Preerythrocytic, live-attenuated Plasmodium falciparum vaccine candidates by design

dc.contributor.authorVanBuskirk, Kelley M.
dc.contributor.authorO'Neill, Matthew T.
dc.contributor.authorDe La Vega, Patricia
dc.contributor.authorMaier, Alex
dc.contributor.authorKrzych, Urszula
dc.contributor.authorWilliams, Jack
dc.contributor.authorDowler, Megan G.
dc.contributor.authorSacci, John B.
dc.contributor.authorKangwanrangsan, Niwat
dc.contributor.authorTsuboi, Takafumi
dc.contributor.authorKnetem an, Norman M.
dc.contributor.authorHeppner, Donald G.
dc.contributor.authorMurdock, Brant A.
dc.contributor.authorMikolajczak, Sebastian A.
dc.contributor.authorAly, Ahmed S.I.
dc.contributor.authorCowman, Alan F.
dc.contributor.authorKappe, Stefan H.I.
dc.date.accessioned2015-12-13T22:48:26Z
dc.date.issued2009
dc.date.updated2016-02-24T09:41:53Z
dc.description.abstractFalciparum malaria is initiated when Anopheles mosquitoes transmit the Plasmodium sporozoite stage during a blood meal. Irradiated sporozoites confer sterile protection against subsequent malaria infection in animal models and humans. This level of protection is unmatched by current recombinant malaria vaccines. However, the live-attenuated vaccine approach faces formidable obstacles, including development of accurate, reproducible attenuation techniques. We tested whether Plasmodium falciparum could be attenuated at the early liver stage by genetic engineering. The P. falciparum genetically attenuated parasites (GAPs) harbor individual deletions or simultaneous deletions of the sporozoite-expressed genes P52 and P36. Gene deletions were done by double-cross-over recombination to avoid genetic reversion of the knockout parasites. The gene deletions did not affect parasite replication throughout the erythrocytic cycle, gametocyte production, mosquito infections, and sporozoite production rates. However, the deletions caused parasite developmental arrest during hepatocyte infection. The double-gene deletion line exhibited a more severe intrahepatocytic growth defect compared with the single-gene deletion lines, and it did not persist. This defect was assessed in an in vitro liver-stage growth assay and in a chimeric mouse model harboring human hepatocytes. The strong phenotype of the double knockout GAP justifies its human testing as a whole-organism vaccine candidate using the established sporozoite challenge model. GAPs might provide a safe and reproducible platform to develop an efficacious whole-cell malaria vaccine that prevents infection at the preerythrocytic stage.
dc.identifier.issn0027-8424
dc.identifier.urihttp://hdl.handle.net/1885/80100
dc.publisherNational Academy of Sciences (USA)
dc.sourcePNAS - Proceedings of the National Academy of Sciences of the United States of America
dc.subjectKeywords: live vaccine; malaria vaccine; plasmodium falciparum vaccine; protein p 36; protein p52; protozoal protein; unclassified drug; live vaccine; malaria vaccine; protozoal protein; animal experiment; animal model; animal tissue; Anopheles stephensi; article; Genetically attenuated parasites; Malaria vaccine; P36; P52; Sporozoite
dc.titlePreerythrocytic, live-attenuated Plasmodium falciparum vaccine candidates by design
dc.typeJournal article
local.bibliographicCitation.issue31
local.bibliographicCitation.lastpage13009
local.bibliographicCitation.startpage13004
local.contributor.affiliationVanBuskirk, Kelley M., Seattle Biomedical Research Institute
local.contributor.affiliationO'Neill, Matthew T., The Walter and Eliza Hall Institute of Medical Research
local.contributor.affiliationDe La Vega, Patricia, Walter Reed Army Institute for Research
local.contributor.affiliationMaier, Alex, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationKrzych, Urszula, University of Maryland School of Medicine
local.contributor.affiliationWilliams, Jack, Walter Reed Army Institute for Research
local.contributor.affiliationDowler, Megan G., Walter Reed Army Insitute for Research
local.contributor.affiliationSacci, John B., University of Maryland School of Medicine
local.contributor.affiliationKangwanrangsan, Niwat, Ehime University
local.contributor.affiliationTsuboi, Takafumi, Ehime University
local.contributor.affiliationKnetem an, Norman M., University of Alberta
local.contributor.affiliationHeppner, Donald G., Walter Reed Army Institute for Research
local.contributor.affiliationMurdock, Brant A., Seattle Biomedical Research Institute
local.contributor.affiliationMikolajczak, Sebastian A., Seattle Biomedical Research Institute
local.contributor.affiliationAly, Ahmed S.I., Seattle Biomedical Research Institute
local.contributor.affiliationCowman, Alan F., The Walter and Eliza Hall Insitute of Medical Research
local.contributor.affiliationKappe, Stefan H.I., Seattle Biomedical Research Institute
local.contributor.authoremailu5083795@anu.edu.au
local.contributor.authoruidMaier, Alex, u5083795
local.description.embargo2037-12-31
local.description.notesImported from ARIES
local.identifier.absfor060199 - Biochemistry and Cell Biology not elsewhere classified
local.identifier.absseo970106 - Expanding Knowledge in the Biological Sciences
local.identifier.absseo920109 - Infectious Diseases
local.identifier.ariespublicationf5625xPUB8426
local.identifier.citationvolume106
local.identifier.doi10.1073/pnas.0906387106
local.identifier.scopusID2-s2.0-69149109035
local.identifier.thomsonID000268667600079
local.identifier.uidSubmittedByf5625
local.type.statusPublished Version

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