title: Genetically attenuated Plasmodium berghei liver stages induce sterile protracted protection that is mediated by major histocompatibility complex Class I-dependent interferon-gamma-producing CD8+ T cells.
abstract: At present, radiation-attenuated plasmodia sporozoites ( gamma -spz) is the only vaccine that induces sterile and lasting protection in malaria-naive humans and laboratory rodents. However, gamma -spz are not without risks. For example, the heterogeneity of the gamma -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 beta (2)m were not protected. Pbuis3(-)/4(-) spz-immune CD8(+) T cells consisted of effector/memory phenotypes and produced interferon- gamma . 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.
authors.affiliation: Division of Malaria Vaccine Development, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
authors.forename: Ousman
authors.initials: O
authors.lastname: Jobe
authors.forename: Joanne
authors.initials: J
authors.lastname: Lumsden
authors.forename: Ann-Kristin
authors.initials: AK
authors.lastname: Mueller
authors.forename: Jackie
authors.initials: J
authors.lastname: Williams
authors.forename: Hilda
authors.initials: H
authors.lastname: Silva-Rivera
authors.forename: Stefan H I
authors.initials: SH
authors.lastname: Kappe
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schwenk
authors.forename: Kai
authors.initials: K
authors.lastname: Matuschewski
authors.forename: Urszula
authors.initials: U
authors.lastname: Krzych
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D005260:Female; D017353:Gene Deletion; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology*; D007115:Immunization Schedule; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000096:biosynthesis; D008099:Liver / Q000276:immunology; D008288:Malaria / Q000276:immunology* / Q000517:prevention & control*; D017780:Malaria Vaccines / Q000008:administration & dosage* / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010962:Plasmodium berghei / Q000235:genetics* / Q000254:growth & development*; D034101:Sporozoites / Q000276:immunology*; D014611:Vaccination; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000235:genetics; D001613:beta 2-Microglobulin / Q000235:genetics
chemical_list: D015395:Histocompatibility Antigens Class I; D017780:Malaria Vaccines; D014613:Vaccines, Attenuated; D001613:beta 2-Microglobulin; D007371:Interferon-gamma