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

At present, radiation-attenuated plasmodia sporozoites (γ-spz) is the only vaccine that induces sterile and lasting protection in malaria-naive humans and laboratory rodents. However, γ-spz are not without risks. For example, the heterogeneity of the γ-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 andprotractedprotection in C57BL/6 mice. Protection was linked to CD8+ T cells, given that mice deficient in β2 m were not protected. Pbuis3(-)/4(-) spz-immune CD8+ T cells consisted of effector/memory phenotypes and produced interferon-γ. 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.