npj Vaccines (Nov 2022)
Creation and preclinical evaluation of genetically attenuated malaria parasites arresting growth late in the liver
- Blandine Franke-Fayard,
- Catherin Marin-Mogollon,
- Fiona J. A. Geurten,
- Séverine Chevalley-Maurel,
- Jai Ramesar,
- Hans Kroeze,
- Els Baalbergen,
- Els Wessels,
- Ludivine Baron,
- Valérie Soulard,
- Thomas Martinson,
- Maya Aleshnick,
- Antonius T. G. Huijs,
- Amit K. Subudhi,
- Yukiko Miyazaki,
- Ahmad Syibli Othman,
- Surendra Kumar Kolli,
- Olivia A. C. Lamers,
- Magali Roques,
- Rebecca R. Stanway,
- Sean C. Murphy,
- Lander Foquet,
- Diana Moita,
- António M. Mendes,
- Miguel Prudêncio,
- Koen J. Dechering,
- Volker T. Heussler,
- Arnab Pain,
- Brandon K. Wilder,
- Meta Roestenberg,
- Chris J. Janse
Affiliations
- Blandine Franke-Fayard
- Malaria Research Group, Department of Parasitology, Leiden University medical Center
- Catherin Marin-Mogollon
- Malaria Research Group, Department of Parasitology, Leiden University medical Center
- Fiona J. A. Geurten
- Malaria Research Group, Department of Parasitology, Leiden University medical Center
- Séverine Chevalley-Maurel
- Malaria Research Group, Department of Parasitology, Leiden University medical Center
- Jai Ramesar
- Malaria Research Group, Department of Parasitology, Leiden University medical Center
- Hans Kroeze
- Malaria Research Group, Department of Parasitology, Leiden University medical Center
- Els Baalbergen
- Malaria Research Group, Department of Parasitology, Leiden University medical Center
- Els Wessels
- Department of Medical Microbiology, Leiden University Medical Center
- Ludivine Baron
- Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National pour la Recherche Scientifique (CNRS), Centre d’Immunologie et des Maladies Infectieuses, CIMI
- Valérie Soulard
- Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National pour la Recherche Scientifique (CNRS), Centre d’Immunologie et des Maladies Infectieuses, CIMI
- Thomas Martinson
- Vaccine and Gene Therapy Institute, Oregon Health and Science University
- Maya Aleshnick
- Vaccine and Gene Therapy Institute, Oregon Health and Science University
- Antonius T. G. Huijs
- TropIQ Health Sciences
- Amit K. Subudhi
- Pathogen Genomics Laboratory, Biological and Environmental Sciences and Engineering (BESE) Division, King Abdullah University of Science and Technology (KAUST)
- Yukiko Miyazaki
- Malaria Research Group, Department of Parasitology, Leiden University medical Center
- Ahmad Syibli Othman
- Universiti Sultan Zainal Abidin, Faculty of Health Sciences
- Surendra Kumar Kolli
- Malaria Research Group, Department of Parasitology, Leiden University medical Center
- Olivia A. C. Lamers
- Malaria Research Group, Department of Parasitology, Leiden University medical Center
- Magali Roques
- Institute of Cell Biology, University of Bern
- Rebecca R. Stanway
- Institute of Cell Biology, University of Bern
- Sean C. Murphy
- Department of Laboratory Medicine and Pathology, University of Washington
- Lander Foquet
- Yecuris Corporation
- Diana Moita
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa
- António M. Mendes
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa
- Miguel Prudêncio
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa
- Koen J. Dechering
- TropIQ Health Sciences
- Volker T. Heussler
- Institute of Cell Biology, University of Bern
- Arnab Pain
- Pathogen Genomics Laboratory, Biological and Environmental Sciences and Engineering (BESE) Division, King Abdullah University of Science and Technology (KAUST)
- Brandon K. Wilder
- Vaccine and Gene Therapy Institute, Oregon Health and Science University
- Meta Roestenberg
- Malaria Research Group, Department of Parasitology, Leiden University medical Center
- Chris J. Janse
- Malaria Research Group, Department of Parasitology, Leiden University medical Center
- DOI
- https://doi.org/10.1038/s41541-022-00558-x
- Journal volume & issue
-
Vol. 7,
no. 1
pp. 1 – 17
Abstract
Abstract Whole-sporozoite (WSp) malaria vaccines induce protective immune responses in animal malaria models and in humans. A recent clinical trial with a WSp vaccine comprising genetically attenuated parasites (GAP) which arrest growth early in the liver (PfSPZ-GA1), showed that GAPs can be safely administered to humans and immunogenicity is comparable to radiation-attenuated PfSPZ Vaccine. GAPs that arrest late in the liver stage (LA-GAP) have potential for increased potency as shown in rodent malaria models. Here we describe the generation of four putative P. falciparum LA-GAPs, generated by CRISPR/Cas9-mediated gene deletion. One out of four gene-deletion mutants produced sporozoites in sufficient numbers for further preclinical evaluation. This mutant, PfΔmei2, lacking the mei2-like RNA gene, showed late liver growth arrest in human liver-chimeric mice with human erythrocytes, absence of unwanted genetic alterations and sensitivity to antimalarial drugs. These features of PfΔmei2 make it a promising vaccine candidate, supporting further clinical evaluation. PfΔmei2 (GA2) has passed regulatory approval for safety and efficacy testing in humans based on the findings reported in this study.
