Novel serologic assays of P. falciparum exposure for improved surveillance in control and elimination.

 描述（由申请人提供）：决定如何最有效地利用有限的资源进行疟疾控制，需要准确测量恶性疟原虫（Pf）的暴露情况，这在空间和时间上变化很大，特别是在对干预措施的反应中。不幸的是，对于常规监测和监督，现有措施受到高成本或低准确性的限制。感染力（FOI，每人每次感染的数量）可以在队列研究中测量，提供准确的暴露测量，但费用太高，在研究环境之外不实用。寄生虫流行率（寄生虫率，PR），可以使用横截面调查测量，因此是更负担得起的，但在准确性有限的接触措施。血清学检测提供了潜在的提供数据接近质量的FOI在获得PR的成本。我们的初步数据表明，适当选择的抗体反应的测量可以提供有关个人的先前暴露的定量信息，产生精确的信息内和社区之间的暴露以及随时间的变化。该项目的目标是开发一套信息丰富的新型血清学检测方法，用于低成本和准确估计疟疾流行国家的Pf暴露。我们的总体假设是，这些检测将提供更准确的估计比PR的整个频谱的Pf暴露强度的暴露。我们在开发和评估这些检测方法方面处于独特的地位，可以访问来自四大洲二十多项纵向研究的样品和数据，以及在相关实验室和分析方法方面具有丰富专业知识的团队。我们的初步数据证明了我们的目标中概述的方法的概念证明，表明这种方法很可能成功，我们的团队有能力成功开展拟议的工作。本研究有3个目的：1）确定有限数量的血清学标记物最能预测Pf暴露。我们将使用蛋白质微阵列来筛选具有一系列年龄和暴露设置的受试者中对1000种Pf抗原的抗体反应，这些受试者具有良好的暴露历史。2)建立一套简便、准确的血清学检测方法，用于评价Pf暴露。我们将使用多重微珠阵列，使用纵向样本评估目标1中确定的抗体应答的详细动力学，并使用这些数据开发基于ELISA的测定，以估计来自横截面调查的FOI。3)使用FOI作为金标准，比较血清学与PR作为暴露估计值。使用独立样本，我们将比较血清学与PR估计社区暴露的能力，量化社区内暴露随时间的变化，并检测社区内的空间热点。我们预计，该项目将开发和验证一种简单而强大的疟疾控制和消除新工具，这将大大提高全球Pf监测的准确性，促进合理的疟疾控制和消除政策。

 DESCRIPTION (provided by applicant): Deciding how to most effectively use limited resources for malaria control requires accurate measures of exposure to Plasmodium falciparum (Pf), which varies dramatically over space and time, especially in response to interventions. Unfortunately, for routine monitoring and surveillance, existing measures are limited by high costs or low accuracy. The force of infection (FOI, number of infections per person time) can be measured in cohort studies, giving accurate measures of exposure, but at too much expense to be practical beyond research settings. Parasite prevalence (parasite rate, PR), can be measured using cross-sectional surveys and is therefore more affordable, but is limited in accuracy as a measure of exposure. Serologic assays offer the potential to provide data approaching the quality of FOI at the cost of obtaining PR. Our preliminary data demonstrate that measurement of appropriately chosen antibody responses can provide quantitative information about an individual's prior exposure, yielding precise information about exposure within and between communities as well as changes over time. The goal of this project is to develop an informative set of novel serologic assays for low-cost and accurate estimation of Pf exposure in countries with a range of malaria endemicity. Our overall hypothesis is that these assays will provide more accurate estimates of exposure than PR across the spectrum of Pf exposure intensity. We are in a unique position to develop and evaluate these assays, with access to samples and data from more than two dozen longitudinal studies spanning 4 continents, and a team with substantial expertise in relevant laboratory and analytical methods. Our preliminary data demonstrate proof of concept for the approach outlined in our Aims, indicating that this approach is likely to succeed and that our team has the capacity to successfully carry out the proposed work. This study has 3 aims: 1) To identify a limited number of serologic markers most predictive of Pf exposure. We will use a protein microarray to screen antibody responses to 1000 Pf antigens in subjects with a range of ages and exposure settings, with well-characterized exposure histories. 2) To develop a set of simple, accurate serologic assays to evaluate Pf exposure. We will use a multiplex bead array to evaluate the detailed kinetics of antibody responses identified in Aim 1 using longitudinal samples, and use these data to develop ELISA-based assays to estimate FOI from cross-sectional surveys. 3) To compare serology vs. PR as estimates of exposure using FOI as the gold standard. Using independent samples, we will compare the ability of serology vs. PR to estimate exposure in communities, quantify changes in exposure within communities over time, and detect spatial hotspots within communities. We anticipate that this project will develop and validate a simple, yet powerful new tool for malaria control and elimination that will dramatically improve the accuracy of global Pf surveillance, facilitating rational malaria control and elimination policy.