Background:  Natural transmission of HIV occurs through mucosal surfaces at low efficiency, but few simian immunodeficiency virus (SIV) vaccine studies have examined protective immunity under conditions designed to model these conditions.

Methods:  We investigated the efficacy of a multigenic DNA/MVA prime/boost vaccination regimen to induce mucosal immune responses to SIV and protect against repeated low-dose vaginal SIV challenge. Of 20 female macaques, 8 were vaccinees (4 Mamu A*01⁺) were immunized (IM) at week 0 and week 6 with plasmids expressing multiple SIV proteins (Gag, Pol, Env, Nef, Tat, Vif) followed by MVA boosting (5 x 10⁸ pfu, Gag-Pol-Env and Rev-Tat-Nef, ID, and IM) at week 36; 8 controls (4 Mamu A*01⁺) received control modified vaccinia virus Ankara (MVA); and 4 additional Mamu A*01⁺ animals were immunized with attenuated SIV∆nef. At 8 weeks after MVA boosting, animals were vaginally challenged with SIV_mac251 (1000 TCID₅₀) administered at weekly intervals for as long as 17 weeks or until plasma viremia was detected.

Results:  DNA/MVA immunization induced vigorous interferon-gamma (IFN-g) ELISpot responses to Gag, Env, and Nef, with Gag-specific spot forming cells (SFC) that exceeded 3500 SFC/10⁶ PBMC 2 weeks after the MVA boost.  Gag_181-189 tetramer-binding cells in DNA/MVA vaccinees were detected in vaginal and rectal biopsies at similar frequencies to those observed in peripheral blood 2 weeks after the MVA boost. Following repeated low-dose vaginal challenges, 8 of 8 controls, 7 of 8 of DNA/MVA-vaccinated macaques, and 3 of 4 SIV∆nef-vaccinated animals were infected. The DNA/MVA prime boost regimen resulted in a 33-fold reduction in peak viremia at week 2, a 380-fold reduction in viremia at week 6, and a 340-fold reduction in viremia 15 to17 weeks after infection compared to controls. Compared with DNA/MVA-vaccinated animals, SIV∆nef-immunized animals demonstrated lower peak viremia but similar post-acute control of viremia. Control of viremia in DNA/MVA-vaccinated animals was associated with significant anamnestic SIV-specific CD8⁺ T cell responses, with peak values of A*01/Gag_181-189 tetramer-binding CD8⁺ T cells ranging from 10.6% to 36%, compared to 1.8%±1.2% in controls. Improved control of viremia was observed in both A*01⁺ and A*01^­ vaccines with preservation of CD4⁺ T cell counts.

Conclusions:  Our results demonstrate the ability of a multigenic DNA/MVA prime/boost vaccine to induce CD8⁺ T cell responses in rectal and vaginal tissues and provide substantial reduction in viremia after repeated low dose vaginal challenge.