Adjuvant PROSTVAC-V/F in Subjects at High Risk for Relapse After Radical Prostatectomy

Inclusion Criteria: 1. Age \>21 2. Completed radical prostatectomy for pathologically-verified adenocarcinoma of the prostate no more than 120 days prior to start of treatment. The following procedures are acceptable: radical retropubic prostatectomy (RRP), laparoscopic radical prostatectomy (with or without robotic assistance; LAPD), radical perineal prostatectomy (RPP). 3. Post-operative PSA \<0.2ng/mL by 120 days after prostatectomy 4. Must have one or more of the following: * pT3b or pT4 primary tumor * Gleason score 8-10 * pN1 lymph node disease * positive surgical margins * pre-operative PSA of \> 10ng/mL * presence of any tertiary Gleason 5 component on the prostatectomy pathology report. Note: Patients with pT3a disease who lack one of the above criteria, and who refuse adjuvant radiation, may also be enrolled. 5. ECOG performance status 0-1 6. Adequate hematologic, renal, liver function per parameters in Table 1 7. Subject of fathering potential must agree to use an adequate method of contraception to avoid conception throughout the study and for at least 4 weeks after the last dose of study drug to minimize the risk of pregnancy. 8. Subjects must have had a negative bone scan, and CT of abdomen and pelvis within 16 weeks prior to registration. Additional forms of imaging (Prostascint scan, MRI) may be substituted for a CT scan of the abdomen and pelvis if clinically indicated. Exclusion Criteria: 1. Pure small cell carcinoma of the prostate 2. Radiographically-demonstrable metastases at any time prior to the time of enrollment 3. Diagnosis of cancer requiring systemic therapy in the past 5 years 4. Presence of any major medical condition which, in the opinion of the investigator, precludes participation in the study 5. Neoadjuvant or adjuvant therapy of any kind 6. Chronic administration (defined as daily or every other day for continued use \> 14 days) of systemic glucocorticoids within 28 days of the first planned dose of PROSTVAC-V/F. Use of inhaled steroids, nasal sprays, and all topical preparations (creams, solutions, gels, ointments, etc.) for up to 5% of the body surface area is allowed. 7. Use of systemic immunosuppressant agents including anti-metabolites, glucocorticoids, TNF antagonists, antibodies to IL6 or IL6R, calcineurin inhibitors, mTOR antagonists 8. Prior history of serious toxicity or a systemic reaction to vaccinia immunization such as myopericarditis progressive vaccinia infection, or eczema vaccinatum. 9. Inflammatory or exfoliative skin diseases such as eczema, psoriasis that disrupt epidermis 10. Active infections requiring systemic therapy 11. Serologic evidence of HIV/AIDS. 12. Positive hepatitis C serology or active hepatitis B infection. 13. History of allergy to eggs, egg products, aminoglycoside antibiotics 14. History of myocardial disease, such as myocarditis, cardiomyopathy, congestive heart failure, ischemic cardiomyopathy 15. Prior solid organ or stem cell transplant 16. History of or active autoimmune disease (e.g., autoimmune neutropenia, thrombocytopenia, or hemolytic anemia, systemic lupus, localized lupus, Sjogren's syndrome, scleroderma, myasthenia gravis, Goodpasture's syndrome, or Addison's disease). Persons with vitiligo, Hashimoto's thyroiditis, or Graves disease are not excluded. 17. Vaccination with live attenuated vaccine within 28 days prior to day 1 of PROSTVAC-V/F administration or vaccination with a killed vaccine within 14 days prior to day 1 of PROSTVAC-V/F. 18. Inability to avoid close contact or household contact with the following high-risk individuals for three weeks after the Day 1 vaccination or until the vaccination site heals completely: (a) children ≤ 3 years of age; (b) pregnant or nursing women; (c) individuals with prior or concurrent extensive eczema or other eczemoid skin disorders; or (d) immunocompromised individuals, such as those with HIV. 19. Any condition which, in the opinion of the investigator, would prevent full participation in this trial (including Follow-Up), or would interfere with the evaluation of the trial endpoints.