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
Goonetilleke N., Moore S., Dally L., Winstone N., Cebere I., Mahmoud A., Pinheiro S., Gillespie G., Brown D., Loach V., Roberts J., Guimaraes-Walker A., Hayes P., Loughran K., Smith C., De Bont J., Verlinde C., Vooijs D., Schmidt C., Boaz M., Gilmour J., Fast P., Dorrell L., Hanke T., McMichael AJ.
<jats:title>ABSTRACT</jats:title> <jats:p>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<jats:sup>+</jats:sup> T-cell epitopes. The trial had two groups. One group received either two doses of MVA.HIVA (2× MVA.HIVA) (<jats:italic>n</jats:italic> = 8) or two doses of placebo (2× placebo) (<jats:italic>n</jats:italic> = 4). The second group received 2× pTHr.HIVA followed by one dose of MVA.HIVA (<jats:italic>n</jats:italic> = 8) or 3× placebo (<jats:italic>n</jats:italic> = 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/10<jats:sup>6</jats:sup> 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 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<jats:sup>+</jats:sup> 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<jats:sup>+</jats:sup> T-cell epitopes, with 6 volunteers having responses to more than one epitope. Five out of 12 responders also developed CD8<jats:sup>+</jats:sup> 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.</jats:p>