Background:  Topical DermaVir vaccine consists of plasmid DNA formulated in a mannosylated nanoparticle to target antigen-presenting cells and to protect DNA from intracellular degradation. DermaVir has been shown to induce antigen-specific cellular immune responses in mice and both naïve and chronically simian immunodeficiency virus (SIV)-infected macaques, and to control SIV. DermaVir’s safety and effectiveness prompted the initiation of clinical trials for the treatment of HIV⁺ individuals (GIHU004; ACTG5176). To improve DermaVir immunogenicity, we included interleukin (IL)-7 and IL-15 in the formulation, as these cytokines have been shown to enhance proliferation and survival of T-cells.

Methods:  Balb/C mice were immunized with DermaVir formulated with pVax (control) or HIV Gag DNA (pGag) without or with an IL-7 (pIL-7) or IL-15 (pIL-15)-encoding plasmids at low concentration of 0.025 mg DNA/mouse, without or with an HIV Gag-expressing vaccinia vector (VacV-Gag) boost. Effector T-cells were measured by a standard ELISpot interferon (IFN)-g and IL-4; splenocytes were stimulated with 4 peptide pools spanning the complete HIV Gag sequence or with HIV p24 protein, for 24 hours. Memory T cells were measured by cultured ELISpot IFN-g, using the same ELISpot procedure after splenocytes were cultured with the corresponding peptide pools for 5 days.

Results:  Mice immunized with pGag + pIL-7 or pIL-15 mounted 1.3-fold higher Gag-specific effector IFN-g responses than mice immunized with pGag; mice immunized with pGag + pIL-15 also mounted 1.2-fold higher effector IL-4 responses. The inclusion of both pIL-7 and pIL-15 enhanced Gag-specific memory T cell responses from 150±106, to 400±212 and 550±160 spots/million cultured splenocytes in mice immunized with pGag, pGag + pIL-7, and pGag + pIL-15, respectively. Gag-specific memory T cell responses were remarkably improved by adding IL-15 in DermaVir primed/VacV-Gag boosted mice (493±58 compared with 273±60 with pGag alone). CD8 depletion showed that CD8⁺ T cells are the main mediators of antigen-specific T cell responses.

Conclusions:  These results demonstrate that IL-7 and IL-15 remarkably enhance memory T cells induced by DermaVir. These cytokines were effective both after DermaVir prime and DermaVir+vaccinia prime-boost regimens. Since the goal of therapeutic vaccination is to induce memory T cells that can expand to effectors in the presence of HIV, IL-7 and IL-15 represent important adjuvant candidates.