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The Canarypox/gp120/Alum vaccines decreased the risk of HIV acquisition in humans. We demonstrate here the efficacy of this vaccine regimen also in the SIVmac251 macaque model when we used the alum but not the MF59 adjuvant. Analysis of innate and adaptive cell responses, envelope antibodies Fc profiles and glycoforms demonstrated a lower inflammatory response with alum than MF59. Alum elicited mucosal V2 peptide-specific IgG associated with vaccine efficacy whereas the MF59 induced mucosal V2 peptide-specific IgG associated with increased risk of infection. Alum modulated the expression of 12 genes, 7 of which are part of the RAS pathway, that correlates with vaccine efficacy and were linked to innate responses that preserve mucosal integrity and adaptive mucosal antibody response to V2. Thus, activation of the RAS pathway, preservation of mucosal integrity and mucosal antibody to V2 in concert, reduce the risk of SIVmac251 acquisition. Fifty-four (54) rhesus macaques were randomized into two vaccination groups. One group (n=27) was primed twice with ALVAC-SIV (at week 0 and week 4) and boosted twice with ALVAC-SIV/gp120 in MF59 adjuvant (at week 12 and week 24). The second group (n=27) was primed twice with ALVAC-SIV (at week 0 and week 4) and boosted twice with ALVAC-SIV/gp120 in Alum adjuvant (at week 12 and week 24). Blood samples were taken pre-vaccination, 24 hours after the first prime (post-1st imunization at week 0) and 24 hours after the first boost (post-3rd immunization at week 12). All the samples were taken before SIV challenge. Blood samples were conserved in PAXgene tubes. RNA was extracted and hybridized to Illumina beadchips. technical replicate: P162_P382_post1st, P162_P382_post1st_rep1

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