PT  - JOURNAL ARTICLE
AU  - Kublin, James G.
AU  - Mikolajczak, Sebastian A.
AU  - Sack, Brandon K.
AU  - Fishbaugher, Matt E.
AU  - Seilie, Annette
AU  - Shelton, Lisa
AU  - VonGoedert, Tracie
AU  - Firat, Melike
AU  - Magee, Sara
AU  - Fritzen, Emma
AU  - Betz, Will
AU  - Kain, Heather S.
AU  - Dankwa, Dorender A.
AU  - Steel, Ryan W. J.
AU  - Vaughan, Ashley M.
AU  - Noah Sather, D.
AU  - Murphy, Sean C.
AU  - Kappe, Stefan H. I.
TI  - Complete attenuation of genetically engineered <em>Plasmodium falciparum</em> sporozoites in human subjects
AID  - 10.1126/scitranslmed.aad9099
DP  - 2017 Jan 04
TA  - Science Translational Medicine
PG  - eaad9099
VI  - 9
IP  - 371
4099  - http://stm.sciencemag.org/content/9/371/eaad9099.short
4100  - http://stm.sciencemag.org/content/9/371/eaad9099.full
AB  - Vaccination with weakened infectious forms of the malaria parasite is the most promising approach to protect against malaria infection. However, creating genetically defined and weakened parasite strains that are safe for vaccination remains challenging. In a new study, Kublin et al. show that genetic engineering of the malaria parasite by the precise removal of three genes creates a parasite strain that infects humans and is well tolerated but cannot cause malaria. These genetically attenuated parasites thus appear safe for vaccination and stimulate the human immune system to generate responses that have the potential to block infection.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.