title: 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. Cross-validated 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 ELISA-based 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.
authors.affiliation: Department of Medicine, University of California, San Francisco, CA 94110; Division of Infectious Diseases, School of Public Health, University of California, Berkeley, CA 94720; Global Health Group, University of California, San Francisco, CA 94158;
authors.forename: Danica A
authors.identifier: http://orcid.org/0000-0001-9595-7769
authors.initials: DA
authors.lastname: Helb
authors.affiliation: Department Immunology and Infection, London School of Hygiene and Tropical Medicine, London WC1E 7HT, United Kingdom;
authors.forename: Kevin K A
authors.initials: KK
authors.lastname: Tetteh
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of California, Irvine, CA 92697;
authors.forename: Philip L
authors.initials: PL
authors.lastname: Felgner
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20852;
authors.forename: Jeff
authors.initials: J
authors.lastname: Skinner
authors.affiliation: Division of Biostatistics, School of Public Health, University of California, Berkeley, CA 94720;
authors.forename: Alan
authors.initials: A
authors.lastname: Hubbard
authors.affiliation: Infectious Diseases Research Collaboration, Kampala, Uganda;
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Arinaitwe
authors.affiliation: Department of Medicine, Makerere University College of Health Sciences, Kampala, Uganda;
authors.forename: Harriet
authors.initials: H
authors.lastname: Mayanja-Kizza
authors.affiliation: Infectious Diseases Research Collaboration, Kampala, Uganda;
authors.forename: Isaac
authors.initials: I
authors.lastname: Ssewanyana
authors.affiliation: Department of Medicine, Makerere University College of Health Sciences, Kampala, Uganda;
authors.forename: Moses R
authors.initials: MR
authors.lastname: Kamya
authors.affiliation: Center for Biomedical Research, Burnet Institute for Medical Research and Public Health, Melbourne, VIC, Canada 3004;
authors.forename: James G
authors.initials: JG
authors.lastname: Beeson
authors.affiliation: Center for Global Health, Centers for Disease Control and Prevention, Atlanta, GA 30333;
authors.forename: Jordan
authors.initials: J
authors.lastname: Tappero
authors.affiliation: Spatial Ecology and Epidemiology Group, Department of Zoology, University of Oxford, Oxford OX1 3PS, United Kingdom; Sanaria Institute for Global Health and Tropical Medicine, Rockville, MD 20850.
authors.forename: David L
authors.initials: DL
authors.lastname: Smith
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20852;
authors.forename: Peter D
authors.initials: PD
authors.lastname: Crompton
authors.affiliation: Department of Medicine, University of California, San Francisco, CA 94110;
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
authors.affiliation: Department of Medicine, University of California, San Francisco, CA 94110;
authors.forename: Grant
authors.initials: G
authors.lastname: Dorsey
authors.affiliation: Department Immunology and Infection, London School of Hygiene and Tropical Medicine, London WC1E 7HT, United Kingdom;
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Drakeley
authors.affiliation: Department of Medicine, University of California, San Francisco, CA 94110; bryan.greenhouse@ucsf.edu.
authors.forename: Bryan
authors.initials: B
authors.lastname: Greenhouse
mesh_terms: D000913:Antibodies, Protozoan / Q000276:immunology; D000917:Antibody Formation / Q000276:immunology; D000918:Antibody Specificity / Q000276:immunology; D000953:Antigens, Protozoan / Q000276:immunology; D015415:Biomarkers / Q000097:blood*; D002648:Child; D002675:Child, Preschool; D005260:Female; D063990:Gene Ontology; D005843:Geography; D006801:Humans; D015994:Incidence; D016778:Malaria, Falciparum / Q000097:blood* / Q000453:epidemiology / Q000276:immunology / Q000469:parasitology*; D008297:Male; D008302:Mali / Q000453:epidemiology; D010963:Plasmodium falciparum / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D012372:ROC Curve; D012111:Residence Characteristics; D016896:Treatment Outcome; D014454:Uganda / Q000453:epidemiology
chemical_list: D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D015415:Biomarkers
keywords: Plasmodium falciparum malaria; antigen discovery; epidemiology; immunoepidemiology; serology