Where sleeping malaria parasites lie

A study of malaria infection, illness and transmission rates among children in Papua New Guinea’s East Sepik Province has yielded a therapeutic strategy that could quell or even eliminate infections by two of the most persistent malaria parasites: Plasmodium vivax and Plasmodium ovale.

The international study, led by PNG-based malaria researcher Dr Leanne Robinson of the Population Heath and Immunity Division of the Walter and Eliza Hall Institute, has been published in the journal PLOS Medicine.

Most antimalarial drugs target only the blood phase of the parasite, and the benefits of treatment are only transient. A mathematical model of transmission developed by Robinson and her colleagues would have only transient benefits for children with relapsing malaria.

Now, Robinson and a consortium of Australian, Swiss, UK and Spanish researchers have shown that adding primaquine to a cocktail of standard antimalarial drugs dramatically reduces relapse rates among children in areas where three mosquito-borne malaria parasite species (Plasmodium falciparum,  P. vivax and P. ovale) are hyperendemic — that is, where infection rates among children are extremely high.

Primaquine specifically targets a phase in the life cycle of both P. vivax and P. ovale parasites, called a hypnozoite, which lies dormant in liver cells (the term derives from the Greek ‘hypnos’, meaning ‘sleep’). Here, they are undetectable even by supersensitive polymerase chain reaction.

While PCR will confirm that drugs have cleared the parasites from the bloodstream, they can emerge from the liver months or years later, transform into the blood stage and reinfect the subject’s red blood cells. Results from the randomised placebo-controlled trial and mathematical model suggested that the hypnozoites are responsible for four out of five relapse episodes in children with vivax malaria and three out of five relapses in ovale-infected children.

The study enrolled 524 children aged five to 10 years in the trial; PCR was used to determine that they were infected with either P. vivax or P. ovale. Half were assigned to the trial arm and, over a 20-day period, were administered the full, three-drug cocktail of antimalarials: chloroquine and artemether-lumefantrine (blood stage) and primaquine (liver stage). Children involved in the placebo arm of the trial received only the blood-stage drugs.

The children were followed up actively for eight months to determine relapse rates in groups. Among vivax-infected children in the full-treatment arm, the rate of relapse was only 0.63 cases per year. For children in the placebo arm, it was 2.62 cases per year — more than four times higher. For ovale-infected children in the full-treatment arm, the relapse risk was 0.06 cases per year, compared with 0.14 — 2.3 times higher — for the placebo group.

The consortium developed a stochastic model of transmission to estimate the potential effect of mass drug administration (MDA) for preventing recurrent P. vivax infections. From the trial data, the model predicted that diagnosis by highly sensitive, quantitative, real-time PCR, and mass treatment with the full cocktail of standard blood-stage drugs plus primaquine to target resting hypnozoites, should be “highly efficacious” in reducing transmission rates of both vivax and ovale malaria in areas where infection rates are very high.

An accompanying editor’s summary of the research paper said, “Nevertheless, these findings highlight the importance of developing new anti-hypnozoite drugs and MDA programs that target areas and risk groups with confirmed local transmission of P. vivax to achieve global malaria control and elimination.”

Image caption: A Plasmodium vivax-infected red blood cell. Standard malaria drugs like chloroquine and artemether-lumefantrine that target the blood stage of the parasites are ineffectual in clearing the resting hypnozoite stage, which hides out in the liver and causes relapsing bouts of malaria. A full, three-drug cocktail is predicted to drastically reduce relapse rates and malaria transmission.