Therapeutic Vaccination with MVA E2 Can Eliminate Precancerous Lesions (CIN 1,CIN 2,and CIN 3) Associated with Infection by Oncogenic Human Papillomavirus

Abstract

Human papillomavirus (HPV) infection is associated with cervical cancer. Papillomaviruses can induce diseases ranging from warts and condylomata to lesions that can progress to malignant neoplasias. Cervical cancer is a serious problem in developing countries because it is usually not detected at an early stage. In Mexico, a woman dies every 2 hr from this malignancy. In a phase I/II clinical trial, we evaluated the potential use of the MVA E2 recombinant vaccinia virus to treat cervical intraepithelial neoplasia CIN 1, CIN 2, and CIN 3 lesions associated with human papillomavirus (HPV) infection. Seventy-eight women with CIN 1-, CIN 2-, and CIN 3-grade lesions were treated with either an MVA E2 recombinant virus vaccine or with cryosurgery. Thirty-six women received the recombinant virus vaccine at a total of 10⁷ MVA E2 virus particles injected directly into the uterus once every week over a 6-week period. Forty-two patients were treated with cryosurgery. Reduction of lesions was monitored weekly by colposcopy and cytologic analysis. The type of immune response after MVA E2 injection was determined by measuring antibody titers against MVA E2 virus and the E2 protein, and by the presence of cytotoxic activity against cancer cells bearing papillomavirus DNA. The presence of papillomavirus was determined by with the hybrid capture method. Thirty-four of 36 patients showed complete elimination of precancerous lesions after treatment with the MVA E2 vaccine. In two patients, precancerous lesions were reduced from grade CIN 3 to CIN 1. Three other patients presented isolated koilocytes after treatment with MVA E2. Colposcopy revealed no lesions in 85% of patients, and only small aceto-white spots were detected in 15% of patients after treatment with MVA E2. All patients developed antibodies against the MVA E2 vaccine, and vaccination generated a specific cytotoxic response against HPV-transformed cells. Furthermore, 50% of patients showed no evidence of papillomavirus after treatment with MVA E2, while the remaining 50% showed persistence of HPV DNA, but at approximately only 10% of the original viral load. The presence of cells cytotoxic to HPV-transformed cells, and the generation of antibodies against MVA E2, correlated with the elimination of lesions and with a remarkable reduction of HPV viral load in all patients treated with MVA E2. Additionally, the MVA E2 vaccine did not produce any apparent side effects in any of the patients treated. Cryosurgery eliminated the lesions of CIN 1 in all patients, but patients so treated did not develop cytotoxic activity against cancer cells. These results show that therapeutic vaccination with MVA E2 vaccine is an excellent prospective means for stimulating the immune system and causing the regression of precancerous CIN 1, CIN 2, and CIN 3 lesions when the vaccine is given locally.