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Protective Efficacy Induced by Genetically Attenuated Mid-to-Late Liver-Stage Arresting Plasmodium berghei Δmrp2 Parasites

Maarten van der VeldenDepartment of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands.

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Sanna R. RijpmaDepartment of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands.

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Vivienne VerweijDepartment of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands.

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Geert-Jan van GemertDepartment of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands.

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Séverine Chevalley-MaurelLeiden Malaria Research Group, Department of Parasitology, Center of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.

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Marga van de Vegte-BolmerDepartment of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands.

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Blandine M. Franke-FayardLeiden Malaria Research Group, Department of Parasitology, Center of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.

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Frans G. M. RusselDepartment of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands.

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Chris J. JanseLeiden Malaria Research Group, Department of Parasitology, Center of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.

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Robert W. SauerweinDepartment of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands.

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Jan B. KoenderinkDepartment of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands.

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Whole parasite immunization strategies employing genetically attenuated parasites (GAP), which arrest during liver-stage development, have been applied successfully for induction of sterile malaria protection in rodents. Recently, we generated a Plasmodium berghei GAP-lacking expression of multidrug resistance-associated protein (MRP2) (PbΔmrp2) that was capable of partial schizogony in hepatocytes but showed complete growth arrest. Here, we investigated the protective efficacy after intravenous (IV) immunization of BALB/c and C57BL/6J mice with PbΔmrp2 sporozoites. Low-dose immunization using 400 PbΔmrp2 sporozoites induced 100% sterile protection in BALB/c mice after IV challenge with 10,000 wild-type sporozoites. In addition, almost full protection (90%) was obtained after three immunizations with 10,000 sporozoites in C57BL/6J mice. Parasite liver loads in nonprotected PbΔmrp2-challenged C57BL/6J mice were reduced by 86% ± 5% on average compared with naive control mice. The mid-to-late arresting PbΔmrp2 GAP was equipotent in induction of protective immunity to the early arresting PbΔb9Δslarp GAP. The combined data support a clear basis for further exploration of Plasmodium falciparum parasites lacking mrp2 as a suitable GAP vaccine candidate.

Author Notes

* Address correspondence to Jan B. Koenderink, Radboud University Medical Center, Geert Grooteplein Zuid 28, 6500 HB, Nijmegen, The Netherlands. E-mail: jan.koenderink@radboudumc.nl
† These authors contributed equally to this work.

Authors' addresses: Maarten van der Velden, Frans G. M. Russel, and Jan B. Koenderink, Department of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands, E-mails: maarten.vandervelden@radboudumc.nl, frans.russel@radboudumc.nl, and jan.koenderink@radboudumc.nl. Sanna R. Rijpma, Geert-Jan van Gemert, Marga van de Vegte-Bolmer, Robert W. Sauerwein, Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands, E-mails: sanna.rijpma@radboudumc.nl, geert-jan.vangemert@radboudumc.nl, marga.vandevegte-bolmer@radboudumc.nl, and robert.sauerwein@radboudumc.nl. Vivienne Verweij, Donders Institute for Brain, Cognition, Radboud University Medical Center, Nijmegen, The Netherlands, and Behaviour, and Department of Anatomy, Radboud University Medical Center, Nijmegen, The Netherlands, E-mail: vivienne.verweij@radboudumc.nl. Séverine Chevalley-Maurel, Blandine M. Franke-Fayard, and Chris J. Janse, Leiden Malaria Research Group, Department of Parasitology, Center of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands, E-mails: s.c.chevalley@lumc.nl, b.franke-fayard@lumc.nl, and c.j.janse@lumc.nl.

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