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A randomized feasibility trial comparing four antimalarial drug regimens to induce Plasmodium falciparum gametocytemia in the controlled human malaria infection model.
Elife. 2018 02 27; 7E

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).

Authors+Show Affiliations

Department of Medical Microbiology, Radboud university medical center, Nijmegen, Netherlands.Department of Medical Microbiology, Radboud university medical center, Nijmegen, Netherlands.Department of Public Health, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands.Department of Medical Microbiology, Radboud university medical center, Nijmegen, Netherlands.Department of Medical Microbiology, Radboud university medical center, Nijmegen, Netherlands.Department of Medical Microbiology, Radboud university medical center, Nijmegen, Netherlands.Department of Medical Microbiology, Radboud university medical center, Nijmegen, Netherlands.Department of Medical Microbiology, Radboud university medical center, Nijmegen, Netherlands.Department of Medical Microbiology, Radboud university medical center, Nijmegen, Netherlands.Department of Medical Microbiology, Radboud university medical center, Nijmegen, Netherlands.Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands.Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands.PATH Malaria Vaccine Initiative, Washington, United States.Department of Medical Microbiology, Radboud university medical center, Nijmegen, Netherlands.Department of Public Health, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands.MRC Tropical Epidemiology Group, London School of Hygiene and Tropical Medicine, London, United Kingdom.Clinical Tropical Medicine Laboratory, QIMR Berghofer, Brisbane, Australia.PATH Malaria Vaccine Initiative, Washington, United States.Clinical Tropical Medicine Laboratory, QIMR Berghofer, Brisbane, Australia.Department of Medical Microbiology, Radboud university medical center, Nijmegen, Netherlands.Department of Medical Microbiology, Radboud university medical center, Nijmegen, Netherlands.

Pub Type(s)

Comparative Study
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29482720

Citation

Reuling, Isaie J., et al. "A Randomized Feasibility Trial Comparing Four Antimalarial Drug Regimens to Induce Plasmodium Falciparum Gametocytemia in the Controlled Human Malaria Infection Model." ELife, vol. 7, 2018.
Reuling IJ, van de Schans LA, Coffeng LE, et al. A randomized feasibility trial comparing four antimalarial drug regimens to induce Plasmodium falciparum gametocytemia in the controlled human malaria infection model. Elife. 2018;7.
Reuling, I. J., van de Schans, L. A., Coffeng, L. E., Lanke, K., Meerstein-Kessel, L., Graumans, W., van Gemert, G. J., Teelen, K., Siebelink-Stoter, R., van de Vegte-Bolmer, M., de Mast, Q., van der Ven, A. J., Ivinson, K., Hermsen, C. C., de Vlas, S., Bradley, J., Collins, K. A., Ockenhouse, C. F., McCarthy, J., ... Bousema, T. (2018). A randomized feasibility trial comparing four antimalarial drug regimens to induce Plasmodium falciparum gametocytemia in the controlled human malaria infection model. ELife, 7. https://doi.org/10.7554/eLife.31549
Reuling IJ, et al. A Randomized Feasibility Trial Comparing Four Antimalarial Drug Regimens to Induce Plasmodium Falciparum Gametocytemia in the Controlled Human Malaria Infection Model. Elife. 2018 02 27;7 PubMed PMID: 29482720.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A randomized feasibility trial comparing four antimalarial drug regimens to induce Plasmodium falciparum gametocytemia in the controlled human malaria infection model. AU - Reuling,Isaie J, AU - van de Schans,Lisanne A, AU - Coffeng,Luc E, AU - Lanke,Kjerstin, AU - Meerstein-Kessel,Lisette, AU - Graumans,Wouter, AU - van Gemert,Geert-Jan, AU - Teelen,Karina, AU - Siebelink-Stoter,Rianne, AU - van de Vegte-Bolmer,Marga, AU - de Mast,Quirijn, AU - van der Ven,André J, AU - Ivinson,Karen, AU - Hermsen,Cornelus C, AU - de Vlas,Sake, AU - Bradley,John, AU - Collins,Katharine A, AU - Ockenhouse,Christian F, AU - McCarthy,James, AU - Sauerwein,Robert W, AU - Bousema,Teun, Y1 - 2018/02/27/ PY - 2017/08/25/received PY - 2018/01/14/accepted PY - 2018/2/28/entrez PY - 2018/2/28/pubmed PY - 2019/7/10/medline KW - p. falciparum KW - Malaria KW - Plasmodium falciparum KW - gametocytes KW - infectious disease KW - microbiology KW - transmission JF - eLife JO - Elife VL - 7 N2 - 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). SN - 2050-084X UR - https://www.unboundmedicine.com/medline/citation/29482720/A_randomized_feasibility_trial_comparing_four_antimalarial_drug_regimens_to_induce_Plasmodium_falciparum_gametocytemia_in_the_controlled_human_malaria_infection_model_ L2 - https://doi.org/10.7554/eLife.31549 DB - PRIME DP - Unbound Medicine ER -