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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.