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This study aimed to investigate the immunogenicity of a cancer vaccine consisting of the NeuGcGM3 ganglioside combined with the outer membrane protein complex of Neisseria meningitides to form very small size particles. The vaccine is administered together with Montanide ISA51, as adjuvant treatment for breast cancer patients. After surgical resection and standard first-line chemo/radiotherapy, breast cancer patients in stage II–III were enrolled in a phase III clinical trial and allocated into 2 strata, according to the number of positive lymph nodes [stratum I (0–3); stratum II (≥4)]. Subsequently, patients were randomly assigned to receive the vaccine or placebo. The treatment consisted of 5 vaccine doses (200 μg) every 2 weeks and thereafter monthly reimmunizations to complete 15 doses. The vaccine was well-tolerated and high titers of immunoglobulin M and immunoglobulin G anti-NeuGcGM3 antibodies were similarly detected in each stratum. Hyperimmune sera were able to specifically recognize and kill the NeuGcGM3-expressing L1210 tumor cell line, and these functional capacities were significantly associated with a better clinical outcome in patients of stratum II. Besides, postimmune sera had the capacity to revert in vitro the immunosuppression induced by NeuGcGM3, as measured by the prevention of CD4 downmodulation on human T lymphocytes. Vaccination had no impact on the frequency of regulatory T cells or circulating NK cells. This study demonstrated, for the first time, the immunogenicity of the NeuGcGM3/VSSP/Montanide ISA 51 vaccine in the adjuvant setting and describes the functionality of induced anti-NeuGcGM3 antibodies as potential surrogate biomarkers of clinical benefit.