Science Translational Medicine – 04 January 2017 Vol 9, Issue 371

Science Translational Medicine
04 January 2017 Vol 9, Issue 371

Research Article
Complete attenuation of genetically engineered Plasmodium falciparum sporozoites in human subjects
By James G. Kublin, Sebastian A. Mikolajczak, Brandon K. Sack, 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
Science Translational Medicine04 Jan 2017 Restricted Access
A triple punch knocks out the malaria parasite
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.