Susceptibility to Plasmodium vivax Malaria: New Perspectives from Madagascar

Malaria therapy, experimental and epidemiological studies have shown that erythrocyte Duffy blood group-negative people, largely of African ancestry, are resistant to erythrocyte P. vivax infection. This established a paradigm that the Duffy antigen is required for P. vivax erythrocyte invasion. P. vivax is endemic in Madagascar, where admixture of Duffy-negative and Duffy-positive populations of diverse ethnic backgrounds has occurred over 2 millennia. There, we investigated susceptibility to P. vivax blood-stage infection and disease in association with Duffy blood group polymorphism. Duffy blood group genotyping identified 72% Duffy-negative individuals (FY*B^ES/*B^ES) in community surveys conducted at eight sentinel sites. Flow cytometry and adsorption-elution results confirmed the absence of Duffy antigen expression on Duffy-negative erythrocytes. P. vivax PCR-positivity was observed in 8.8% (42/476) of asymptomatic Duffy-negative people. Clinical vivax malaria was identified in Duffy-negative subjects with nine P. vivax mono-infections and eight mixed Plasmodium species infections that included P. vivax (4.9% and 4.4% of 183 participants, respectively). Microscopy examination of blood smears confirmed blood-stage development of P. vivax, including gametocytes. Genotyping of polymorphic surface and microsatellite markers suggested that multiple P. vivax strains were infecting Duffy-negative people. Among surveyed study sites, human population-based observations suggest that Duffy-negatives became susceptible to blood-stage P. vivax infection when the frequency of Duffy-positives reached at least 25%. In Madagascar, P. vivax has broken through its dependence on the Duffy antigen for establishing human blood-stage infection and disease. Complex parasite and human genetic factors appear to contribute to this novel finding. Strategies incorporating genomic epidemiology may help to identify the parasite and host molecules underlying Duffy-independent P. vivax invasion of human erythrocytes.