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A controlled human malaria infection model enabling evaluation of transmission-blocking interventions
Katharine A. Collins, … , Jörg J. Möhrle, James S. McCarthy
Katharine A. Collins, … , Jörg J. Möhrle, James S. McCarthy
Published February 1, 2018
Citation Information: J Clin Invest. 2018;128(4):1551-1562. https://doi.org/10.1172/JCI98012.
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Clinical Research and Public Health Infectious disease Article has an altmetric score of 23

A controlled human malaria infection model enabling evaluation of transmission-blocking interventions

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Abstract

BACKGROUND. Drugs and vaccines that can interrupt the transmission of Plasmodium falciparum will be important for malaria control and elimination. However, models for early clinical evaluation of candidate transmission-blocking interventions are currently unavailable. Here, we describe a new model for evaluating malaria transmission from humans to Anopheles mosquitoes using controlled human malaria infection (CHMI). METHODS. Seventeen healthy malaria-naive volunteers underwent CHMI by intravenous inoculation of P. falciparum–infected erythrocytes to initiate blood-stage infection. Seven to eight days after inoculation, participants received piperaquine (480 mg) to attenuate asexual parasite replication while allowing gametocytes to develop and mature. Primary end points were development of gametocytemia, the transmissibility of gametocytes from humans to mosquitoes, and the safety and tolerability of the CHMI transmission model. To investigate in vivo gametocytocidal drug activity in this model, participants were either given an experimental antimalarial, artefenomel (500 mg), or a known gametocytocidal drug, primaquine (15 mg), or remained untreated during the period of gametocyte carriage. RESULTS. Male and female gametocytes were detected in all participants, and transmission to mosquitoes was achieved from 8 of 11 (73%) participants evaluated. Compared with results in untreated controls (n = 7), primaquine (15 mg, n = 5) significantly reduced gametocyte burden (P = 0.01), while artefenomel (500 mg, n = 4) had no effect. Adverse events (AEs) were mostly mild or moderate. Three AEs were assessed as severe — fatigue, elevated alanine aminotransferase, and elevated aspartate aminotransferase — and were attributed to malaria infection. Transaminase elevations were transient, asymptomatic, and resolved without intervention. CONCLUSION. We report the safe and reproducible induction of P. falciparum gametocytes in healthy malaria-naive volunteers at densities infectious to mosquitoes, thereby demonstrating the potential for evaluating transmission-blocking interventions in this model. TRIAL REGISTRATION. ClinicalTrials.gov NCT02431637 and NCT02431650. FUNDING. Bill & Melinda Gates Foundation.

Authors

Katharine A. Collins, Claire Y.T. Wang, Matthew Adams, Hayley Mitchell, Melanie Rampton, Suzanne Elliott, Isaie J. Reuling, Teun Bousema, Robert Sauerwein, Stephan Chalon, Jörg J. Möhrle, James S. McCarthy

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Figure 7

Gametocyte infectivity and clearance.

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Gametocyte infectivity and clearance.
(A) The peak gametocytemia (male a...
(A) The peak gametocytemia (male and female gametocytes) for participants who were noninfectious throughout the study compared with participants who were infectious on at least one occasion. Box plots indicate the median and whiskers show the minimum and maximum responses. Groups compared using Mann-Whitney U test. (B) Percentage reduction in gametocytemia (as measured by 18S rDNA qPCR in samples where ring-stage parasites were not present) between day of drug treatment and 5 days after treatment with 15 mg primaquine (n = 5), 500 mg artefenomel (n = 4), or no drug (negative control, n = 7). One participant from the negative control group is not represented due to the presence of ring-stage parasites precluding analysis of gametocyte clearance. Lines indicate the median response and groups compared by Kruskal-Wallis test with Dunn’s multiple comparison test comparing all groups.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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