Showing papers by "Peter Aaby published in 2011"

Randomized Trial of BCG Vaccination at Birth to Low-Birth-Weight Children: Beneficial Nonspecific Effects in the Neonatal Period?

Abstract: Background. Observational studies have suggested that BCG may have nonspecific beneficial effects on survival. Low-birth-weight (LBW) children are not given BCG at birth in Guinea-Bissau; we conducted a randomized trial of BCG at birth (early BCG) vs delayed BCG. Methods. In the period 2004-2008 we recruited 2320 LBW children in Bissau. The children were visited at home at 2, 6, and 12 months of age. With a pretrial infant mortality of 250 per 1000, we hypothesized a 25% reduction in infant mortality for LBW children. Results. Infant mortality was only 101 per 1000 during the trial. In the primary analysis, infant mortality was reduced insignificantly by 17% (mortality rate ratio [MRR] = .83 [.63-1.08]). In secondary analyses, early BCG vaccine was safe with an MRR of .49 (.21-1.15) after 3 days and .55 (.34-.89) after 4 weeks. The reduction in neonatal mortality was mainly due to fewer cases of neonatal sepsis, respiratory infection, and fever. The impact of early BCG on infant mortality was marked for children weighing <1.5 kg (MRR = .43 [.21-.85]) who had lower coverage for diphtheria-tetanus-pertussis vaccinations. Conclusions. Though early BCG did not reduce infant mortality significantly, it may have a beneficial effect in the neonatal period. This could be important for public health because BCG is often delayed in low-income countries. (Less)

Smallpox vaccination and all-cause infectious disease hospitalization: a Danish register-based cohort study

Abstract: BACKGROUND: There is growing evidence from observational studies and randomized trials in low-income countries that vaccinations have non-specific effects. Administration of live vaccines reduces overall child morbidity and mortality, presumably due to protection against non-targeted infections. In Denmark, the live vaccine against smallpox was phased out in the 1970s due to the eradication of smallpox. We used the phasing-out period to investigate the effect of smallpox vaccination on the risk of hospitalization for infections. METHODS: From the Copenhagen School Health Records Register, a cohort of 4048 individuals was sampled, of whom 3559 had information about receiving or not receiving smallpox vaccination. Infectious disease hospitalizations were identified in the Danish National Patient Register. RESULTS: During 87 228 person-years of follow-up, 1440 infectious disease hospitalizations occurred. Smallpox-vaccinated individuals had a reduced risk of all-cause infectious disease hospitalization compared with smallpox-unvaccinated individuals [hazard ratio (HR) 0.84; 95% confidence interval (CI) 0.72-0.98]. The reduced risk of hospitalizations was seen for most subgroups of infectious diseases. The effect may have been most pronounced after early smallpox vaccination (vaccination age <3.5 years: HR 0.81; 95% CI 0.69-0.95; vaccination age ≥3.5 years: HR 0.91 95% CI 0.76-1.10). Among the smallpox-vaccinated, the risk of infectious disease hospitalization increased 6% with each 1-year increase in vaccination age (HR 1.06; 95% CI 1.02-1.10). CONCLUSION: Smallpox vaccination is associated with a reduced risk of infectious disease hospitalization in a high-income setting.

Interleukin 12B (IL12B) genetic variation and pulmonary tuberculosis: a study of cohorts from The Gambia, Guinea-Bissau, United States and Argentina.

Abstract: We examined whether polymorphisms in interleukin-12B (IL12B) associate with susceptibility to pulmonary tuberculosis (PTB) in two West African populations (from The Gambia and Guinea-Bissau) and in two independent populations from North and South America Nine polymorphisms (seven SNPs, one insertion/deletion, one microsatellite) were analyzed in 321 PTB cases and 346 controls from Guinea-Bissau and 280 PTB cases and 286 controls from The Gambia For replication we studied 281 case and 179 control African-American samples and 221 cases and 144 controls of European ancestry from the US and Argentina First-stage single locus analyses revealed signals of association at IL12B 39 UTR SNP rs3212227 (unadjusted allelic p = 004; additive genotypic p = 005, OR = 078, 95% CI [061–099]) in Guinea-Bissau and rs11574790 (unadjusted allelic p = 005; additive genotypic p = 005, OR = 076, 95% CI [058–100]) in The Gambia Association of rs3212227 was then replicated in African-Americans (rs3212227 allelic p = 0002; additive genotypic p = 005, OR = 078, 95% CI [061–100]); most importantly, in the African-American cohort, multiple significant signals of association (seven of the nine polymorphisms tested) were detected throughout the gene These data suggest that genetic variation in IL12B ,a highly relevant candidate gene, is a risk factor for PTB in populations of African ancestry, although further studies will be required to confirm this association and identify the precise mechanism underlying it

