Novel serologic assays of P. falciparum exposure for improved surveillance in control and elimination. R01 resubmision

Investigator: Bryan R. Greenhouse, MD
Sponsor: NIH National Institute of Allergy and Infectious Disease

Location(s): Uganda


Making appropriate decisions about how to spend resources on malaria control interventions requires knowing which interventions are working and where they are needed. Answering these questions requires measurement of exposure to parasites causing malaria, but current methods are either too expensive or inaccurate. In this project, we will develop low-cost, accurate methods for measuring exposure based on simple antibody tests, which provide a record of past exposure.

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