Sporozoite Vaccine Induces Genetically Restricted T Cell Elimination of Malaria from Hepatocytes

Abstract

The target of the CD8+ T cell-dependent immunity that protects mice immunized with irradiation-attenuated malaria sporozoites has not been established. Immune BALB/c mice were shown to develop malaria-specific, CD8+ T cell-dependent inflammatory infiltrates in their livers after challenge with Plasmodium berghei sporozoites. Spleen cells from immune BALB/c and C57BL/6 mice eliminated hepatocytes infected with the liver stage of P. berghei in vitro. The activity against infected hepatocytes is not inhibited by antibodies to interferon-gamma and is not present in culture supernatants. It is genetically restricted, an indication that malaria antigens on the hepatocyte surface are recognized by immune T effector cells. Subunit vaccine development will require identification of the antigens recognized by these T cells and a method of immunization that induces such immunity.

Induction of Plasmodium falciparum sporozoite-neutralizing antibodies upon vaccination with recombinant Pfs16 vaccinia virus and/or recombinant Pfs16 protein produced in yeast

“…The liver stages are attractive targets [38][39][40] for vaccine development because they are susceptible for immune attack for much longer than sporozoites, i.e., at least five days compared to a few minutes [40,41]. Moreover, both CD4 + and CD8 4 -T cells have been shown to attack malaria-infected hepato cytes, either by direct cytotoxicity or indirectly by cytokines, suggesting that P. falciparum epitopes are expressed on the surface of infected hepatocytes in association with MHC Class-I or -II molecules [40,[42][43][44]. The presence of P fsl6 during P. falci parum liver-stage development suggests that P fsl6 vaccines could also elicit cytotoxic T-cell responses directed to P. falciparum-infected hepatocytes.…”

Pre–erythrocytic–stage immune effector mechanisms inPlasmodiumspp. infections

“…Lond. B (1997) contrast, the immunity in BALB/c mice immunized with irradiated P. berghei (Ho¡man et al 1989) or P. yoelii (Rodrigues et al 1991) sporozoites was not a¡ected by interferon-g depletion. In vitro, treatment of hepatocytes infected with Plasmodium spp.…”

“…Subsequently, in vivo, adoptive transfer of spleen cells from sporozoite-immunized mice (Verhave et al 1978) or immune T cells (Egan et al 1987) into naive mice protected against malaria in the absence of antibodies. In vitro, spleen cells from immune mice eliminated infected hepatocytes from in vitro culture in an MHC-restricted and species-speci¢c manner (Ho¡man et al 1989(Ho¡man et al , 1990a; this activity was not reversed by anti-interferon-g antibody and not duplicated by culture supernatants.…”

“…In contrast, the liver stage of the malaria parasite's life cycle lasts for 24^48 h in the rodent malarias and for 5^14 d in the human malarias, depending on the species. It is now well established that CD8+ and CD4+ T cells can recognize parasite-derived peptides presented by class I or class II molecules, respectively, on the surface of infected hepatocytes (Ho¡man et al 1989(Ho¡man et al , 1990aWeiss et al 1990Weiss et al , 1996Renia et al 1993). Indeed, because hepatocytes are the only host cells encountered by the parasite during the course of its life cycle that express major histocompatibility complex (MHC) molecules, the infected hepatocyte is the primary target of cell-mediated immune responses.…”

Broadly distributed T cell reactivity, with no immunodominant loci, to the pre-erythrocytic antigen thrombospondin-related adhesive protein ofPlasmodium falciparum in West Africans

“…CS protein antigen-specific cellular and humoral immune responses confer protection against sporozoite challenge in animals [13][14][15][16][17][18][19], although the evidence for a protective role in humans is inconclusive [20][21][22][23]. Furthermore, CS protein-specific T cells eliminate infected hepatocytes from in vitro culture [24]. Therefore, CS protein is considered to be a major vaccine candidate.…”