Plasmodium determinants critical for the generation of pre-erythrocytic sterile immunity

Abstract

An effective vaccine that will provide sterile protection against Plasmodium, the etiologic agent of malaria, is crucial for disease eradication. Efforts in the last five decades culminated in a WHOendorsed malaria vaccine. Albeit significantly reducing severe disease cases, this vaccine consistently fails at conferring sterile immunity to vaccinees. The high protection attained following experimental immunization with attenuated parasites halting their development soon after hepatocyte infection raises the possibility that early events during pre-erythrocytic infection are important for protective immunity against Plasmodium. Prior to the productive infection of an hepatocyte, Plasmodium parasites journey across biological barriers by traversing several host cells first in the skin, and subsequently in the liver sinosoids and parenchyma. By employing the cell traversal-deficient parasite lines Pbspect1- and Pbplp1- , we show that cell traversal is crucial for the establishment of sterile protection upon radiation-attenuated sporozoitesbased immunization of C57BL/6J mice. Furthermore, we show that loss of protection in the absence of cell traversal is independent of the timing of intrahepatic development arrest of parasites, as CPS-based immunizations with Pbspect1- parasites equaly failed to confer full protection upon infectious challenge. Analysis of the immune mechanisms relevant for sterile protection revealed that, while humoral resposes were not impacted by the lack of cell traversal, the establishment of CD8+ T cell responses following vaccination was impaired in Pbspect1- RAS-immunized mice. Together, our data suggest that cell traversal by Plasmodium parasites is a critical determinant for the establishment of sterile protection following vaccination by eliciting and/or maintaining cellular immunity aimed at eliminating Plasmodium intrahepatic forms. These findings challenge the current understanding that malaria vaccination largely depends on parasite development, and raise the possibility that enhancing cell traversal motility of immunizing parasites may constitute a valid strategy to boost malaria vaccine candidates efficacy and take us one step closer to a malaria-free world.