Complete attenuation of genetically engineered Plasmodium falciparum sporozoites in human subjects

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...

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Bibliographic Details
Published in:Science translational medicine 2017-01, Vol.9 (371)
Main Authors: Kublin, James G, Mikolajczak, Sebastian A, Sack, Brandon K, Fishbaugher, Matt E, Seilie, Annette, Shelton, Lisa, VonGoedert, Tracie, Firat, Melike, Magee, Sara, Fritzen, Emma, Betz, Will, Kain, Heather S, Dankwa, Dorender A, Steel, Ryan W J, Vaughan, Ashley M, Noah Sather, D, Murphy, Sean C, Kappe, Stefan H I
Format: Article
Language:English
Subjects:
Adult
Animals
Antibodies, Protozoan - blood
Female
Gene Deletion
Genetic Engineering
Humans
Immunoglobulin G - blood
Malaria Vaccines - genetics
Malaria Vaccines - immunology
Malaria, Falciparum - prevention & control
Male
Mice
Mice, Inbred BALB C
Middle Aged
Plasmodium falciparum
Plasmodium falciparum - genetics
Plasmodium falciparum - immunology
Protozoan Proteins - genetics
Sporozoites - genetics
Sporozoites - immunology
Vaccines, Attenuated - genetics
Vaccines, Attenuated - immunology
Young Adult
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Summary: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.
ISSN:1946-6234
1946-6242
DOI:10.1126/scitranslmed.aad9099