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

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 1

Study design schematic.

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Study design schematic. Malaria-naive volunteers (n = 17) were inoculate...
Malaria-naive volunteers (n = 17) were inoculated with pRBCs on day 0 (D0). Blood samples were taken for PCR analysis to measure both asexual parasites and gametocytes from day 4 pi and continued until the end of the study. Piperaquine (PIP 480 mg) treatment was administered on either day 7 or day 8 pi, and any subsequent recrudescent asexual infections were treated with piperaquine (PIP 960 mg). Mosquito-feeding assays were performed between day 17 and day 30 pi by feeding mosquitoes by live bite (direct skin feeding) on the participants or by membrane feeding on venous blood (Aim 1). During the period of gametocyte carriage, participants either received primaquine (15 mg) or artefenomel (500 mg) or did not receive either intervention (Aim 2). All participants received a course of artemether/lumefantrine and, if required, a single dose of primaquine (45 mg) to clear all parasites at the end of the study (Supplemental Table 1).