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Background  A lack of defined correlates of immunity for malaria, combined with the inability to induce long-lived sterile immune responses in a human host, demonstrate a need for improved understanding of potentially protective immune mechanisms for enhanced vaccine efficacy. Protective sterile immunity (>90%) against the  Plasmodium falciparum  circumsporozoite protein (CSP) has been achieved using a transgenically modified  Plasmodium berghei  sporozoite (Tg- Pb / Pf CSP) and a self-assembling protein nanoparticle (SAPN) vaccine presenting CSP epitopes ( Pf CSP-SAPN). Here, several possible mechanisms involved in the independently protective humoral and cellular responses induced following SAPN immunization are described.    Methods  Inbred mice were vaccinated with  Pf CSP-SAPN in PBS. Serum antibodies were harvested and effects on  P .  falciparum  sporozoites mobility and integrity were examined using phase contrast microscopy. The functionality of SAPN-induced antibodies on inhibition of sporozoite invasion and growth within primary human hepatocytes was also examined. The internal processing of SAPN by bone marrow-derived dendritic cells (BMDDC), using organelle-specific, fluorescent-tagged antibody or gold-encapsulated SAPN, was observed using confocal or electron microscopy, respectively.    Results  The results of this work demonstrate that  Pf CSP-SAPN induces epitope-specific antibody titers, predominantly of the Th2 isotype IgG1, and that serum antibodies from PfCSP-SAPN-immunized mice appear to target  P .  falciparum  sporozoites via the classical pathway of complement. This results in sporozoite death as indicated by cessation of motility and the circumsporozoite precipitation reaction. Moreover,  Pf CSP-SAPN-induced antibodies are able to inhibit wild-type  P .  falciparum  sporozoite invasion and growth within cultured primary human hepatocytes. In addition, the observation that  Pf CSP-SAPN are processed (and presented) to the immune system by dendritic cells in a slow and continuous fashion via transporter associated with antigen processing (TAP) recruitment to the early endosome (EE), and have partially delayed processing through the endoplasmic reticulum, has the potential to induce the long-lived, effector memory CD8 +  T-cells as described previously.    Conclusion  This paper describes the examination of humoral and cellular immune mechanisms induced by  Pf CSP-SAPN vaccination which result in sterile host protection against a transgenic  P .  berghei  malaria sporozoite expressing the  P .  falciparum  CSP, and which significantly inhibits native  P .  falciparum  sporozoites from invading and developing within cultured human hepatocytes. These results may indicate the type and mode of action of protective antibodies needed to control  P .  falciparum  sporozoites from infecting humans as well as a potential mechanism of induction of protective long-lived effector memory CD8 +  T-cells.

malaria journal

Mechanisms of protective immune responses induced by the Plasmodium falciparum circumsporozoite protein-based, self-assembling protein nanoparticle vaccine