An all-in-one pipeline for the in vitro discovery and in vivo testing of Plasmodium falciparum malaria transmission blocking drugs

Nicolas M. B. Brancucci (), Christin Gumpp, Geert-Jan Gemert, Xiao Yu, Armin Passecker, Flore Nardella, Basil T. Thommen, Marc Chambon, Gerardo Turcatti, Ludovic Halby, Benjamin Blasco, Maëlle Duffey, Paola B. Arimondo, Teun Bousema, Artur Scherf, Didier Leroy, Taco W. A. Kooij, Matthias Rottmann () and Till S. Voss ()
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Nicolas M. B. Brancucci: Swiss Tropical and Public Health Institute
Christin Gumpp: Swiss Tropical and Public Health Institute
Geert-Jan Gemert: Radboud University Medical Center
Xiao Yu: Swiss Tropical and Public Health Institute
Armin Passecker: Swiss Tropical and Public Health Institute
Flore Nardella: Université de Paris-Cité
Basil T. Thommen: Swiss Tropical and Public Health Institute
Marc Chambon: École Polytechnique Fédérale de Lausanne (EPFL)
Gerardo Turcatti: École Polytechnique Fédérale de Lausanne (EPFL)
Ludovic Halby: Université de Paris-Cité
Benjamin Blasco: Medicines for Malaria Venture
Maëlle Duffey: Medicines for Malaria Venture
Paola B. Arimondo: Université de Paris-Cité
Teun Bousema: Radboud University Medical Center
Artur Scherf: Université de Paris-Cité
Didier Leroy: Medicines for Malaria Venture
Taco W. A. Kooij: Radboud University Medical Center
Matthias Rottmann: Swiss Tropical and Public Health Institute
Till S. Voss: Swiss Tropical and Public Health Institute

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract Elimination of malaria will require new drugs with potent activity against Plasmodium falciparum mature stage V gametocytes, the only stages infective to the mosquito vector. The identification and comprehensive validation of molecules active against these quiescent stages is difficult due to the specific biology of gametocytes, challenges linked to their cultivation in vitro and the lack of animal models suitable for evaluating the transmission-blocking potential of drug candidates in vivo. Here, we present a transmission-blocking drug discovery and development platform that builds on transgenic NF54/iGP1_RE9Hulg8 parasites engineered to conditionally produce large numbers of stage V gametocytes expressing a red-shifted firefly luciferase viability reporter. Besides developing a robust in vitro screening assay for the reliable identification of stage V gametocytocidal compounds, we also establish a preclinical in vivo malaria transmission model based on infecting female humanized NODscidIL2Rγnull mice with pure NF54/iGP1_RE9Hulg8 stage V gametocytes. Using whole animal bioluminescence imaging, we assess the in vivo gametocyte killing and clearance kinetics of antimalarial reference drugs and clinical drug candidates and identify markedly different pharmacodynamic response profiles. Finally, we combine this mouse model with mosquito feeding assays and thus firmly establish a valuable tool for the systematic in vivo evaluation of transmission-blocking drug efficacy.

Date: 2025
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DOI: 10.1038/s41467-025-62014-3

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