Naturally acquired Duffy-binding protein-specific binding inhibitory antibodies confer protection from blood-stage Plasmodium vivax infection

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 105; no. 24; pp. 8363 - 8368
• Main Authors: King, Christopher L, Michon, Pascal, Shakri, Ahmad Rushdi, Marcotty, Alexandra, Stanisic, Danielle, Zimmerman, Peter A, Cole-Tobian, Jennifer L, Mueller, Ivo, Chitnis, Chetan E
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 17.06.2008; National Acad Sciences
• Subjects: Animals; Antibodies; Antibodies, Blocking - blood; Antibodies, Blocking - immunology; Antibodies, Protozoan - blood; Antibodies, Protozoan - immunology; Antigens; Antigens, Protozoan - genetics; Antigens, Protozoan - immunology; Binding sites; Biological Sciences; Blood plasma; Child; Child, Preschool; Children; Children & youth; Cohort Studies; Correlation analysis; Enzyme-Linked Immunosorbent Assay; Erythrocytes; Female; Humans; Infections; Malaria; Malaria Vaccines - immunology; Malaria, Vivax - blood; Malaria, Vivax - immunology; Malaria, Vivax - prevention & control; Male; New Guinea; Parasitemia; Parasites; Plasmodium vivax; Plasmodium vivax - growth & development; Plasmodium vivax - immunology; Prospective Studies; Proteins; Protozoan Proteins - genetics; Protozoan Proteins - immunology; Receptors, Cell Surface - genetics; Receptors, Cell Surface - immunology; Reinfection; Vaccination; New Guinea; Papua New Guinea
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0800371105

Individuals residing in malaria-endemic regions acquire protective immunity after repeated infection with malaria parasites; however, mechanisms of protective immunity and their immune correlates are poorly understood. Blood-stage infection with Plasmodium vivax depends completely on interaction of P. vivax Duffy-binding protein (PvDBP) with the Duffy antigen on host erythrocytes. Here, we performed a prospective cohort treatment/reinfection study of children (5-14 years) residing in a P. vivax-endemic region of Papua New Guinea (PNG) in which children were cleared of blood-stage infection and then examined biweekly for reinfection for 25 weeks. To test the hypothesis that naturally acquired binding inhibitory antibodies (BIAbs) targeting PvDBP region II (PvDBPII) provide protection against P. vivax infection, we used a quantitative receptor-binding assay to distinguish between antibodies that merely recognize PvDBP and those that inhibit binding to Duffy. The presence of high-level BIAbs (>90% inhibition of PvDBPII-Duffy binding, n = 18) before treatment was associated with delayed time to P. vivax reinfection diagnosed by light microscopy (P = 0.02), 55% reduced risk of P. vivax reinfection (Hazard's ratio = 0.45, P = 0.04), and 48% reduction in geometric mean P. vivax parasitemia (P < 0.001) when compared with children with low-level BIAbs (n = 148). Further, we found that stable, high-level BIAbs displayed strain-transcending inhibition by reducing reinfection with similar efficiency of PNG P. vivax strains characterized by six diverse PvDBPII haplotypes. These observations demonstrate a functional correlate of protective immunity in vivo and provide support for developing a vaccine against P. vivax malaria based on PvDBPII.