title: A genetically attenuated malaria vaccine candidate based on P. falciparum b9/slarp gene-deficient sporozoites.
abstract: A highly efficacious pre-erythrocytic stage vaccine would be an important tool for the control and elimination of malaria but is currently unavailable. High-level protection in humans can be achieved by experimental immunization with Plasmodium falciparum sporozoites attenuated by radiation or under anti-malarial drug coverage. Immunization with genetically attenuated parasites (GAP) would be an attractive alternative approach. In this study, we present data on safety and protective efficacy using sporozoites with deletions of two genes, that is the newly identified b9 and slarp, which govern independent and critical processes for successful liver-stage development. In the rodent malaria model, PbΔb9ΔslarpGAP was completely attenuated showing no breakthrough infections while efficiently inducing high-level protection. The human PfΔb9ΔslarpGAP generated without drug resistance markers were infective to human hepatocytes in vitro and to humanized mice engrafted with human hepatocytes in vivo but completely aborted development after infection. These findings support the clinical development of a PfΔb9ΔslarpSPZ vaccine.
authors.affiliation: Department of Medical Microbiology, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands.
authors.forename: Ben C L
authors.initials: BC
authors.lastname: van Schaijk
authors.affiliation: Department of Medical Microbiology, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands.
authors.forename: Ivo H J
authors.initials: IH
authors.lastname: Ploemen
authors.affiliation: Leiden Malaria Research Group, Parasitology, Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Annoura
authors.affiliation: Department of Medical Microbiology, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands.
authors.forename: Martijn W
authors.initials: MW
authors.lastname: Vos
authors.affiliation: Center for Vaccinology, Ghent University and University Hospital, Ghent, Belgium.
authors.forename: Lander
authors.initials: L
authors.lastname: Foquet
authors.affiliation: Department of Medical Microbiology, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands.
authors.forename: Geert-Jan
authors.initials: GJ
authors.lastname: van Gemert
authors.affiliation: Leiden Malaria Research Group, Parasitology, Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Severine
authors.initials: S
authors.lastname: Chevalley-Maurel
authors.affiliation: Department of Medical Microbiology, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands.
authors.forename: Marga
authors.initials: M
authors.lastname: van de Vegte-Bolmer
authors.affiliation: Leiden Malaria Research Group, Parasitology, Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Sajid
authors.affiliation: Centre d'Immunologie et des Maladies Infectieuses, Université Pierre et Marie Curie-Paris 6, Paris, France.
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Franetich
authors.affiliation: Centre d'Immunologie et des Maladies Infectieuses, Université Pierre et Marie Curie-Paris 6, Paris, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Lorthiois
authors.affiliation: Center for Vaccinology, Ghent University and University Hospital, Ghent, Belgium.
authors.forename: Geert
authors.initials: G
authors.lastname: Leroux-Roels
authors.affiliation: Center for Vaccinology, Ghent University and University Hospital, Ghent, Belgium.
authors.forename: Philip
authors.initials: P
authors.lastname: Meuleman
authors.affiliation: Department of Medical Microbiology, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands.
authors.forename: Cornelius C
authors.initials: CC
authors.lastname: Hermsen
authors.affiliation: Centre d'Immunologie et des Maladies Infectieuses, Université Pierre et Marie Curie-Paris 6, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Mazier
authors.affiliation: Sanaria Inc., Rockville, United States.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Hoffman
authors.affiliation: Leiden Malaria Research Group, Parasitology, Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Janse
authors.affiliation: Leiden Malaria Research Group, Parasitology, Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Shahid M
authors.initials: SM
authors.lastname: Khan
authors.affiliation: Department of Medical Microbiology, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Sauerwein
mesh_terms: D000818:Animals; D006801:Humans; D008099:Liver / Q000469:parasitology; D017780:Malaria Vaccines / Q000235:genetics* / Q000276:immunology; D016778:Malaria, Falciparum / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010963:Plasmodium falciparum / Q000235:genetics / Q000276:immunology*; D034101:Sporozoites / Q000276:immunology*; D014613:Vaccines, Attenuated / Q000235:genetics* / Q000276:immunology
chemical_list: D017780:Malaria Vaccines; D014613:Vaccines, Attenuated
keywords: Plasmodium; genetically attenuated parasite; human; human biology; infectious disease; malaria; medicine; microbiology; mouse; sporozoite; vaccine