title: Persistence of protective immunity to malaria induced by DNA priming and poxvirus boosting: characterization of effector and memory CD8(+)-T-cell populations.
abstract: The persistence of immunity to malaria induced in mice by a heterologous DNA priming and poxvirus boosting regimen was characterized. Mice were immunized by priming with DNA vaccine plasmids encoding the Plasmodium yoelii circumsporozoite protein (PyCSP) and murine granulocyte-macrophage colony-stimulating factor and boosting with recombinant vaccinia encoding PyCSP. BALB/c mice immunized with either high-dose (100 microg of p PyCSP plus 30 microg of pGM-CSF) or low-dose (1 microg of p PyCSP plus 1 microg of pGM-CSF DNA) priming were protected against challenge with 50 P. yoelii sporozoites. Protection 2 weeks after immunization was 70 to 100%, persisted at this level for at least 20 weeks, and declined to 30 to 40% by 28 weeks. Eight of eight mice protected at 20 weeks were still protected when rechallenged at 40 weeks. The antigen (Ag)-specific effector CD8(+)-T-cell population present 2 weeks after boosting had ex vivo Ag-specific cytolytic activity, expressed both gamma interferon (IFN-gamma) and tumor necrosis factor alpha, and constituted 12 to 20% of splenic CD8(+) T cells. In contrast, the memory CD8(+)-Ag-specific-cell population at 28 weeks lacked cytolytic activity and constituted only 6% of splenic CD8(+) T cells, but at the single-cell level it produced significantly higher levels of IFN-gamma than the effectors. High levels of Ag- or parasite-specific antibodies present 2 weeks after boosting had declined three- to sevenfold by 28 weeks. Low-dose priming was similarly immunogenic and as protective as high-dose priming against a 50-, but not a 250-, sporozoite challenge. These results demonstrate that a heterologous priming and boosting vaccination can provide lasting protection against malaria in this model system.
authors.affiliation: Malaria Program, Naval Medical Research Center, Silver Spring, Maryland 20910-7500, USA. sedegah@nmrc.navy.mil
authors.forename: Martha
authors.initials: M
authors.lastname: Sedegah
authors.forename: Gary T
authors.initials: GT
authors.lastname: Brice
authors.forename: William O
authors.initials: WO
authors.lastname: Rogers
authors.forename: Denise L
authors.initials: DL
authors.lastname: Doolan
authors.forename: Yupin
authors.initials: Y
authors.lastname: Charoenvit
authors.forename: Trevor R
authors.initials: TR
authors.lastname: Jones
authors.forename: Victoria F
authors.initials: VF
authors.lastname: Majam
authors.forename: Arnel
authors.initials: A
authors.lastname: Belmonte
authors.forename: Minh
authors.initials: M
authors.lastname: Lu
authors.forename: Maria
authors.initials: M
authors.lastname: Belmonte
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Carucci
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Hoffman
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000953:Antigens, Protozoan / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016054:DNA, Protozoan / Q000276:immunology*; D005260:Female; D005822:Genetic Vectors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology; D007117:Immunization, Secondary; D007156:Immunologic Memory / Q000276:immunology; D008288:Malaria / Q000276:immunology / Q000517:prevention & control*; D017780:Malaria Vaccines / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010967:Plasmodium yoelii / Q000235:genetics / Q000276:immunology*; D015800:Protozoan Proteins / Q000235:genetics / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D013997:Time Factors; D019444:Vaccines, DNA / Q000235:genetics / Q000276:immunology*; D014616:Vaccinia virus
chemical_list: D000953:Antigens, Protozoan; D016054:DNA, Protozoan; D017780:Malaria Vaccines; D015800:Protozoan Proteins; D019444:Vaccines, DNA; C041595:circumsporozoite protein, Protozoan; D016178:Granulocyte-Macrophage Colony-Stimulating Factor