- Introduction
- Materials and Methods
- Ethics statement.
- Study sites.
- Blood sampling.
- Molecular confirmation of P. vivax infection.
- Molecular genotyping.
- Case definition and data analysis.
- Protein microarray analysis using a P. vivax asexual blood-stage proteome array.
- Microarray data analysis.
- Analysis of genome-wide P. vivax single nucleotide polymorphisms.
- Results
- Number of P. vivax malaria episodes.
- Descriptive analysis of serological reactivity to P. vivax antigens using a protein microarray.
- Reactive P. vivax antigens were not found more commonly in reinfection than in relapse and reinfection, and relapse had similar cumulative IgG signals.
- Paired analysis reveals that relapse was not associated with a greater increase in reactivity than reinfection.
- Enrichment of genetic diversity of genes encoding differentially reactive antigens.
- Discussion
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Genome-Scale Protein Microarray Comparison of Human Antibody Responses in Plasmodium vivax Relapse and Reinfection
Large scale antibody responses in Plasmodium vivax malaria remains unexplored in the endemic setting. Protein microarray analysis of asexual-stage P. vivax was used to identify antigens recognized in sera from residents of hypoendemic Peruvian Amazon. Over 24 months, of 106 participants, 91 had two symptomatic P. vivax malaria episodes, 11 had three episodes, 3 had four episodes, and 1 had five episodes. Plasmodium vivax relapse was distinguished from reinfection by a merozoite surface protein-3α restriction fragment length polymorphism polymerase chain reaction (MSP3α PCR-RFLP) assay. Notably, P. vivax reinfection subjects did not have higher reactivity to the entire set of recognized P. vivax blood-stage antigens than relapse subjects, regardless of the number of malaria episodes. The most highly recognized P. vivax proteins were MSP 4, 7, 8, and 10 (PVX_003775, PVX_082650, PVX_097625, and PVX_114145); sexual-stage antigen s16 (PVX_000930); early transcribed membrane protein (PVX_090230); tryptophan-rich antigen (Pv-fam-a) (PVX_092995); apical merozoite antigen 1 (PVX_092275); and proteins of unknown function (PVX_081830, PVX_117680, PVX_118705, PVX_121935, PVX_097730, PVX_110935, PVX_115450, and PVX_082475). Genes encoding reactive proteins exhibited a significant enrichment of non-synonymous nucleotide variation, an observation suggesting immune selection. These data identify candidates for seroepidemiological tools to support malaria elimination efforts in P. vivax-endemic regions.
Author Notes
Financial support: This work was supported by United States Public Health Service grants U19AI089681, D43TW007120, R01AI067727, and K24AI068903 (Joseph M. Vinetz); AI066791, AI095916, and AI089686 (Philip Felgner); and AI075692 (Ruobing Wang and Xiaowu Liang), all from the U.S. National Institutes of Health.
Conflict of interest: The authors have read the journal's policy and declare the following potential conflicts: Philip Felgner has an equity interest in Antigen Discovery, Inc., which is developing products related to the research described in this article. In addition, this author serves on the advisory board of ADI and receives compensation for these services. The terms of this arrangement have been reviewed and approved by the University of California in accordance with its conflict of interest policies. Douglas Molina is an employee of Antigen Discovery, Inc. No other author declares a conflict of interest. This does not alter our adherence to ASTMH/AJTMH journal policies on sharing data and materials.
Authors' addresses: Raul Chuquiyauri and Joseph M. Vinetz, Department of Medicine, Division of Infectious Diseases, University of California San Diego, La Jolla, CA, Laboratorio ICEMR-Amazonia, Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Lima, Perú, and Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima, Perú, E-mails: raulharo@yahoo.com and jvinetz@ucsd.edu. Douglas M. Molina, Philip Felgner, and Xiaowu Liang, Antigen Discovery Inc., Irvine, CA, E-mails: dmolina@antigendiscovery.com, pfelgner@uci.edu, and xliang@antigendiscovery.com. Eli L. Moss and Daniel E. Neafsey, Malaria Research Group, Broad Institute of MIT and Harvard University, Cambridge, MA, E-mails: emoss@broadinstitute.org and neafsey@broadinstitute.org. Ruobing Wang, Seattle Biomed, Seattle, WA, E-mail: ruobing.wang@seattlebiomed.org. Malcolm J. Gardner, Department of Medicine, Division of Global Public Health, University of California San Diego, La Jolla, CA, E-mail: malcolm.gardner@seattlebiomed.org. Kimberly C. Brouwer and Robert H. Gilman, Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, E-mails: kbrouwer@ucsd.edu and gilmanbob@gmail.com. Sonia Torres and Alejandro Llanos-Cuentas, Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima, Perú, E-mails: soniatadimi@yahoo.com and elmer.llanos@upch.pe.