased incidence rate of Cryptosporidium infection (IRR=4.23 (1.04-17.2)). For girls, the incidence rate decreased when they received MV.
Routine immunisations may affect morbidity for non-targeted infections. As in studies of infant mortality, BCG is associated with a low risk for girls relative to boys, whereas DTP is associated with a high female-male IRR of C. parvum infection.
[Show abstract][Hide abstract] ABSTRACT: The 2-fold increase in female mortality after high-titer measles vaccine may have occurred because many children received diphtheria-tetanus-pertussis (DTP) vaccine or inactivated polio vaccine (IPV) after high-titer measles vaccine.
We examined whether DTP vaccine and IPV were associated with increased female mortality when they were the most recent vaccine administered to children who had not received measles vaccine. Setting and Design: IPV was used as a control vaccine in 4 randomized trials of early measles vaccination (MV) with enrollment at 4-6 months of age conducted in Guinea-Bissau. Many children had not received all 3 DTP vaccinations before enrollment, and therefore received DTP after IPV or MV. We examined whether DTP vaccination status at enrollment affected the female-male mortality ratio. Population: 9544 children enrolled in 4 trials. Main outcome measure: The female-male mortality ratio in different vaccine groups.
Females had a higher mortality rate than males among children randomized to receive IPV (mortality rate ratio [MR] 1.52, 95% CI 1.02-2.28), but females had a similar mortality rate to males among children randomized to receive MV (MR 1.01, 0.69-1.46) and among children in the IPV group after they had received MV at 9 months of age or later (MR 0.88, 0.68-1.14). Children who had not received a third dose of DTP before enrollment (and were likely to receive DTP after MV or IPV) tended to have a higher mortality than children who had received all 3 doses of DTP (MR 1.30, 0.97-1.73). This effect was seen only among girls (MR 1.61, 1.08-2.40) and not among boys (MR 1.02, 0.67-1.54). Girls had a lower mortality when MV was the most recent vaccine received rather than DTP or IPV (MR 0.49, 0.28-0.87).
Randomization to IPV was associated with higher female than male mortality. However, the increased female mortality might result from additional doses of DTP received after enrollment and before measles vaccination.
[Show abstract][Hide abstract] ABSTRACT: The sequence of routine immunisations may be important for childhood mortality. Three doses of diphtheria-tetanus-pertussis vaccine (DTP) should be given at 6, 10, and 14 weeks and measles vaccine (MV) at 9 months of age. The sequence is not always respected. We examined in-hospital mortality of children having received DTP with or after measles vaccine.
The only paediatric ward in Bissau, Guinea-Bissau.
Children hospitalised during two periods in 1990-1996 and 2001-2002 who had received MV prior to hospitalisation.
The all-cause case fatality at the hospital for children aged 6-17 months.
The case fatality was increased for children who had received DTP with or after measles vaccine compared with children who had received measles vaccine as the most recent vaccine, the ratio being 2.53 (1.37-4.67) and 1.77 (0.92-3.41) in the two periods, respectively. The combined estimate was 2.10 (1.34-3.28). These results were not explained by differences in nutritional status, number of doses of DTP or discharge policy.
Administration of DTP with, or after MV, may reduce the beneficial effect of MV.
[Show abstract][Hide abstract] ABSTRACT: To investigate whether prophylactic antibiotics can prevent complications of measles.
Community based, randomised, double blind, placebo controlled trial.
Bandim Health Project study area in Bissau, Guinea-Bissau, west Africa.
84 patients with measles during a measles epidemic in Bissau in 1998 (fewer than originally planned owing to interruption by war).
Sulfamethoxazole-trimethoprim (co-trimoxazole) or placebo for seven days.
Pneumonia and admission to hospital. Also weight change during the first month of infection, diarrhoea, severe fever, oral thrush, stomatitis, conjunctivitis, and otitis media.
The median age of the patients with measles was 5.4 (range 0.49-24.8) years. One of 46 participants who received co-trimoxazole developed pneumonia, in contrast to six of 38 participants who received placebo (odds ratio 0.08 (95% confidence interval 0 to 0.56), adjusted for age group). The number needed to treat was 7 (4 to 48). All three participants admitted to hospital had received placebo (P=0.09). The weight gain during the first month after inclusion was 15 (2-29) g/day in the placebo group and 32 (23-42) g/day in the co-trimoxazole group (P=0.04, adjusted for age group, weight for age at inclusion, measles vaccination status, and duration of disease). Significantly less conjunctivitis occurred among recipients of co-trimoxazole than placebo, as well as a non-significant tendency to less diarrhoea, severe fever, oral thrush, and stomatitis. Complications of otitis media were the same in the two groups.
The group that received prophylactic antibiotics had less pneumonia and conjunctivitis and had significantly higher weight gains in the month after inclusion. The results indicate that prophylactic antibiotics may have an important role in the management of measles infection in low income countries.
Clinical trials NCT001168532.
[Show abstract][Hide abstract] ABSTRACT: Recent studies have suggested that bacille Calmette-Guérin (BCG) immunization may have a nonspecific beneficial effect on infant survival and that the effect may be more pronounced among girls. In a prospective birth cohort, we examine whether a positive tuberculin skin test and BCG scar in response to BCG immunization were related to better overall survival in Guinea-Bissau and, if so, whether the effect was sex-specific.
Skin tests and BCG scarring were monitored at ages 2 months (n = 2332) and 6 months (n = 1817) in children born from March 2000 to July 2002. A tuberculosis (TB) surveillance system allowed us to exclude from the analysis children with likely TB exposure. The children were followed for survival until 18 months of age.
Among children with a tuberculin skin test at 2 and 6 months of age, the mortality rate ratio for skin test reactors (>1 mm) versus nonreactors (0-1 mm) was 0.54 (95% confidence interval = 0.30-0.99). Comparing children with and without a BCG scar, the ratio was 0.55 (0.31-0.96). The effect of a skin test reaction or a BCG scar seemed stronger among girls; for those with positive reaction, the mortality ratio was 0.31 (0.11-0.88) among girls and 0.84 (0.39-1.82) among boys; and for BCG scar, the results were 0.41 (0.21-0.82) and 0.88 (0.34-2.30), respectively.
A good response to BCG vaccination is related to lower child mortality. The effect seems most pronounced among girls. The findings may have implications for future vaccine trials and policy.
[Show abstract][Hide abstract] ABSTRACT: The determination of the prevalence of inherited hemoglobin (Hb) disorders in endemic areas is important in order to develop programs for their control and management. The aim of this study is to determine the prevalence of inherited Hb diseases in Guinea-Bissau which is situated on the west coast of Africa, between Senegal and Guinea. One thousand and fifty-seven blood samples were collected and analyzed with high performance liquid chromatography (HPLC) for detection of beta-thalassemia (thal) and Hb variants, and by gap polymerase chain reaction (gap-PCR) for the detection of deletions in the alpha-globin genes. We found 4.7% children were heterozygous for Hb S [beta6(A3)Glu-->Val, GAG -->GTG], 0.2% were homozygous for Hb S, and 0.3% were heterozygous for Hb C [beta6(A3)Glu-->Lys, GAG -->AAG]. One child had heterozygous beta+-thal, 13.8% were heterozygous for the -alpha3.7 deletion, 1.5% were homozygous for the -alpha3.7 deletion, and 1.5% were heterozygous for the -alpha4.2 deletion. We recommend national screening programs to focus primarily on sickle cell disease, since beta-thal is rare, and the observed alpha-thal deletions are of minor genetic importance.