Genetically Attenuated Plasmodium berghei Liver Stages Induce Sterile Protracted Protection That Is Mediated by Major Histocompatibility Complex Class I–Dependent Interferon-y–Producing CD8⁺ T Cells

Authors

• Ousman Jobe, Walter Reed Army Institute of Research
• Joanne Lumsden, Walter Reed Army Institute of Research
• Ann-Kristin Mueller, Heidelberg University School of Medicine
• Jackie Williams, Walter Reed Army Institute of Research
• Hilda Silva-Rivera, Seattle Biomedical Research Institute
• Stefan H. I. Kappe, Seattle Biomedical Research Institute
• Robert J. Schwenk, Walter Reed Army Institute of Research
• Kai Matuschewski, Heidelberg University School of Medicine
• Urszula Krzych, Walter Reed Army Institute of Research

Document Type

Article

Date of this Version

2007

Comments

Published in Genetically Attenuated Malaria Vaccine, JID 2007:196, (15 August), 599

Abstract

At present, radiation-attenuated plasmodia sporozoites (y-spz) is the only vaccine that induces sterile and lasting protection in malaria-naive humans and laboratory rodents. However, g-spz are not without risks. For example, the heterogeneity of the y-spz could explain occasional breakthrough infections. To avoid this possibility, we constructed a double-knockout P. berghei parasite by removing 2 genes, UIS3 and UIS4, that are up-regulated in infective spz.We evaluated the double-knockout Pbuis3(-)/4(-) parasites for protective efficacy and the contribution of CD8+ T cells to protection. Pbuis3(-)/4(-) spz induced sterile and protracted protection in C57BL/6 mice. Protection was linked to CD8+ T cells, given that mice deficient in β₂m were not protected. Pbuis3(-)/4(-) spz–immune CD8⁺ T cells consisted of effector/memory phenotypes and produced interferon-y. On the basis of these observations, we propose that the development of genetically attenuated P. falciparum parasites is warranted for tests in clinical trials as a pre-erythrocytic stage vaccine candidate.