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Anti-malarial Antibody Responses & Applications for Assessing Malaria Exposure

Abstract

This dissertation describes the discovery of highly informative serologic biomarkers of recent exposure to Plasmodium falciparum, the most deadly species causing malaria. An innovative approach that combined detailed individual-level exposure data, high-throughput screening of hundreds of antibody responses, and robust statistical methods was used to identify the most informative signatures of exposure. The novel antigens described here and, more importantly, the outlined approach for biomarker discovery will allow for the development of public health and research tools that are imperative for the control and elimination of malaria. Additionally, the methodologies outlined here are highly applicable to the discovery of biomarkers of exposure for other infectious diseases.

Serology has been used for decades to measure exposure to Plasmodium species and other infectious diseases. While useful, most existing assays for measuring P. falciparum exposure have been based on population-level responses to a few target antigens chosen by convenience rather than utility, resulting in relatively coarse exposure estimates. Here, detailed assessments of malaria exposure in Malian and Ugandan children were used to identify novel serologic biomarkers of malaria exposure and calibrate responses to quantitative estimates of individual exposure. The power of obtaining these individual-level estimates was illustrated by their ability to accurately identify individuals with infection in the recent past; to obtain precise estimates of malaria incidence in a population from cross-sectional samples of as few as 20 individuals; and to accurately estimate heterogeneity in recent exposure within a community using data from a single time point.

Interest in the development of improved serologic assays has increased in recent years as more investment is made in malaria control and elimination. There is need for widely available, accurate estimates of malaria exposure that will allow for targeting and evaluation of public health interventions. This dissertation initiates a response to the call to develop accurate field-based assays for rapid and cost-effective assessment of malaria exposure, with the ultimate goal of putting cohort-quality data into the hands of malaria control programs.

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