HighlightsOral vaccines exhibit poor performance in low-income settings.Enterovirus and Campylobacter carriage are associated with lower OPV immunogenicity.Enterovirus carriage is associated with lower Rotarix immunogenicity and efficacy.
Abstract. Oral vaccines appear less effective in children in the developing world. Proposed biologic reasons include concurrent enteric infections, malnutrition, breast milk interference, and environmental enteropathy (EE). Rigorous study design and careful data management are essential to begin to understand this complex problem while assuring research subject safety. Herein, we describe the methodology and lessons learned in the PROVIDE study (Dhaka, Bangladesh). A randomized clinical trial platform evaluated the efficacy of delayed-dose oral rotavirus vaccine as well as the benefit of an injectable polio vaccine replacing one dose of oral polio vaccine. This rigorous infrastructure supported the additional examination of hypotheses of vaccine underperformance. Primary and secondary efficacy and immunogenicity measures for rotavirus and polio vaccines were measured, as well as the impact of EE and additional exploratory variables. Methods for the enrollment and 2-year follow-up of a 700 child birth cohort are described, including core laboratory, safety, regulatory, and data management practices. Intense efforts to standardize clinical, laboratory, and data management procedures in a developing world setting provide clinical trials rigor to all outcomes. Although this study infrastructure requires extensive time and effort, it allows optimized safety and confidence in the validity of data gathered in complex, developing country settings. BACKGROUND AND RATIONALE
Recent studies suggest small intestine bacterial overgrowth (SIBO) is common among developing world children. SIBO’s pathogenesis and effect in the developing world are unclear. Our objective was to determine the prevalence of SIBO in Bangladeshi children and its association with malnutrition. Secondary objectives included determination of SIBO’s association with sanitation, diarrheal disease, and environmental enteropathy. We performed a cross-sectional analysis of 90 Bangladeshi 2-year-olds monitored since birth from an impoverished neighborhood. SIBO was diagnosed via glucose hydrogen breath testing, with a cutoff of a 12-ppm increase over baseline used for SIBO positivity. Multivariable logistic regression was performed to investigate SIBO predictors. Differences in concomitant inflammation and permeability between SIBO-positive and -negative children were compared with multiple comparison adjustment. A total of 16.7% (15/90) of the children had SIBO. The strongest predictors of SIBO were decreased length-for-age Z score since birth (odds ratio [OR], 0.13; 95% confidence interval [CI], 0.03 to 0.60) and an open sewer outside the home (OR, 4.78; 95% CI, 1.06 to 21.62). Recent or frequent diarrheal disease did not predict SIBO. The markers of intestinal inflammation fecal Reg 1β (116.8 versus 65.6 µg/ml; P = 0.02) and fecal calprotectin (1,834.6 versus 766.7 µg/g; P = 0.004) were elevated in SIBO-positive children. Measures of intestinal permeability and systemic inflammation did not differ between the groups. These findings suggest linear growth faltering and poor sanitation are associated with SIBO independently of recent or frequent diarrheal disease. SIBO is associated with intestinal inflammation but not increased permeability or systemic inflammation.
BackgroundLewis and secretor histo–blood group antigens (HBGAs) have been associated with decreased susceptibility to P[8] genotype rotavirus (RV) infections. Efficacy of vaccines containing attenuated P[8] strains is decreased in low-income countries. Host phenotype might impact vaccine efficacy (VE) by altering susceptibility to vaccination or RV diarrhea (RVD). We performed a substudy in a monovalent RV vaccine (RV1) efficacy trial in Bangladesh to determine the impact of Lewis and secretor status on risk of RVD and VE.MethodsIn infants randomized to receive RV1 or no RV1 at 10 and 17 weeks with 1 year of complete active diarrheal surveillance, we performed Lewis and secretor phenotyping and genotyped the infecting strain of each episode of RVD.ResultsA vaccine containing P[8] RV protected secretors and nonsecretors similarly. However, unvaccinated nonsecretors had a reduced risk of RVD (relative risk, 0.53 [95% confidence interval, .36–.79]) mediated by complete protection from P[4] but not P[8] RVs. This effect reduced VE in nonsecretors to 31.7%, compared to 56.2% among secretors, and decreased VE for the overall cohort.ConclusionsHost HBGA status may impact VE estimates by altering susceptibility to RV in unvaccinated children; future trials should therefore account for HBGA status.Clinical Trials RegistrationNCT01375647.
