Host cell traversal by Plasmodium parasites drives sterilizing T cell-mediated immunity following immunization

The development of a vaccine capable of conferring sterile protection against Plasmodium, the causative agent of malaria, is a major priority for global eradication efforts. Whole-organism vaccines using liver-infective sporozoites provide high levels of sterile protection against pre-erythrocytic infection. Yet, determinants of sporozoite immunogenicity remain poorly characterized. Here we demonstrate, using rodent models of vaccination, that the ability of Plasmodium sporozoites to actively migrate through multiple host cells before infecting hepatocytes is required for sterilizing immunity, regardless of the extent of intrahepatic development of immunizing parasites. We further establish host cell traversal as a dominant contributor to the induction of sterile protection. Impaired cell traversal precludes protective liver-resident memory CD8 T cell responses following vaccination but not the production of antiplasmodial antibodies. Our findings show that intrahepatic parasite development alone does not fully account for the magnitude and durability of protection induced by whole-sporozoite vaccination, and highlight parasite behaviour traits as critical immunogenic events shaping sterilizing cellular immunity against Plasmodium liver stages.