Immune Response to Pre-Erythrocytic Stages of Malaria Parasites

Abstract

Immunization with radiation-attenuated Plasmodium spp. sporozoites induces sterile protective immunity against parasite challenge. This immunity is targeted primarily against the intrahepatic parasite and appears to be sustained long term even in the absence of sporozoite exposure. It is mediated by multifactorial mechanisms, including T cells directed against parasite antigens expressed in the liver stage of the parasite life cycle and antibodies directed against sporozoite surface proteins. In rodent models, CD8+ T cells have been implicated as the principal effector cells, and IFN-gamma as a critical effector molecule. IL-4 secreting CD4+ T cells are required for induction of the CD8+ T cell responses, and Th1 CD4+ T cells provide help for optimal CD8+ T cell effector activity. Components of the innate immune system, including gamma-delta T cells, natural killer cells and natural killer T cells, also play a role. The precise nature of pre-erythrocytic stage immunity in humans, including the contribution of these immune responses to the age-dependent immunity naturally acquired by residents of malaria endemic areas, is still poorly defined. The importance of immune effector targets at the pre-erythrocytic stage of the parasite life cycle is highlighted by the fact that infection-blocking immunity in humans rarely, if ever, occurs under natural conditions. Herein, we review our current understanding of the molecular and cellular aspects of pre-erythrocytic stage immunity.

Multiple functions of human T cells generated by experimental malaria challenge

“…Host survival requires that the immune response is sufficient to control parasitemia, but does not cause excessive immunopathology [3]. A protective role for IFN-g-secreting effector T cells is well established and has been exploited in numerous vaccination approaches [4][5][6]. Indeed, in one particular study volunteers were immunized with low doses of Plasmodium-infected RBC (iRBC), and they produced T-cell IFN-g responses against blood-stage Ag that were associated with protection from challenge in the absence of Ab responses [7].…”

From the circumsporozoite protein to the RTS,S/AS candidate vaccine

“…Protection appeared to depend on the persistence of these thwarted forms in the liver. 17 Repeated immunizations with IrSp by the intravenous route are required to achieve sterile immunity in mice. Protection in humans was achieved following bites from irradiated mosquitoes infected with P. falciparum or P. vivax.…”

A quantitative analysis of transmission efficiency versus intensity for malaria

“…Once in a human or other vertebrate host, transmitted sporozoites could also fail to advance to the blood stages by chance. Some infections may be prevented by an acquired pre-erythrocytic immunity to malaria, but despite evidence that immunity to pre-erythrocytic stages can be induced artificially, there is very little direct evidence that pre-erythrocytic immunity blocks a high fraction of incoming infections 23 . Immunity to blood stages of the parasites, especially in those who have well-developed bloodstage immunity, could also cause inefficient transmission by rapidly clearing primary merozoites or suppressing parasite densities below levels that are detectable by microscopy, thereby preventing patent (that is, detectable) infections 19,24 .…”