Impact of tuberculosis exposure at home on mortality in children under 5 years of age in Guinea-Bissau

Abstract: Objective To assess mortality related to exposure to tuberculosis (TB) at home among children in urban areas of Guinea-Bissau. Methods In four suburban areas included in the demographic surveillance system of the Bandim Health Project in Bissau, the mortality of children aged <5 years living with an adult with TB was compared with the mortality of children in the general population. Results Children <5 years of age exposed to an adult with intrathoracic TB had 66% higher mortality than unexposed children (HR 1.66, 95% CI 1.2 to 2.3). The risk was higher for children living in the same family as a TB case (HR 2.15, 95% CI 1.3 to 3.7) than for children living in the same house but not belonging to the same family as the TB case (HR 1.51, 95% CI 1.0 to 2.2). For children whose mother had TB, mortality was increased eightfold (HR 7.82, 95% CI 2.1 to 30). The risk of death was particularly increased from 6 months following exposure (HR 2.16, 95% CI 1.5 to 3.2) and the highest rate of excess mortality was found in children aged 3e4 years. Excess mortality was highest among children with close contact with an adult with sputum-positive pulmonary TB (HR 1.90, 95% CI 1.1 to 3.2), but contact with a sputum-negative case was also associated with increased mortality (HR 1.55, 95% CI 1.0 to 2.3). Adjusting for potential confounding factors did not change these results. The mortality among children living in the same houses 3 years earlier was not increased (HR 0.90, 95% CI 0.6 to 1.3). Conclusion Intimate family contact with a TB case represents a significant risk factor for child mortality in a low-income country.

Adherence to isoniazid preventive therapy in children exposed to tuberculosis: a prospective study from Guinea-Bissau.

Abstract: OBJECTIVE: To assess adherence to isoniazid preventive therapy (IPT) in children exposed to adult pulmonary tuberculosis (TB) at home. METHODS: Children were enrolled on IPT if they were aged = 1.0 mm. Children were included from the demographic surveillance system of the Bandim Health Project in Bissau, Guinea-Bissau. The main outcome measures were adherence, completion rates and side effects during 9 months of IPT. The main outcome was 6 consecutive months of at least 80% adherence. RESULTS: A total of 2631 children were identified as contacts of adult TB cases. Among the children identified, 1895 (72%) were evaluated for eligibility for IPT, and 820 were enrolled in the study: 609 were aged 5 years and 211 aged 5-15 years. A total of 79% of the prescribed doses were taken, with 65% of the children taking >80% of their doses. In all, 51% completed more than 6 consecutive months of IPT. CONCLUSION: Overall adherence to IPT was better than previously reported from TB-endemic areas, with 76% of the children completing at least 6 months of treatment, with more than 80% adherence. (Less)

HTLV-1 and HIV-2 infection are associated with increased mortality in a rural west African community.

Abstract: Background: Survival of people with HIV-2 and HTLV-1 infection is better than that of HIV-1 infected people, but long-term follow-up data are rare. We compared mortality rates of HIV-1, HIV-2, and HTLV-1 infected subjects with those of retrovirus-uninfected people in a rural community in Guinea-Bissau. Methods: In 1990, 1997 and 2007, adult residents (aged >= 15 years) were interviewed, a blood sample was drawn and retroviral status was determined. An annual census was used to ascertain the vital status of all subjects. Cox regression analysis was used to estimate mortality hazard ratios (HR), comparing retrovirus-infected versus uninfected people. Results: A total of 5376 subjects were included; 197 with HIV-1, 424 with HIV-2 and 325 with HTLV-1 infection. The median follow-up time was 10.9 years (range 0.0-20.3). The crude mortality rates were 9.6 per 100 person-years of observation (95% confidence interval 7.1-12.9) for HIV-1, 4.1 (3.4-5.0) for HIV-2, 3.6 (2.9-4.6) for HTLV-1, and 1.6 (1.5-1.8) for retrovirus-negative subjects. The HR comparing the mortality rate of infected to that of uninfected subjects varied significantly with age. The adjusted HR for HIV-1 infection varied from 4.0 in the oldest age group (>= 60 years) to 12.7 in the youngest (15-29 years). The HR for HIV-2 infection varied from 1.2 (oldest) to 9.1 (youngest), and for HTLV-1 infection from 1.2 (oldest) to 3.8 (youngest). Conclusions: HTLV-1 infection is associated with significantly increased mortality. The mortality rate of HIV-2 infection, although lower than that of HIV-1 infection, is also increased, especially among young people. (Less)

Non-specific and sex-differential effects of routine vaccines: What evidence is needed to take these effects into consideration in low-income countries?

