title: Induction of multifunctional human immunodeficiency virus type 1 (HIV-1)-specific T cells capable of proliferation in healthy subjects by using a prime-boost regimen of DNA- and modified vaccinia virus Ankara-vectored vaccines expressing HIV-1 Gag coupled to CD8+ T-cell epitopes.
abstract: A double-blind randomized phase I trial was conducted in human immunodeficiency virus type 1 (HIV-1)-negative subjects receiving vaccines vectored by plasmid DNA and modified vaccinia virus Ankara (MVA) expressing HIV-1 p24/p17 gag linked to a string of CD8(+) T-cell epitopes. The trial had two groups. One group received either two doses of MVA.HIVA (2x MVA.HIVA) (n=8) or two doses of placebo (2x placebo) (n=4). The second group received 2x pTHr.HIVA followed by one dose of MVA.HIVA (n=8) or 3x placebo (n=4). In the pTHr.HIVA-MVA.HIVA group, HIV-1-specific T-cell responses peaked 1 week after MVA.HIVA vaccination in both ex vivo gamma interferon (IFN-gamma) ELISPOT (group mean, 210 spot-forming cells/10(6) cells) and proliferation (group mean stimulation index, 37), with assays detecting positive responses in four out of eight and five out of eight subjects, respectively. No HIV-1-specific T-cell responses were detected in either assay in the 2x MVA.HIVA group or subjects receiving placebo. Using a highly sensitive and reproducible cultured IFN-gamma ELISPOT assay, positive responses mainly mediated by CD4(+) T cells were detected in eight out of eight vaccinees in the pTHr.HIVA-MVA.HIVA group and four out of eight vaccinees in the 2x MVA.HIVA group. Importantly, no false-positive responses were detected in the eight subjects receiving placebo. Of the 12 responders, 11 developed responses to previously identified immunodominant CD4(+) T-cell epitopes, with 6 volunteers having responses to more than one epitope. Five out of 12 responders also developed CD8(+) T-cell responses to the epitope string. Induced T cells produced a variety of anti-viral cytokines, including tumor necrosis factor alpha and macrophage inflammatory protein 1 beta. These data demonstrate that prime-boost vaccination with recombinant DNA and MVA vectors can induce multifunctional HIV-1-specific T cells in the majority of vaccinees.
authors.affiliation: Centre for Clinical Vaccinology and Tropical Medicine and MRC Human Immunology Unit, University of Oxford, Oxford OX3 7LJ, United Kingdom. nilu.goonetilleke@ndm.ox.ac.uk
authors.forename: Nilu
authors.initials: N
authors.lastname: Goonetilleke
authors.forename: Stephen
authors.initials: S
authors.lastname: Moore
authors.forename: Len
authors.initials: L
authors.lastname: Dally
authors.forename: Nicola
authors.initials: N
authors.lastname: Winstone
authors.forename: Inese
authors.initials: I
authors.lastname: Cebere
authors.forename: Abdul
authors.initials: A
authors.lastname: Mahmoud
authors.forename: Susana
authors.initials: S
authors.lastname: Pinheiro
authors.forename: Geraldine
authors.initials: G
authors.lastname: Gillespie
authors.forename: Denise
authors.initials: D
authors.lastname: Brown
authors.forename: Vanessa
authors.initials: V
authors.lastname: Loach
authors.forename: Joanna
authors.initials: J
authors.lastname: Roberts
authors.forename: Ana
authors.initials: A
authors.lastname: Guimaraes-Walker
authors.forename: Peter
authors.initials: P
authors.lastname: Hayes
authors.forename: Kelley
authors.initials: K
authors.lastname: Loughran
authors.forename: Carole
authors.initials: C
authors.lastname: Smith
authors.forename: Jan
authors.initials: J
authors.lastname: De Bont
authors.forename: Carl
authors.initials: C
authors.lastname: Verlinde
authors.forename: Danii
authors.initials: D
authors.lastname: Vooijs
authors.forename: Claudia
authors.initials: C
authors.lastname: Schmidt
authors.forename: Mark
authors.initials: M
authors.lastname: Boaz
authors.forename: Jill
authors.initials: J
authors.lastname: Gilmour
authors.forename: Pat
authors.initials: P
authors.lastname: Fast
authors.forename: Lucy
authors.initials: L
authors.lastname: Dorrell
authors.forename: Tomas
authors.initials: T
authors.lastname: Hanke
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: McMichael
mesh_terms: D016915:AIDS Vaccines / Q000235:genetics / Q000276:immunology*; D000595:Amino Acid Sequence; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D004311:Double-Blind Method; D018984:Epitopes, T-Lymphocyte / Q000276:immunology* / Q000378:metabolism; D015683:Gene Products, gag / Q000276:immunology* / Q000378:metabolism; D005822:Genetic Vectors; D015658:HIV Infections / Q000517:prevention & control; D015497:HIV-1 / Q000235:genetics / Q000276:immunology; D006801:Humans; D007117:Immunization, Secondary; D008213:Lymphocyte Activation / Q000276:immunology*; D008969:Molecular Sequence Data; D019444:Vaccines, DNA / Q000235:genetics / Q000276:immunology*; D014614:Vaccines, Synthetic / Q000235:genetics / Q000276:immunology; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology
chemical_list: D016915:AIDS Vaccines; D018984:Epitopes, T-Lymphocyte; D015683:Gene Products, gag; D019444:Vaccines, DNA; D014614:Vaccines, Synthetic