Complete attenuation of genetically engineered Plasmodium falciparum sporozoites in human subjects

James G. Kublin, Sebastian A. Mikolajczak, Brandon Wilder, Matt E. Fishbaugher, Annette Seilie, Lisa Shelton, Tracie VonGoedert, Melike Firat, Sara Magee, Emma Fritzen, Will Betz, Heather S. Kain, Dorender A. Dankwa, Ryan W.J. Steel, Ashley M. Vaughan, D. Noah Sather, Sean C. Murphy, Stefan H.I. Kappe

Research output: Contribution to journalArticle

44 Scopus citations

Abstract

Immunization of humans with whole sporozoites confers complete, sterilizing immunity against malaria infection. However, achieving consistent safety while maintaining immunogenicity of whole parasite vaccines remains a formidable challenge. We generated a genetically attenuated Plasmodium falciparum (Pf) malaria parasite by deleting three genes expressed in the pre-erythrocytic stage (Pf p52-/p36-/sap1-). We then tested the safety and immunogenicity of the genetically engineered (Pf GAP3KO) sporozoites in human volunteers. Pf GAP3KO sporozoites were delivered to 10 volunteers using infected mosquito bites with a single exposure consisting of 150 to 200 bites per subject. All subjects remained blood stage-negative and developed inhibitory antibodies to sporozoites. GAP3KO rodent malaria parasites engendered complete, protracted immunity against infectious sporozoite challenge in mice. The results warrant further clinical testing of Pf GAP3KO and its potential development into a vaccine strain.

Original languageEnglish (US)
Article numbereaad9099
JournalScience Translational Medicine
Volume9
Issue number371
DOIs
StatePublished - Jan 4 2017
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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    Kublin, J. G., Mikolajczak, S. A., Wilder, B., Fishbaugher, M. E., Seilie, A., Shelton, L., VonGoedert, T., Firat, M., Magee, S., Fritzen, E., Betz, W., Kain, H. S., Dankwa, D. A., Steel, R. W. J., Vaughan, A. M., Sather, D. N., Murphy, S. C., & Kappe, S. H. I. (2017). Complete attenuation of genetically engineered Plasmodium falciparum sporozoites in human subjects. Science Translational Medicine, 9(371), [eaad9099]. https://doi.org/10.1126/scitranslmed.aad9099