Abstract: None of the original vaccines used in the child immunization programmes in low-income countries, including BCG, diphtheria-tetanus-pertussis (DTP), oral polio vaccine (OPV), and measles vaccine (MV), were tested for their overall effect on child mortality before being introduced. It was assumed that the effect on overall child mortality would be equivalent to the proportion of deaths caused by the targeted disease(s) (1). However, this is no longer a tenable assumption. Many studies have shown that these routine vaccines may have more general effects on the immune system than merely protecting against the targeted disease, i.e. so-called non-specific effects (NSE) (2). The NSE may well be more important for overall child survival than the lives saved by specific disease prevention (2-4). The WHO´s Global Advisory Committee on Vaccine Safety (GACVS) has recently stated that it will keep a watch on the non-specific effects (NSE) of vaccination. GACVS indicated that "conclusive evidence for or against non-specific effects of vaccines on mortality, including a potential deleterious effect of DTP vaccination on children's survival as has been reported in some studies, was unlikely to be obtained from observational studies" (5). By insisting on new RCTs to provide conclusive evidence, GACVS is making it very difficult if not impossible to test the NSEs of the currently recommended vaccines. It would usually be considered unethical to test currently recommended vaccines as part of a trial withholding these vaccines from some children (6).

Enhanced tuberculosis identification through 1-month follow-up of smear-negative tuberculosis suspects.

Abstract: SETTING: Bandim Health Project Bissau Guinea-Bissau. OBJECTIVE: To conduct tuberculosis (TB) screening among former TB suspects in whom TB had been ruled out on initial consultation and therefore assumed to be TB-negative (aTBneg). DESIGN: In a cohort follow-up study aTBneg suspects were screened for symptoms from 1 month after the initial negative sputum smear examination. Symptomatic individuals were referred for clinical re-examination and human immunodeficiency virus (HIV) testing. RESULTS: Among 428 TB suspects presenting over a 10-month period in 2007 80% (343) were smear-negative. Of these 21 were subsequently diagnosed with smear-negative TB. Of the remaining 322 aTBneg patients 212 were followed up and symptoms were examined >/=1 month after initial examination. Among followed up patients 89 (42%) were still symptomatic: five were diagnosed with TB on the basis of repeated sputum smears and chest X-ray. Of 44 symptomatic patients 39% (n = 17) were HIV-infected. Thirteen (4%) of the 322 aTBneg suspects died before follow-up. CONCLUSION: A large proportion of aTBneg patients remained symptomatic after 1 month. Several TB cases had initially not been diagnosed and HIV infection was highly prevalent. aTBneg suspects have a high mortality rate and need increased attention from both TB and HIV programmes.

Vitamin A Supplementation at Birth Might Prime the Response to Subsequent Vitamin A Supplements in Girls. Three Year Follow-Up of a Randomized Trial

Abstract: 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.

The impact of different doses of vitamin A supplementation on male and female mortality. A randomised trial from Guinea-Bissau

Abstract: Vitamin A supplementation (VAS) given to children between 6 months and 5 years of age is known to reduce mortality in low-income countries. We have previously observed that girls benefit more from a lower dose of VAS than the one recommended by WHO, the effect being strongest if diphtheria-tetanus-pertussis vaccine (DTP) was the most recent vaccination. We aimed to test these observations. During national immunisations days in Guinea-Bissau, West Africa, combining oral polio vaccination and VAS, we randomised 8626 children between 6 months and 5 years of age to receive the dose of VAS recommended by WHO or half this dose. Mortality rate ratios (MRRs) were assessed after 6 and 12 month. The overall mortality rate among participants was lower than expected. There was no significant difference in mortality at 6 months and 12 months of follow up between the low dose VAS group and the recommended dose VAS group. The MRRs were 1.23 (0.60-2.54) after 6 months and 1.17 (0.73-1.87) after 12 months. This tendency was similar in boys and girls. The low dose was not associated with lower mortality in girls if the most recent vaccine was DTP (MRR = 0.60 (0.14-2.50) after 6 months). Our sample size does not permit firm conclusions since mortality was lower than expected. We could not confirm a beneficial effect of a lower dose of VAS on mortality in girls. The study was registered under clinicaltrials.gov, number NCT00168636

CD4 Intragenic SNPs Associate With HIV-2 Plasma Viral Load and CD4 Count in a Community-Based Study From Guinea-Bissau, West Africa

