Background: Transmission of HIV infection occurs predominantly via mucosal routes. The ability of vaccines to induce mucosal immunity may be a necessary requirement for protection against HIV infection and AIDS.

Methods: We have investigated the immuno-stimulatory properties of a DNA vaccine, which produces SHIV particles similar in protein content to wild type virus, but non infectious because of 22 mutations in NC, RT, and IN. To evaluate the induction of SHIV specific immunity, 5 groups of Rhesus macaques were vaccinated either rectally (2 groups) or nasally (3 groups) with SHIV DNA at times 0, 2, and 6 months. Two (2) of 3 nasally vaccinated groups also simultaneously received DNA expressing IL-2 or IL12 intranasally. Two (2) months after the last DNA immunization, one rectal group and all 3 nasal groups also received rMVA expressing Gag, Pol, and Env. All groups were evaluated for SHIV-specific immune responses throughout the vaccination regimen.

Results: SHIV-specific IgA was detected sporadically in secretions after vaccination with DNA alone. When viral DNA was administered together with IL-2 or IL-12 DNA, SHIV-specific IgA was detected earlier and more consistently. SHIV-specific IgG responses were present systemically in some groups and boosted by mucosal administration of rMVA. Cell-mediated immune responses were found both at mucosal and systemic sites. These responses were most prevalent when animals were vaccinated intranasally or when rectally vaccinated macaques were boosted with MVA. Furthermore, the nasal route of vaccination stimulated surprisingly strong Env-specific, systemic cellular responses, higher than the Gag responses detected in these animals. which were comparable in magnitude to those observed by others using a DNA-adenovirus vaccination regime. Following rectal challenge with cloned SHIV89.6P, all animals became infected, but significant control of viremia was observed in the animals in which systemic cellular responses were detected.

Conclusions: The data indicate that mucosal administration of a DNA vaccine can significantly stimulate both mucosal and systemic humoral and cell-mediated responses, in particular when administered nasally. However, the efficacy of the mucosal responses cannot be accurately evaluated in these animal trials because of the extremely high titers of virus used for the challenge and may be better evaluated after natural virus exposure where the virus inoculum is relatively small.