Novel serologic biomarkers provide accurate estimates of recent Plasmodium falciparum exposure for individuals and communities

Abstract

Tools to reliably measure Plasmodium falciparum (Pf) exposure in individuals and communities are needed to guide and evaluate malaria control interventions. Serologic assays can potentially produce precise exposure estimates at low cost; however, current approaches based on responses to a few characterized antigens are not designed to estimate exposure in individuals. Pf-specific antibody responses differ by antigen, suggesting that selection of antigens with defined kinetic profiles will improve estimates of Pf exposure. To identify novel serologic biomarkers of malaria exposure, we evaluated responses to 856 Pf antigens by protein microarray in 186 Ugandan children, for whom detailed Pf exposure data were available. Using data-adaptive statistical methods, we identified combinations of antibody responses that maximized information on an individual's recent exposure. Responses to three novel Pf antigens accurately classified whether an individual had been infected within the last 30, 90, or 365 d (cross-validated area under the curve = 0.86-0.93), whereas responses to six antigens accurately estimated an individual's malaria incidence in the prior year. Crossvalidated incidence predictions for individuals in different communities provided accurate stratification of exposure between populations and suggest that precise estimates of community exposure can be obtained from sampling a small subset of that community. In addition, serologic incidence predictions from cross-sectional samples characterized heterogeneity within a community similarly to 1 y of continuous passive surveillance. Development of simple ELISAbased assays derived from the successful selection strategy outlined here offers the potential to generate rich epidemiologic surveillance data that will be widely accessible to malaria control programs.any countries have extensive programs to reduce the burden of Plasmodium falciparum (Pf), the parasite responsible for most malaria morbidity and mortality (1). Effectively using limited resources for malaria control or elimination and evaluating interventions require accurate measurements of the risk of being infected with Pf (2-15). To reflect the rate at which individuals are infected with Pf in a useful way, metrics used to estimate exposure in a community need to account for dynamic changes over space and time, especially in response to control interventions (16)(17)(18).A variety of metrics can be used to estimate Pf exposure, but tools that are more precise and low cost are needed for population surveillance. Existing metrics have varying intrinsic levels of precision and accuracy and are subject to a variety of extrinsic factors, such as cost, time, and availability of trained personnel (19). For example, entomological measurements provide information on mosquito to human transmission for a community but are expensive, require specially trained staff, and lack standardized procedures, all of which reduce precision and/or make interpretation difficult (19)(20)(21)(22). Parasite prevalence can be meas...

Serological markers to measure recent changes in malaria at population level in Cambodia

“…Hereafter, the means of the duplicates were calculated per sample of each Ag. All analyses were carried out on the natural logarithm (ln) of the raw MFI in accordance with Helb et al [13]. …”

“…Where the EIR and PP mainly focus on the presence or absence of the infection [11] serology focuses on antibodies (Abs) that remain in the blood longer than the parasite. This is profitable in measuring host-parasite contact, and may provide information on recent or past malaria exposure, but only in case the half-lives of the Abs are known [11, 13, 14]. …”

“…Methods to estimate the half-life of serological markers are still in its infancy, therefore, to reach this goal, three different approaches [13, 21] were applied directly on continuous Ab intensity values (Fig. 1) instead of using (arbitrary) thresholds to distinguish positives from negatives [22].…”

Towards Development of Improved Serodiagnostics for Tularemia by Use of Francisella tularensis Proteome Microarrays

“…Ideally, antibodies to such an antigen would be strongly reactive during the acute phase of tularemia, but their reactivities would rapidly wane thereafter. A similar strategy has been employed in toxoplasmosis with some degree of success (39) and more recently in malaria, where a number of Plasmodium falciparum antigens that predicted recent exposure were identified by a proteome array (40). Examination of the data in Fig.…”

Examination of Antibody Responses as a Measure of Exposure to Malaria in the Indigenous Batwa and Their Non-Indigenous Neighbors in Southwestern Uganda

“…4 At an individual level, antibody responses can provide an alternative measure against which to assess risk of exposure to infection. 5,6 This study presents the results of a seroepidemiological study investigating exposure to malaria in the indigenous Batwa and neighboring non-indigenous populations in Kanungu District, located in southwestern Uganda, bordering the Democratic Republic of Congo. The district is largely rural and is characterized by mesoendemic malaria transmission with intermittent epidemics of disease.…”