A next generation genetically attenuated Plasmodium falciparum parasite created by triple gene deletion
- Author(s)
- Mikolajczak, SA; Lakshmanan, V; Fishbaugher, M; Camargo, N; Harupa, A; Kaushansky, A; Douglass, AN; Baldwin, M; Healer, J; O'Neill, M; Phuong, T; Cowman, A; Kappe, SH;
- Details
- Publication Year 2014-05-14,Volume 22,Issue #9,Page 1707-1715
- Journal Title
- Mol Ther
- Publication Type
- Journal Article
- Abstract
- Immunization with live-attenuated Plasmodium sporozoites completely protects against malaria infection. Genetic engineering offers a versatile platform to create live-attenuated sporozoite vaccine candidates. We previously generated a genetically attenuated parasite (GAP) by deleting the P52 and P36 genes in the NF54 wildtype (WT) strain of P. falciparum (Pf p52-/p36- GAP). Preclinical assessment of p52-/p36- GAP in a humanized mouse model indicated an early and severe liver stage growth defect. However, human exposure to >200 Pf p52-/p36- GAP-infected mosquito bites in a safety trial resulted in peripheral parasitemia in one of six volunteers, revealing that this GAP was incompletely attenuated. We have now created a triple gene deleted GAP by additionally removing the SAP1 gene (Pf p52-/p36-/sap1- GAP) and employed FLP/FRT recombination for drug selectable marker cassette removal. This next generation GAP was indistinguishable from WT parasites in blood stage and mosquito stage development. Using an improved humanized mouse model transplanted with human hepatocytes and human red blood cells, we show that despite a high dose sporozoite challenge, Pf p52-/p36-/sap1- GAP did not transition to blood stage infection and appeared to be completely attenuated. Thus, clinical testing of Pf p52-/p36-/sap1- GAP assessing safety, immunogenicity and efficacy against sporozoite challenge is warranted.Molecular Therapy (2014); doi:10.1038/mt.2014.85.
- Publisher
- NPG
- Research Division(s)
- Infection And Immunity
- Publisher's Version
- https://doi.org/mt201485 [pii]; 10.1038/mt.2014.85 [doi]
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Creation Date: 2014-05-20 08:08:54