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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 wild-type (WT) strain of Plasmodium 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 flippase (FLP)/flippase recognition target (FRT) recombination …