A genetically attenuated malaria vaccine candidate based on P. falciparum b9/slarp gene-deficient sporozoites
Ben C L van Schaijk,
Ivo H J Ploemen,
Takeshi Annoura,
Martijn W Vos,
Lander Foquet,
Geert-Jan van Gemert,
Severine Chevalley-Maurel,
Marga van de Vegte-Bolmer,
Mohammed Sajid,
Jean-Francois Franetich,
Audrey Lorthiois,
Geert Leroux-Roels,
Philip Meuleman,
Cornelius C Hermsen,
Dominique Mazier,
Stephen L Hoffman,
Chris J Janse,
Shahid M Khan,
Robert W Sauerwein
Affiliations
Ben C L van Schaijk
Department of Medical Microbiology, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands
Ivo H J Ploemen
Department of Medical Microbiology, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands
Takeshi Annoura
Leiden Malaria Research Group, Parasitology, Leiden University Medical Center, Leiden, Netherlands
Martijn W Vos
Department of Medical Microbiology, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands
Lander Foquet
Center for Vaccinology, Ghent University and University Hospital, Ghent, Belgium
Geert-Jan van Gemert
Department of Medical Microbiology, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands
Severine Chevalley-Maurel
Leiden Malaria Research Group, Parasitology, Leiden University Medical Center, Leiden, Netherlands
Marga van de Vegte-Bolmer
Department of Medical Microbiology, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands
Mohammed Sajid
Leiden Malaria Research Group, Parasitology, Leiden University Medical Center, Leiden, Netherlands
Jean-Francois Franetich
Centre d'Immunologie et des Maladies Infectieuses, Université Pierre et Marie Curie-Paris 6, Paris, France; Centre d'Immunologie et des Maladies Infectieuses, INSERM, U1135, Paris, Paris, France
Audrey Lorthiois
Centre d'Immunologie et des Maladies Infectieuses, Université Pierre et Marie Curie-Paris 6, Paris, France; Centre d'Immunologie et des Maladies Infectieuses, INSERM, U1135, Paris, Paris, France
Geert Leroux-Roels
Center for Vaccinology, Ghent University and University Hospital, Ghent, Belgium
Philip Meuleman
Center for Vaccinology, Ghent University and University Hospital, Ghent, Belgium
Cornelius C Hermsen
Department of Medical Microbiology, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands
Dominique Mazier
Centre d'Immunologie et des Maladies Infectieuses, Université Pierre et Marie Curie-Paris 6, Paris, France; Centre d'Immunologie et des Maladies Infectieuses, INSERM, U1135, Paris, Paris, France; Service Parasitologie-Mycologie, Assistance Publique—Hôpitaux de Paris, Groupe hospitalier Pitié-Salpêtrière, Paris, France
Stephen L Hoffman
Sanaria Inc., Rockville, United States
Chris J Janse
Leiden Malaria Research Group, Parasitology, Leiden University Medical Center, Leiden, Netherlands
Shahid M Khan
Leiden Malaria Research Group, Parasitology, Leiden University Medical Center, Leiden, Netherlands
Robert W Sauerwein
Department of Medical Microbiology, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands
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.