Abstract: Objectives: The human genetics of HIV-2 infection and disease progression is understudied. Therefore, we studied the effect of variation in 2 genes that encode products critical to HIV pathogenesis and disease progression: CD4 and CD209. Design: This cross-sectional study consisted of 143 HIV-2, 30 HIV-1 + HIV-2 and 29 HIV-1-infected subjects and 194 uninfected controls recruited from rural Guinea-Bissau. Methods: We genotyped 14 CD4 and 4 CD209 single nucleotide polymorphisms (SNPs) that were tested for association with HIV infection, HIV-2 plasma viral load (high vs. low), and CD4+ T-cell count (high vs. low). Results: The most significant association was between a CD4 haplotype rs11575097-rs10849523 and high viral load [odds ratio (OR): = 2.37, 95% confidence interval (CI): 1.35 to 4.19, P = 0.001, corrected for multiple testing], suggesting increased genetic susceptibility to HIV-2 disease progression for individuals carrying the high-risk haplotype. Significant associations were also observed at a CD4 SNP (rs2255301) with HIV-2 infection (OR: = 2.36, 95% CI: 1.19 to 4.65, P = 0.01) and any HIV infection (OR: = 2.50, 95% CI: 1.34 to 4.69, P = 0.004). Conclusions: Our results support a role of CD4 polymorphisms in HIV-2 infection, in agreement with recent data showing that CD4 gene variants increase risk to HIV-1 in Kenyan female sex workers. These findings indicate at least some commonality in HIV-1 and HIV-2 susceptibility.

The effect of high-dose vitamin A supplementation at birth on measles incidence during the first 12 months of life in boys and girls: an unplanned study within a randomised trial.

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.

Risk factors for measles in young infants in an urban African area with high measles vaccination coverage.

Abstract: BACKGROUND: We examined risk factors for measles infection before measles vaccination at 9 months of age in Guinea-Bissau. METHODS: 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. RESULTS: 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-Guerin 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. INTERPRETATION: 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.

Maternal proviral load and vertical transmission of Human T cell Lymphotropic Virus type 1 in Guinea-Bissau

Abstract: The relative importance of routes of transmission of human T cell lymphotropic virus type 1 (HTLV-1) in Guinea-Bissau is largely unknown; vertical transmission is thought to be important, but there are very few existing data. We aimed to examine factors associated with transmission in mothers and children in Guinea-Bissau, where HTLV-1 is endemic (prevalence of 5% in the adult population). A cross-sectional survey was performed among mothers and their children (aged <15 years) in a rural community in Guinea-Bissau. A questionnaire to identify risk factors for infection and a blood sample were obtained. HTLV-1 proviral load in peripheral blood was determined and PCR was performed to compare long terminal repeat (LTR) sequences in mother–child pairs. Fourteen out of 55 children (25%) of 31 HTLV-1-infected mothers were infected versus none of 70 children of 30 uninfected mothers. The only factor significantly associated with HTLV-1 infection in the child was the proviral load of the mother; the risk...

The Effect of 50 000 IU Vitamin A with BCG Vaccine at Birth on Growth in the First Year of Life.

Abstract: 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 (), and the difference was borderline significant between the DTP and MV windows for girls ().

Sequence analysis of HIV-1 isolates from Guinea-Bissau: selection of vaccine epitopes relevant in both West African and European countries

Abstract: For a CD8 epitope-based vaccine to match different geographic locations, the targeted epitopes for cytotoxic T-lymphocytes (CTLs) must be present in the local circulating HIV-1 strains. Secondly, the vaccine epitopes should match the host population HLA types. We characterized two new HIV-1 isolates from Guinea-Bissau. Also, we have identified 15 subdominant CD8 epitopes representing common HLA super-types theoretically covering most HLA alleles in any population. Herein we demonstrate that the selected vaccine epitopes are well conserved and simultaneously present in sequences from West Africa and Denmark. Use of the selected epitopes will likely ensure ≥10 immune targets in the majority of candidates for experimental therapeutic vaccination in both geographic regions. Our results warrant testing of the selected vaccine epitopes in both geographic locations.

Molecular epidemiology of endemic Human T-Lymphotropic virus 1 (HTLV-1) in a community in rural Guinea-Bissau

Abstract: Background HTLV-1 is endemic in parts of Africa and the highest prevalence (5%) in West Africa has been reported in Caio, a rural area in Guinea-Bissau. It is unknown which HTLV-1 subtypes are present in this community. Objective To compare local HTLV-1 sequence variation and to describe the phylogeny of the virus in the Caio population.