Protective Efficacy Induced by Genetically Attenuated Mid-to-Late Liver-Stage Arresting Plasmodium berghei Δmrp2 Parasites.
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.
Department of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands.
Maarten
M
van der Velden
Department of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands.
Sanna R
SR
Rijpma
Department of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands.
Vivienne
V
Verweij
Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands.
Geert-Jan
GJ
van Gemert
Leiden Malaria Research Group, Department of Parasitology, Center of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
Séverine
S
Chevalley-Maurel
Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands.
Marga
M
van de Vegte-Bolmer
Leiden Malaria Research Group, Department of Parasitology, Center of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
Blandine M
BM
Franke-Fayard
Department of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands.
Frans G M
FG
Russel
Leiden Malaria Research Group, Department of Parasitology, Center of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
Chris J
CJ
Janse
Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands.
Robert W
RW
Sauerwein
Department of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands. jan.koenderink@radboudumc.nl.
Jan B
JB
Koenderink
D000818:Animals; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D007114:Immunization; D008099:Liver / Q000276:immunology / Q000469:parasitology; D008288:Malaria / Q000276:immunology / Q000469:parasitology / Q000517:prevention & control*; D017780:Malaria Vaccines / Q000008:administration & dosage / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D030781:Organisms, Genetically Modified / Q000276:immunology / Q000378:metabolism; D018512:Parasitemia / Q000276:immunology / Q000469:parasitology / Q000517:prevention & control*; D010962:Plasmodium berghei / Q000235:genetics / Q000276:immunology*; D015800:Protozoan Proteins / Q000235:genetics / Q000276:immunology*; D034101:Sporozoites / Q000276:immunology* / Q000378:metabolism; D014613:Vaccines, Attenuated
D017780:Malaria Vaccines; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D015800:Protozoan Proteins; D014613:Vaccines, Attenuated