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.