Relapses of Plasmodium vivax Infection Result from Clonal Hypnozoites Activated at Predetermined Intervals

Plasmodium vivax infections are characterized by varying numbers of relapses occurring at different intervals as a result of activation of liver-stage hypnozoites. Parasite or host factors that determine the number and timing of relapses are unclear. In the present article, we report the analysis of relapse patterns and molecular characterization of parasites collected from Australian soldiers experiencing relapses of vivax malaria after exposure in East Timor. Although high molecular diversity was observed, a single allelic type was identified in association with 99% of relapses. Importantly, in 71% of patients experiencing >1 relapse, the allelic types were clonal and different in the 2 different relapses. These results, combined with those from a computer simulation model, suggest that a single hypnozoite clone was activated, causing a relapse, and that multiple relapses most likely arose from coordinated activation of hypnozoites originating from different parasite strains. These findings suggest remarkable regulation of relapse intervals in vivax malaria.