A randomized feasibility trial comparing four antimalarial drug regimens to induce Plasmodium falciparum gametocytemia in the controlled human malaria infection model

Abstract

Background Malaria elimination strategies require a thorough understanding of parasite transmission from human to mosquito. A clinical model to induce gametocytes to understand their dynamics and evaluate transmission-blocking interventions (TBI) is currently unavailable. Here, we explore the use of the well-established Controlled Human Malaria Infection model (CHMI) to induce gametocyte carriage with different antimalarial drug regimens. Methods In a single centre, open-label randomised trial, healthy malaria-naive participants (aged 18–35 years) were infected with Plasmodium falciparum by bites of infected Anopheles mosquitoes (ClinicalTrials.gov, NCT02836002). Participants were randomly allocated to four different treatment arms (n = 4 per arm) comprising low-dose (LD) piperaquine (PIP) or sulfadoxine-pyrimethamine (SP), followed by a curative regimen upon recrudescence. Male and female gametocyte densities were determined by molecular assays. Findings Mature gametocytes were observed in all participants (16/16, 100%). Gametocytes appeared 8.5–12 days after the first detection of asexual parasites. Peak gametocyte densities and gametocyte burden was highest in the LD-PIP/SP arm, and associated with the preceding asexual parasite biomass (p=0.026). Male gametocytes had a mean estimated circulation time of 2.7 days (95% CI 1.5–3.9) compared to 5.1 days (95% CI 4.1–6.1) for female gametocytes. Exploratory mosquito feeding assays showed successful sporadic mosquito infections. There were no serious adverse events or significant differences in the occurrence and severity of adverse events between study arms (p=0.49 and p=0.28). Conclusions The early appearance of gametocytes indicates gametocyte commitment during the first wave of asexual parasites emerging from the liver. Treatment by LD-PIP followed by a curative SP regimen, results in the highest gametocyte densities and the largest number of gametocyte-positive days. This model can be used to evaluate the effect of drugs and vaccines on gametocyte dynamics, and lays the foundation for fulfilling the critical unmet need to evaluate transmission-blocking interventions against falciparum malaria for downstream selection and clinical development. Funding PATH Malaria Vaccine Initiative (MVI)

Two-Faced Immunity? The Evidence for Antibody Enhancement of Malaria Transmission

“…A hypothesis that emerged from studies in animal models was that gamete antibodies might have both TE and TR properties, which manifest according to their concentration that varies over time (Figure 1) [30]. Such detailed assessments in humans may become more viable with controlled human malaria infections allowing gametocyte production [57,58] but existing data from naturally acquired malaria infections inevitably start from the point of patency or symptom presentation, excluding the assessment of transmission-modulation early in the infection during antibody proliferation.…”

Liver Injury in Uncomplicated Malaria is an Overlooked Phenomenon: An Observational Study

“…The underlying pathogenesis of liver damage is largely unknown. Furthermore, liver involvement has only been incidentally investigated in uncomplicated malaria [ [14] , [15] , [16] ].…”

Persistence of P. Falciparum Ring-Stage Parasites 42 Days After Artemisinin and Non-Artemisinin Combination Therapy in Naturally Infected Malians

“…In addition, our longer period of follow-up also allowed us to explore associations of ring-stage persistence with subsequent gametocyte carriage. Whilst data collection was not speci cally designed for this, we were able to relate ring-stage densities with gametocyte densities 7 and 14 days later, roughly the period needed for gametocyte production (20), and observed no association. The investment of parasites that persist under drug-pressure in either asexual multiplication or gametocyte production re ects a delicate balance (21).…”