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

肠道病原体感染在资源匮乏的环境中给儿童造成了巨大的疾病负担。 了解高负担人群中的病原体特异性传播，以及传播是否减少 通过环境干预(减少接触)或改善营养(减少易感性)至关重要 对于为全球公共卫生计划提供信息很重要。在初步研究中，我们的团队已经开发出多个 检测免疫球蛋白G(Ig G)对不同肠道病原体的反应的珠状试验，以及 根据肠道病原体抗体反应测量传播变化的血清流行病学方法。 在罕见病例的研究中，基于抗体的方法应补充基于粪便的PCR感染方法 测量(而不是连续监测)，因为抗体反应结合了随时间的暴露， 从而提供有关在两次测量之间开始和消除感染的附加信息。 我们的总体目标是使用血清流行病学方法来衡量对肠道的干预效果 病原体传播，并利用大规模试验开发结合多重检测的新方法 利用空间流行病学来定位多种病原体负担最高的社区。我们的团队最近 在肯尼亚和孟加拉国完成了提供水、卫生设施、洗手的整群随机试验 (WASH)，对孕妇进行营养干预，并测量主要终点(生长、腹泻) 在他们24个月大的新生儿中。每项试验都招募了700个社区，并将其随机化。 血液样本是在每个国家的≈1,500名儿童的纵向子研究中采集的，年龄分别为6岁、12岁、 和24个月的因素组(控制、WSH、营养、营养+WSH)，每个约4,000名儿童 在24个月大的时候出生。我们建议使用一种包括以下内容的多重珠状试验来检测免疫球蛋白反应 9种肠道病原体的抗原：贾第虫属、隐孢子虫属、溶组织内阿米巴属、类圆线虫属、 蛔虫属、弯曲杆菌属、产肠毒素大肠埃希菌属、沙门氏菌属、诺如病毒属。 在目标1中，我们将使用析因试验设计来衡量洗涤和营养干预对 各国以抗体为基础的肠道病原体传播措施，包括平均免疫球蛋白反应， 血清阳性率和感染力。我们假设干预措施减少了肠道传播 通过减少暴露(WASH)和减少对感染的敏感性(营养)来减少病原体。在目标2中，我们 将把多重抗体数据与空间模型结合起来，绘制肠道病原体暴露的景观图，并 开发可推广的方法，以确定具有最高、多种病原体负担的社区。我们假设 基于抗体的措施将与其他感染措施保持一致，并将在地理上 在热点地区重叠，确定具有最高多病原体负担的社区。富有特色的审判 在两个国家，确保结果将是严格的和与政策相关的。这些目标的实现将显著地 推进血清学检测在肠道病原体干预研究和人群监测中的应用。

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.