학술논문
A genetically engineered Plasmodium falciparumparasite vaccine provides protection from controlled human malaria infection
Document Type
Article
Author
Murphy, Sean C.; Vaughan, Ashley M.; Kublin, James G.; Fishbauger, Matthew; Seilie, Annette M.; Cruz, Kurtis P.; Mankowski, Tracie; Firat, Melike; Magee, Sara; Betz, Will; Kain, Heather; Camargo, Nelly; Haile, Meseret T.; Armstrong, Janna; Fritzen, Emma; Hertoghs, Nina; Kumar, Sudhir; Sather, D. Noah; Pinder, Leeya F.; Deye, Gregory A.; Galbiati, Shirley; Geber, Casey; Butts, Jessica; Jackson, Lisa A.; Kappe, Stefan H. I.
Source
Science Translational Medicine; August 2022, Vol. 14 Issue: 659
Subject
Language
ISSN
19466234; 19466242
Abstract
Genetically engineered live Plasmodium falciparumsporozoites constitute a potential platform for creating consistently attenuated, genetically defined, whole-parasite vaccines against malaria through targeted gene deletions. Such genetically attenuated parasites (GAPs) do not require attenuation by irradiation or concomitant drug treatment. We previously developed a P. falciparum(Pf) GAP with deletions in P52, P36, and SAP1genes (PfGAP3KO) and demonstrated its safety and immunogenicity in humans. Here, we further assessed safety, tolerability, and immunogenicity of the PfGAP3KO vaccine and tested its efficacy against controlled human malaria infection (CHMI) in malaria-naïve subjects. The vaccine was delivered by three (n= 6) or five (n= 8) immunizations with ~200 PfGAP3KO-infected mosquito bites per immunization. PfGAP3KO was safe and well tolerated with no breakthrough P. falciparumblood stage infections. Vaccine-related adverse events were predominately localized urticaria related to the numerous mosquito bites administered per vaccination. CHMI via bites with mosquitoes carrying fully infectious Pf NF54 parasites was carried out 1 month after the last immunization. Half of the study participants who received either three or five PfGAP3KO immunizations remained P. falciparumblood stage negative, as shown by a lack of detection of Plasmodium18SrRNA in the blood for 28 days after CHMI. Six protected study participants received a second CHMI 6 months later, and one remained completely protected. Thus, the PfGAP3KO vaccine was safe and immunogenic and was capable of inducing protection against sporozoite infection. These results warrant further evaluation of PfGAP3KO vaccine efficacy in dose-range finding trials with an injectable formulation.