Only N vaccination induced a significant increase in plasma SIV-IgG titers. Significantly higher systemic, rectal and vaginal SIV-specific T-cell responses were detected in the oral group during the immunization. The median number of challenges required to become infected was significantly higher in the GI group (32; 16 for O, 12 for V, 9 for N, 11 for controls). Repeated SIV exposure expanded vaginal anti-SIV T-cells in some of the animals. Seven vaccinated RM (3 in the O, 3 in the N and 1 in the GI group) suppressed the viremia after the initial infection peak and maintained it undetectable over the course of the trial. Immunized, infected animals had significantly lower levels of systemic T-cell immune activation, better preservation of CD4+ central memory and α4β7high+ CD4+ T-cells, with consequent better protection from AIDS. However a lower protection from AIDS progression was observed in the GI group compared to the other vaccinated RM, with a median survival of 24 weeks. A significantly higher loss of CD4+ CM T-cells, detected early on in this group, correctly predicted its poor long-term outcome.