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Background Ductal carcinoma in situ (DCIS) is a preinvasive form of breast cancer. Current treatment consists of surgery, radiation, and often systemic therapy exposing patients to unnecessary health risks. Vaccines targeting DCIS may be a way to intercept preinvasive lesions and prevent the development of invasive breast cancer.Methods We developed a Th1 selective multiantigen, polyepitope plasmid-DNA vaccine encoding segments of IGFBP-2, HER2, and IGF-IR, all antigens expressed in hormone receptor positive and negative DCIS. We then performed a Phase I study in participants with non-metastatic breast cancer with no evidence of disease. The primary objective was to assess the safety of 3 monthly intradermal doses (150, 300, or 600 µg) of the tri-antigen vaccine with granulocyte macrophage colony-stimulating factor as an adjuvant. 32 participants were enrolled, 10 per dose level. Toxicity evaluations occurred monthly with vaccination and at 1 and 6 months after the last vaccine. Blood was collected at baseline and at 1 and 6 months after the last immunization to assess cellular immune responses. Participants were followed annually for 5 years for long-term toxicity.Results There was no significant difference in adverse events (AEs) across dose levels and all related AEs were grades 1 or 2. All doses were immunogenic; responders included 70% of participants at the 150 µg dose level, 67% at the 300 µg dose, and 40% at the 600 µg dose level. All participants at the 300 µg dose retained significant Th1-antigen-specific immune response at 6 months after end of immunizations. T-cells derived from vaccine immunologic responders exhibited gene expression profiles that indicated an increased metabolic fitness as compared with immunologic non-responders.Conclusions The tri-antigen vaccine appears safe and immunogenic. The intermediate dose (300 µg) was chosen as the Phase II dose due to the long-term persistence of immunity after vaccination. The vaccine will be studied in Phase II trials for the treatment of DCIS.Trial registration number NCT02780401.