Effect of substituting IPV for tOPV on immunity to poliovirus in Bangladeshi infants: An open-label randomized controlled trial

AbstractBackgroundThe Polio Endgame strategy includes phased withdrawal of oral poliovirus vaccines (OPV) coordinated with introduction of inactivated poliovirus vaccine (IPV) to ensure population immunity. The impact of IPV introduction into a primary OPV series of immunizations in a developing country is uncertain.MethodsBetween May 2011 and November 2012, we enrolled 700 Bangladeshi infant-mother dyads from Dhaka slums into an open-label randomized controlled trial to test whether substituting an injected IPV dose for the standard Expanded Program on Immunization (EPI) fourth tOPV dose at infant age 39 weeks would reduce fecal shedding and enhance systemic immunity. The primary endpoint was mucosal immunity to poliovirus at age one year, measured by fecal excretion of any Sabin virus at five time points up to 25 days post-52 week tOPV challenge, analyzed by the intention to treat principle.FindingsWe randomized 350 families to the tOPV and IPV vaccination arms. Neither study arm resulted in superior intestinal protection at 52 weeks measured by the prevalence of infants shedding any of three poliovirus serotypes, but the IPV dose induced significantly higher seroprevalence and seroconversion rates. This result was identical for poliovirus detection by cell culture or RT-qPCR. The non-significant estimated culture-based shedding risk difference was −3% favoring IPV, and the two vaccination schedules were inferred to be equivalent within a 95% confidence margin of −10% to +4%. Results for shedding analyses stratified by poliovirus type were similar.ConclusionsNeither of the vaccination regimens is superior to the other in enhancing intestinal immunity as measured by poliovirus shedding at 52 weeks of age and the IPV regimen provides similar intestinal immunity to the four tOPV series, although the IPV regimen strongly enhances humoral immunity. The IPV-modified regimen may be considered for vaccination programs without loss of intestinal protection

Network analysis of patterns and relevance of enteric pathogen co-infections among infants in a diarrhea-endemic setting.

Despite significant progress in recent decades toward ameliorating the excess burden of diarrheal disease globally, childhood diarrhea remains a leading cause of morbidity and mortality in low-and-middle-income countries (LMICs). Recent large-scale studies of diarrhea etiology in these populations have revealed widespread co-infection with multiple enteric pathogens, in both acute and asymptomatic stool specimens. We applied methods from network science and ecology to better understand the underlying structure of enteric co-infection among infants in two large longitudinal birth cohorts in Bangladesh. We used a configuration model to establish distributions of expected random co-occurrence, based on individual pathogen prevalence alone, for every pathogen pair among 30 enteropathogens detected by qRT-PCR in both diarrheal and asymptomatic stool specimens. We found two pairs, Enterotoxigenic E. coli (ETEC) with Enteropathogenic E. coli (EPEC), and ETEC with Campylobacter spp., co-infected significantly more than expected at random (both pairs co-occurring almost 4 standard deviations above what one could expect due to chance alone). Furthermore, we found a general pattern that bacteria-bacteria pairs appear together more frequently than expected at random, while virus-bacteria pairs tend to appear less frequently than expected based on model predictions. Finally, infants co-infected with leading bacteria-bacteria pairs had more days of diarrhea in the first year of life compared to infants without co-infection (p-value <0.0001). Our methods and results help us understand the structure of enteric co-infection which can guide further work to identify and eliminate common sources of infection or determine biologic mechanisms that promote co-infection

Role of maternal health and infant inflammation in nutritional and neurodevelopmental outcomes of two-year-old Bangladeshi children

Background: Previous 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 findings We 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/Significance: Birth 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

Impact of enterovirus and other enteric pathogens on oral polio and rotavirus vaccine performance in Bangladeshi infants

AbstractBackgroundOral polio vaccine (OPV) and rotavirus vaccine (RV) exhibit poorer performance in low-income settings compared to high-income settings. Prior studies have suggested an inhibitory effect of concurrent non-polio enterovirus (NPEV) infection, but the impact of other enteric infections has not been comprehensively evaluated.MethodsIn urban Bangladesh, we tested stools for a broad range of enteric viruses, bacteria, parasites, and fungi by quantitative PCR from infants at weeks 6 and 10 of life, coincident with the first OPV and RV administration respectively, and examined the association between enteropathogen quantity and subsequent OPV serum neutralizing titers, serum rotavirus IgA, and rotavirus diarrhea.ResultsCampylobacter and enterovirus (EV) quantity at the time of administration of the first dose of OPV was associated with lower OPV1-2 serum neutralizing titers, while enterovirus quantity was also associated with diminished rotavirus IgA (−0.08 change in log titer per tenfold increase in quantity; P=0.037), failure to seroconvert (OR 0.78, 95% CI: 0.64–0.96; P=0.022), and breakthrough rotavirus diarrhea (OR 1.34, 95% CI: 1.05–1.71; P=0.020) after adjusting for potential confounders. These associations were not observed for Sabin strain poliovirus quantity.ConclusionIn this broad survey of enteropathogens and oral vaccine performance we find a particular association between EV carriage, particularly NPEV, and OPV immunogenicity and RV protection. Strategies to reduce EV infections may improve oral vaccine responses.ClinicalTrials.gov Identifier: NCT01375647

Random forests plots of the top 15 variables selected for linear growth and performance on the Bayley-III scales of infant and Toddler Development.

<p>Random forests models were constructed for LAZ at two years (A), the change in LAZ from enrollment to two years (B), and Bayley-III scores at two years of age. The Bayley-III is comprised of 4 components, namely cognitive (C), language (D), motor (E), and social-emotional (F). Color-coding correlates to the three clusters identified when all variables were analyzed using Pearson’s correlation (<a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0006363#pntd.0006363.s001" target="_blank">S1 Fig</a>).</p

Enrollment characteristics of children who completed 2 year anthropomorphic assessments compared with those who did not.

<p>Enrollment characteristics of children who completed 2 year anthropomorphic assessments compared with those who did not.</p

Variables selected by both random forest (top 10 selected variables) and SCAD (all selected variables) analyses for the outcomes of linear growth and performance on the Bayley III scales of infant and Toddler Development.

<p>Variables selected by both random forest (top 10 selected variables) and SCAD (all selected variables) analyses for the outcomes of linear growth and performance on the Bayley III scales of infant and Toddler Development.</p

Variables measured in the PROVIDE study utilized in random forests models to predict linear growth and Bayley-III neurodevelopmental scores at two years of age.

<p>Variables measured in the PROVIDE study utilized in random forests models to predict linear growth and Bayley-III neurodevelopmental scores at two years of age.</p

Anthropometry over the first 2 years of life for the 371 children with complete anthropometric measurements.

<p>Height and weight were taken at 3-month intervals and transformed to standardized Z scores. The X-axis depicts the child’s age while the Y-axis depicts the percentage of children in the cohort who had a LAZ, WAZ, or WHZ <-2 SD.</p