A Canarypox/gp120/alum vaccine decreased the risk of HIV acquisition in humans. We demonstrate here the efficacy of this vaccine regimen in the SIVmac251 macaque model when we used alum but not MF59 adjuvant. We analyzed innate and adaptive cells responses, anti- body Fc profiles and glycoforms and found that alum elicited envelope-de- pendent mucosal NKp44+ Innate Lymphoid Cells producing IL-17, and V2 peptide-specific IgG antibodies, associated with vaccine efficacy. In con- trast, MF59 induced mucosal V2 peptide-specific IgG that associated with increased risk of infection. Alum modulated the expression of 12 genes, seven of which are part of the RAS pathway, which correlated with vaccine efficacy, and in turn that were associated with innate responses and adaptive mucosal antibody responses 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.