Rhesus macaques were subdivided into four groups: vaccine+V2-TTB NP ( n = 12), vaccine+TTB NP ( n = 9), vaccine+empty NP ( n = 9), and concurrent ( n = 9) and historical ( n = 18) controls. A historical systemic vaccine group ( n = 14) was included for immunological comparison. Thirty concurrent animals and fourteen historical animals were primed with DNA-SIV expressing V1gp160 and SIV mac239 p55 gag and boosted with ALVAC-SIV encoding env , gag , and pol alone or with V1gp120 protein formulated in alum alhydrogel at the indicated timepoints, and as previously published 19 . Nine animals remained naive until SIV mac251 challenge. At weeks 0, 4, and 16, V2-TTB NP, TTB NP or empty NP were orally administered. For NP administered groups, 5 weeks following the last vaccination (week 24) vaccine efficacy against SIV mac251 exposure was assessed by exposing all animals to up to 11 weekly intrarectal viral exposures (arrows) until infection was confirmed. Similarly, for historical systemically vaccinated animals, 5 weeks following the last vaccination (week 17) efficacy against SIV mac251 exposure was assessed by exposing all animals to up to 11 weekly intrarectal viral exposures (arrows) until infection was confirmed.