Inclusion Criteria:

• Central pathology review submission; Note: this review for MART-1 positivity is mandatory prior to randomization to confirm eligibility
• Human leukocyte antigen (HLA)-A2-positive
• Histologic proof of stage II, III or IV melanoma that has been completely resected or completely treated with ablative therapy (ex: stereotactic body radiosurgery, radiofrequency ablation, cryoablation) with no current evidence of disease, as demonstrated by imaging within 2 months (stage III or stage IV; must be computed tomography [CT], magnetic resonance imaging [MRI], or positron emission tomography [PET]/CT) or 6 months (stage II; may be chest x-ray, CT, MRI, or PET/CT)
• Absolute neutrophil count (ANC) ≥ 1500 mL
• Hemoglobin (Hgb) > 10 g/dL
• Platelets (PLT) ≥ 50,000 mL
• Aspartate aminotransferase (AST) ≤ 3 x upper limit of normal (ULN)
• Alkaline phosphatase ≤ 3 x ULN
• Ability to provide informed consent
• Willingness to return to Mayo Clinic Rochester for follow-up
• Life expectancy ≥ 12 weeks
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2
• For women of childbearing potential, a negative serum pregnancy test ≤ 7 days prior to registration
• Willingness to provide mandatory blood samples for correlative research

Exclusion Criteria:

• Uncontrolled or current infection
• Known standard therapy for the patient's disease that is potentially curative or proven capable of extending life expectancy
• Known allergy to any of the vaccine or adjuvant components, including eggs
• Any of the following prior therapies with interval since most recent treatment:
  • Chemotherapy ≤ 4 weeks prior to registration
  • Biologic or immunologic therapy ≤ 4 weeks prior to registration
  • Radiation therapy ≤ 4 weeks prior to registration
• Failure to fully recover from side effects of prior therapy or surgery
• Any of the following:
  • Pregnant women
  • Nursing women
  • Women of childbearing potential or their sexual partners who are unwilling to employ adequate contraception (condoms, diaphragm, birth control pills, injections, intrauterine device [IUD], surgical sterilization, subcutaneous implants, or abstinence, etc.)
• Known immune deficiency, including human immunodeficiency virus (HIV) infection
• History of systemic autoimmune disease, as patients with ongoing autoimmunity may be at an increased risk of autoimmune toxicity from the study vaccine
• Current or recent (≤ 4 weeks) use of immunosuppressive medications including systemic (inhaled, oral, or intravenous [IV]) corticosteroids; Note: use of corticosteroids in doses not exceeding those used for adrenal replacement is acceptable
• History of brain metastases; EXCEPTION: patients with a solitary brain metastasis that has been completely resected, and who have no ongoing central nervous system (CNS) symptoms and an MRI documenting no evidence of CNS disease at least 3 months after resection and within 30 days of registration, are eligible for treatment
• Other active malignancy ≤ 5 years prior to registration; EXCEPTIONS: non-melanotic skin cancer or carcinoma-in-situ of the cervix; NOTE: if there is a history of prior malignancy > 5 years prior to registration, the patient must not be receiving other cancer treatment