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
| Autor: | Tomáš Hanke, Pat Fast, Susana Pinheiro, Mark Boaz, Jill Gilmour, Inese Cebere, Nilu Goonetilleke, Joanna Roberts, Jan De Bont, Vanessa Loach, Stephen Moore, C. Schmidt, Peter Hayes, Geraldine M. Gillespie, Carl Verlinde, Denise Brown, Andrew J. McMichael, Nicola Winstone, Len Dally, Kelley Loughran, Carole Smith, Ana Guimarães-Walker, Danii Vooijs, Lucy Dorrell, Abdul Mahmoud |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
viruses
Genetic Vectors Molecular Sequence Data Immunology Immunization Secondary Epitopes T-Lymphocyte Gene Products gag HIV Infections Vaccinia virus CD8-Positive T-Lymphocytes Lymphocyte Activation complex mixtures Microbiology Virus Epitope chemistry.chemical_compound Double-Blind Method Virology Vaccines and Antiviral Agents Vaccines DNA Humans Cytotoxic T cell Poxviridae Amino Acid Sequence Orthopoxvirus Cells Cultured Cell Proliferation AIDS Vaccines Vaccines Synthetic biology ELISPOT biology.organism_classification chemistry Insect Science HIV-1 Vaccinia CD8 |
| Popis: | 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 (2× MVA.HIVA) (n= 8) or two doses of placebo (2× placebo) (n= 4). The second group received 2× pTHr.HIVA followed by one dose of MVA.HIVA (n= 8) or 3× 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-γ) ELISPOT (group mean, 210 spot-forming cells/106cells) 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 2× MVA.HIVA group or subjects receiving placebo. Using a highly sensitive and reproducible cultured IFN-γ 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 2× 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 1β. 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. |
| Databáze: | OpenAIRE |
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