Genetically Attenuated Plasmodium berghei Liver Stages Induce Sterile Protracted Protection That Is Mediated by Major Histocompatibility Complex Class I–Dependent

(See the article by Tarun et al., on pages 608–16.) At present, radiation-attenuated plasmodia sporozoites (g-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 g-spz could explain occasional breakthrough infections. To avoid this pos-sibility, 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 b2m were not protected. Pbuis3()/4() spz–immune CD8+ T cells consisted of effector/memory phenotypes and produced interferon-g. 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. Malaria claims millions of lives annually [1], and a malaria vaccine is urgently needed [2]. Although pre