Therapeutic Vaccination of Infected Patients
Friday, 1:30 - 3:30 pm
Background: Therapeutic vaccines are a potential solution to the global burden of chronic HIV infections and to the limitations of HAART. However, most vaccine candidates tested so far have displayed weak immunogenicity in humans. We are evaluating the safety and immunogenicity of a recombinant modified vaccinia virus Ankara (MVA) gag/multi-epitope vaccine (MVA.HIVA) in persons with chronic HIV-1 infection.
Methods: We recruited 10 subjects who had been receiving HAART for at least 1 year, with a CD4 count > 300 cells/µL and viral load < 50 copies/mL, of whom 8 are scheduled to receive MVA.HIVA, 5 x 107 pfu by intradermal injection 4 weeks apart and 2 are unvaccinated controls. HIV-1-specific CD8+ and CD4+ T-cell responses are evaluated in several parallel assays, including interferon (IFN)-γ ELISpot using a matrix of 90 overlapping 15-mer peptides or optimal epitope peptides, intracellular cytokine staining, HLA class I tetramer, and flow-based proliferation assays.
Results: Of 8 subjects, 6 have completed the immunization schedule without any serious adverse events, the 2 control subjects have reached a comparable time point, and 2 subjects are being followed-up. The vaccine has been well tolerated. Gag-specific T-cell responses were significantly increased in both magnitude and breadth in 6 of 6 vaccinees after 1 or 2 doses of MVA.HIVA, while no change was observed in the control subjects. The total gag-specific response increased by a median 1550 SFU/106 PBMC (p = 0.028) and more peptide pools were targeted at the peak of the response than at baseline. Most of the responses were mediated by CD8+ T cells. However, gag-specific CD4+ T-cell responses were also boosted significantly in 5 of 6 vaccinees, by a median 495 SFU/106 PBMC (p = 0.046) and amplification of gag-specific CD4+IL-2+ cells was observed. Tetramer staining revealed that MVA.HIVA immunisation was associated with transient up-regulation of CD38 solely in CD8+ T cells specific for vaccine-encoded epitopes, without breakthrough viremia. Furthermore, tetramer+ cell populations remained expanded at 6 months. Preliminary data indicate that MVA.HIVA stimulates proliferation of both CD8+ and CD4+ T cells; further analysis is ongoing.
Conclusions: MVA.HIVA is safe and immunogenic in HIV-infected individuals on HAART. Proof-of-concept studies to evaluate the efficacy of vaccine-stimulated T cells to control viremia after HAART interruption are planned.
Keywords: therapeutic vaccine; modified vaccinia virus Ankara (MVA); T lymphocyte