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

肠道病原体感染给资源匮乏环境中的儿童造成巨大的疾病负担。 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（减少暴露）或改善营养（降低易感性）， 这对全球公共卫生计划的制定非常重要。在初步研究中，我们的团队已经开发出了 微珠检测，测量免疫球蛋白G（IgG）对不同肠道病原体的反应，沿着 血清流行病学方法，根据肠道病原体抗体反应测量传播变化。 基于抗体的措施应补充粪便PCR感染措施的研究中， 测量（而不是连续监测），因为抗体反应随时间整合了暴露， 从而提供关于在测量之间开始和消退的感染的附加信息。 我们的总体目标是使用血清流行病学方法来衡量干预对肠道疾病的影响。 病原体传播，并利用大规模试验开发联合收割机多重检测的新方法 利用空间流行病学来定位多病原体负担最高的社区。我们团队最近 在肯尼亚和孟加拉国完成了一系列随机试验， （WASH）和营养干预措施，并测量主要终点（生长，腹泻） 在他们的新生儿到24个月的年龄。每项试验招募和随机化>700个社区。 在每个国家的1,500名儿童的纵向子研究中，在6岁、12岁、 在因子组（对照组、WSH组、营养组、营养+ WSH组）中， 24个月大的国家。我们建议使用多重微珠试验检测IgG应答，包括 九种肠道病原体的抗原：贾第虫属，隐孢子虫，溶组织内阿米巴，类圆线虫属， 蛔虫，弯曲杆菌属，产肠毒素大肠杆菌，沙门氏菌属，和诺如病毒。 在目标1中，我们将使用析因试验设计来衡量WASH和营养干预措施对 每个国家基于抗体的肠道病原体传播指标，包括平均IgG应答， 血清阳性率和感染力。我们假设干预措施减少了肠道病毒的传播， 通过减少接触（WASH）和降低感染易感性（营养）来减少病原体。在目标2中， 将联合收割机多重抗体数据与空间模型相结合，绘制肠道病原体暴露的景观图， 制定可推广的方法，以确定多病原体负担最高的社区。我们假设 基于抗体的措施将与其他感染措施保持一致， 在热点重叠，确定社区与最高的多病原体负担。特征丰富的试验 在两个国家，确保结果严格且与政策相关。这些目标的实现将大大 在肠道病原体干预研究和人口监测中推动使用血清学检测。

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.