Serologic measures of enteric pathogen transmission for intervention studies and population monitoring in low-resource settings

点击翻译按钮获取中文摘要

Enteric pathogen infections cause an immense disease burden among children in low-resource settings. Understanding pathogen-specific transmission in high burden populations, and whether transmission is reduced through environmental intervention (reduced exposure) or improved nutrition (reduced susceptibility) is crucially important for informing global public health programs. In preliminary studies, our team has developed multiplex bead assays that measure immunoglobulin G (IgG) response to diverse enteric pathogens, along with seroepidemiologic methods to measure changes in transmission based on enteric pathogen antibody response. Antibody-based measures should complement stool-based PCR measures of infection in studies with infrequent measurement (rather than continuous monitoring) because antibody response integrates exposure over time, thus providing additional information about infections that begin and resolve between measurements. Our overall objective is to use seroepidemiologic methods to measure intervention effects on enteric pathogen transmission, and to leverage large-scale trials to develop new methods that combine multiplex testing with spatial epidemiology to locate communities with highest multi-pathogen burdens. Our team recently completed cluster randomized trials in Kenya and Bangladesh that delivered water, sanitation, handwashing (WASH), and nutritional interventions to pregnant mothers, and measured primary endpoints (growth, diarrhea) among their newborn children through age 24 months. Each trial enrolled and randomized >700 communities. Blood samples were collected among longitudinal substudies of ≈1,500 children in each country at ages 6, 12, and 24 months across factorial arms (Control, WSH, Nutrition, Nutrition + WSH), and among ~4,000 children per country at age 24 months. We propose to test for IgG responses using a multiplex bead assay that includes antigens to nine enteric pathogens: Giardia sp., Cryptosporidium sp., Entamoeba histolytica, Strongyloides sp., Ascaris sp., Campylobacter sp., enterotoxigenic Escherichia coli, Salmonella sp., and norovirus. In Aim 1, we will use the factorial trial design to measure the effects of WASH and nutrition interventions on antibody-based measures of enteric pathogen transmission in each country, including mean IgG response, seroprevalence, and force of infection. We hypothesize that the interventions reduced transmission of enteric pathogens through reduced exposure (WASH) and reduced susceptibility to infection (nutrition). In Aim 2, we will combine multiplex antibody data with spatial models to map landscapes of enteric pathogen exposure and develop generalizable methods to identify communities with highest, multi-pathogen burdens. We hypothesize that antibody-based measures will align with other measures of infection, and that there will be geographic overlap in hotspots, identifying communities with the highest multi-pathogen burdens. Richly characterized trials in two countries ensure results will be rigorous and policy relevant. Completion of these aims will significantly advance the use of serological assays in enteric pathogen intervention studies and population surveillance.