title: Predicting antidisease immunity using proteome arrays and sera from children naturally exposed to malaria.
abstract: Malaria remains one of the most prevalent and lethal human infectious diseases worldwide. A comprehensive characterization of antibody responses to blood stage malaria is essential to support the development of future vaccines, sero-diagnostic tests, and sero-surveillance methods. We constructed a proteome array containing 4441 recombinant proteins expressed by the blood stages of the two most common human malaria parasites, P. falciparum (Pf) and P. vivax (Pv), and used this array to screen sera of Papua New Guinea children infected with Pf, Pv, or both (Pf/Pv) that were either symptomatic (febrile), or asymptomatic but had parasitemia detectable via microscopy or PCR. We hypothesized that asymptomatic children would develop antigen-specific antibody profiles associated with antidisease immunity, as compared with symptomatic children. The sera from these children recognized hundreds of the arrayed recombinant Pf and Pv proteins. In general, responses in asymptomatic children were highest in those with high parasitemia, suggesting that antibody levels are associated with parasite burden. In contrast, symptomatic children carried fewer antibodies than asymptomatic children with infections detectable by microscopy, particularly in Pv and Pf/Pv groups, suggesting that antibody production may be impaired during symptomatic infections. We used machine-learning algorithms to investigate the relationship between antibody responses and symptoms, and we identified antibody responses to sets of Plasmodium proteins that could predict clinical status of the donors. Several of these antibody responses were identified by multiple comparisons, including those against members of the serine enriched repeat antigen family and merozoite protein 4. Interestingly, both P. falciparum serine enriched repeat antigen-5 and merozoite protein 4 have been previously investigated for use in vaccines. This machine learning approach, never previously applied to proteome arrays, can be used to generate a list of potential seroprotective and/or diagnostic antigens candidates that can be further evaluated in longitudinal studies.
authors.affiliation: From the ‡Seattle Biomedical Research Institute, 307 Westlake Ave N., Suite 500, Seattle, WA 98109 USA;
authors.forename: Olivia C
authors.initials: OC
authors.lastname: Finney
authors.affiliation: From the ‡Seattle Biomedical Research Institute, 307 Westlake Ave N., Suite 500, Seattle, WA 98109 USA; §Institute for Systems Biology, 401 Terry Ave N, Seattle, WA 98109 USA;
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Danziger
authors.affiliation: ¶Antigen Discovery Inc. (ADi), 1 Technology Dr E, Irvine, CA 92618 USA;
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Molina
authors.affiliation: From the ‡Seattle Biomedical Research Institute, 307 Westlake Ave N., Suite 500, Seattle, WA 98109 USA;
authors.forename: Marissa
authors.initials: M
authors.lastname: Vignali
authors.affiliation: From the ‡Seattle Biomedical Research Institute, 307 Westlake Ave N., Suite 500, Seattle, WA 98109 USA;
authors.forename: Aki
authors.initials: A
authors.lastname: Takagi
authors.affiliation: ‖Division of Epidemiology/Biostatistics, Graduate School of Public Health, San Diego State University, Hardy Tower 119, 5500 Campanile Drive, San Diego, CA 92182;
authors.forename: Ming
authors.initials: M
authors.lastname: Ji
authors.affiliation: **Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea; ‡‡Walter & Eliza Hall Institute, 1G Royal Parade, Parkville Victoria 3052, Australia;
authors.forename: Danielle I
authors.initials: DI
authors.lastname: Stanisic
authors.affiliation: **Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea;
authors.forename: Peter M
authors.initials: PM
authors.lastname: Siba
authors.affiliation: ¶Antigen Discovery Inc. (ADi), 1 Technology Dr E, Irvine, CA 92618 USA;
authors.forename: Xiawu
authors.initials: X
authors.lastname: Liang
authors.affiliation: From the ‡Seattle Biomedical Research Institute, 307 Westlake Ave N., Suite 500, Seattle, WA 98109 USA; §Institute for Systems Biology, 401 Terry Ave N, Seattle, WA 98109 USA;
authors.forename: John D
authors.initials: JD
authors.lastname: Aitchison
authors.affiliation: **Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea; ‡‡Walter & Eliza Hall Institute, 1G Royal Parade, Parkville Victoria 3052, Australia; §§Barcelona Centre for International Health Research, Carrer Roselló 132, 08036 Barcelona, Spain.
authors.forename: Ivo
authors.initials: I
authors.lastname: Mueller
authors.affiliation: From the ‡Seattle Biomedical Research Institute, 307 Westlake Ave N., Suite 500, Seattle, WA 98109 USA;
authors.forename: Malcolm J
authors.initials: MJ
authors.lastname: Gardner
authors.affiliation: From the ‡Seattle Biomedical Research Institute, 307 Westlake Ave N., Suite 500, Seattle, WA 98109 USA; ruobing.wang@seattlebiomed.org.
authors.forename: Ruobing
authors.initials: R
authors.lastname: Wang
mesh_terms: D001185:Artificial Intelligence; D002648:Child; D002675:Child, Preschool; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D016780:Malaria, Vivax / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D009512:New Guinea; D010963:Plasmodium falciparum / Q000276:immunology / Q000378:metabolism; D010966:Plasmodium vivax / Q000276:immunology / Q000378:metabolism; D040081:Protein Array Analysis / Q000379:methods*; D015800:Protozoan Proteins / Q000032:analysis* / Q000276:immunology
chemical_list: D015800:Protozoan Proteins