Background Undernutrition is a serious global problem that contributes to increased child morbidity and mortality, impaired neurocognitive development, and decreased educational and economic attainment. Current interventions are only marginally effective, and identification of associated metabolic pathways can offer new strategies for intervention. Methods Plasma samples were collected at 9 and 36 months from a subset of the PROVIDE child cohort ( n = 130). Targeted metabolomics was performed on bile acids, acylcarnitines, amino acids, phosphatidylcholines, and sphingomyelins. Metabolic associations with linear growth and neurocognitive outcomes at four years were evaluated using correlation and penalized-linear regression analysis as well as conditional random forest modeling. Findings Different metabolites were associated with growth and neurocognitive outcomes. Improved growth outcomes were associated with higher concentrations of hydroxy-sphingomyelin and essential amino acids and lower levels of acylcarnitines and bile acid conjugation. Neurocognitive scores were largely associated with phosphatidylcholine species and early metabolic indicators of inflammation. All metabolites identified explain ~45% of growth and neurocognitive variation. Interpretation Growth outcomes were predominantly associated with metabolites measured early in life (9 months), many of which were biomarkers of insufficient diet, environmental enteric dysfunction, and microbiome disruption. Hydroxy-sphingomyelin was a significant predictor of improved growth. Neurocognitive outcome was predominantly associated with 36 month phosphatidylcholines and inflammatory metabolites, which may serve as important biomarkers of optimal neurodevelopment. The distinct sets of metabolites associated with growth and neurocognition suggest that intervention may require targeted approaches towards distinct metabolic pathways. Fund Bill & Melinda Gates Foundation (OP1173478); National Institutes of Health (AI043596, CA044579).
BackgroundPrevious studies have shown maternal, inflammatory, and socioeconomic variables to be associated with growth and neurodevelopment in children from low-income countries. However, these outcomes are multifactorial and work describing which predictors most strongly influence them is lacking.Methodology/Principal findingsWe conducted a longitudinal study of Bangladeshi children from birth to two years to assess oral vaccine efficacy. Variables pertaining to maternal and perinatal health, socioeconomic status, early childhood enteric and systemic inflammation, and anthropometry were collected. Bayley-III neurodevelopmental assessment was conducted at two years. As a secondary analysis, we employed hierarchical cluster and random forests techniques to identify and rank which variables predicted growth and neurodevelopment. Cluster analysis demonstrated three distinct groups of predictors. Mother’s weight and length-for-age Z score (LAZ) at enrollment were the strongest predictors of LAZ at two years. Cognitive score on Bayley-III was strongly predicted by weight-for-age (WAZ) at enrollment, income, and LAZ at enrollment. Top predictors of language included Rotavirus vaccination, plasma IL 5, sCD14, TNFα, mother’s weight, and male gender. Motor function was best predicted by fecal calprotectin, WAZ at enrollment, fecal neopterin, and plasma CRP index. The strongest predictors for social-emotional score included plasma sCD14, income, WAZ at enrollment, and LAZ at enrollment. Based on the random forests’ predictions, the estimated percentage of variation explained was 35.4% for LAZ at two years, 34.3% for ΔLAZ, 42.7% for cognitive score, 28.1% for language, 40.8% for motor, and 37.9% for social-emotional score.Conclusions/SignificanceBirth anthropometry and maternal weight were strong predictors of growth while enteric and systemic inflammation had stronger associations with neurodevelopment. Birth anthropometry was a powerful predictor for all outcomes. These data suggest that further study of stunting in low-income settings should include variables relating to maternal and prenatal health, while investigations focusing on neurodevelopmental outcomes should additionally target causes of systemic and enteric inflammation.
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