title: A T-cell response to a liver-stage Plasmodium antigen is not boosted by repeated sporozoite immunizations.
abstract: Development of an antimalarial subunit vaccine inducing protective cytotoxic T lymphocyte (CTL)-mediated immunity could pave the way for malaria eradication. Experimental immunization with sporozoites induces this type of protective response, but the extremely large number of proteins expressed by Plasmodium parasites has so far prohibited the identification of sufficient discrete T-cell antigens to develop subunit vaccines that produce sterile immunity. Here, using mice singly immunized with Plasmodium yoelii sporozoites and high-throughput screening, we identified a unique CTL response against the parasite ribosomal L3 protein. Unlike CTL responses to the circumsporozoite protein (CSP), the population of L3-specific CTLs was not expanded by multiple sporozoite immunizations. CSP is abundant in the sporozoite itself, whereas L3 expression does not increase until the liver stage. The response induced by a single immunization with sporozoites reduces the parasite load in the liver so greatly during subsequent immunizations that L3-specific responses are only generated during the primary exposure. Functional L3-specific CTLs can, however, be expanded by heterologous prime-boost regimens. Thus, although repeat sporozoite immunization expands responses to preformed antigens like CSP that are present in the sporozoite itself, this immunization strategy may not expand CTLs targeting parasite proteins that are synthesized later. Heterologous strategies may be needed to increase CTL responses across the entire spectrum of Plasmodium liver-stage proteins.
authors.affiliation: Department of Laboratory Medicine, University of Washington Medical Center, Seattle, WA 98195, USA.
authors.forename: Sean C
authors.initials: SC
authors.lastname: Murphy
authors.forename: Arnold
authors.initials: A
authors.lastname: Kas
authors.forename: Brad C
authors.initials: BC
authors.lastname: Stone
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bevan
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002469:Cell Separation; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000276:immunology; D007114:Immunization; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000378:metabolism; D017780:Malaria Vaccines / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D010455:Peptides / Q000276:immunology; D010967:Plasmodium yoelii / Q000276:immunology*; D015800:Protozoan Proteins / Q000276:immunology* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D034101:Sporozoites / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000469:parasitology
chemical_list: D000939:Epitopes; D017780:Malaria Vaccines; D010455:Peptides; D015800:Protozoan Proteins; C041595:circumsporozoite protein, Protozoan; D007371:Interferon-gamma