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OA25.01 Background: The RV144 HIV vaccine trial resulted in limited, but significant protection, from HIV acquisition. Serum antibodies directed to the Env variable regions 1 and 2 (V1/V2) inversely correlated with the risk of HIV-1 infection and sieve analysis demonstrated immunologic pressure on two regions of the V2. Prior macaque studies demonstrated that a similar vaccine for SIV (ALVAC-SIV) induced protection from SIVmac251 acquisition in a low dose neonatal challenge model, but not in adult high dose challenge models. Methods: We challenged ALVAC-SIV/gp120/alum vaccinated adult macaques intrarectally with repeated low doses of SIVmac251 in a study powered to allow benchmarking against the results of RV144. An additional arm of the study evaluated these vaccines together with the oil-in-water emulsion MF59 adjuvant. Results: We found that alum protected macaques from SIVmac251 acquisition while MF59 did not despite its ability to elicit higher systemic T-cell and antibodies responses. MF59 altered homing of antibody producing cells and increased the frequency of CXCR3+ plasmablasts in blood that positively correlated with anti-envelope IgA serum levels and phagocytosis. Alum, in contrast, increased the frequency of plasmablasts expressing the mucosal integrin a4b7 that positively correlated with IgA responses to cyclic V2 in rectal mucosa. In the alum group mucosal IgG to cyclic V2 correlated with lower risk of SIVmac251 acquisition. However, mucosal IgG to linear and cyclic V2 correlated with an increased risk of SIVmac251 acquisition in the MF59 group. The two adjuvants modulated distinct signaling pathways and RAS, a signal transducer that facilitates cross talk among B-cells, T-cells and antigen presenting cells, was demonstrated to be a biomarker of vaccine efficacy in the alum group. Conclusions: These data highlight the importance of the quality of the mucosal antibodies to V2 in protection and suggest that activation of RAS may constitute a novel approach to improve vaccine efficacy against HIV.