New Insight on Malaria Parasite Transmission Could Inform Future Drug Development

A clinical trial involving an established model for studying malaria has yielded new insight on parasite transmission and could assist in future elimination efforts. The study, conducted at the Radboud University Medical Center in the Netherlands and published in eLife, explored the use of the Controlled Human Malaria Infection model (CHMI) to induce the malaria parasite Plasmodium falciparum (P. falciparum) in healthy volunteers. This model is normally used to assess the safety and efficacy of novel antimalarial drugs and vaccines.

Malaria continues to be a significant public health burden. A major challenge to eliminating the disease is its highly efficient transmission by Anopheles mosquitoes. Transmission starts when a small proportion of asexual parasites in the blood of humans transform into male and female sexual-stage parasites called gametocytes. These organisms mature in the bone marrow and then appear in the blood, where they may be taken up by mosquitoes, rendering the insects infectious.

“Malaria elimination strategies require a thorough understanding of parasite transmission from human to mosquito, but a clinical model to investigate parasite dynamics and evaluate interventions that block their transmission is currently unavailable,” says first author Isaie Reuling from the Radboud University Medical Centre. “Here, we present a CHMI model to induce mature gametocytes following mosquito bite infection in healthy volunteers, allowing us to study the biology of these parasites in more detail.”

In the randomised trial, 16 healthy participants aged 18–35 years old were infected with P. falciparum by bites of infected Anopheles mosquitoes. They were then randomly allocated to four different treatment arms comprising low-dose piperaquine (PIP) or sulfadoxine-pyrimethamine (SP).

The researchers first saw that gametocytes were present in all 16 volunteers. They studied the numbers of these parasites in each of the participants using molecular detectors called assays, and found that the numbers matched those of the preceding asexual parasites. “Further, we saw that male and female gametocytes appeared 8.5 to 12 days after the first detection of asexual parasites,” Reuling explains. “This timing suggests that a fraction of the first asexual parasites released into the bloodstream quickly starts to transform into male and female gametocytes.”

“The dynamics of the gametocytes’ maturation and sex ratio identified in our model reflect those found in naturally acquired infections, although their numbers are much lower than in many natural settings,” adds senior author Teun Bousema, PhD, lecturer at the Radboud University Medical Center and the London School of Hygiene and Tropical Medicine, UK. “This suggests that our CHMI model can be used to evaluate the effect of drugs and vaccines on gametocytes for potential use in patients living in areas where malaria is common. The work also lays the foundation for fulfilling the critical unmet need to evaluate transmission-blocking interventions against P. falciparum, so that more effective treatments can be developed in the future.”

The paper, ‘A randomized feasibility trial comparing four antimalarial drug regimens to induce Plasmodium falciparum gametocytemia in the Controlled Human Malaria Infection model,’ can be freely accessed online at https://doi.org/10.7554/eLife.31549.

Source: eLife