**4. Therapeutic vaccine for CIN**

Currently, the standard therapy for CIN is surgical excision such as conization or LEEP. Although these treatments are very effective from the viewpoint of removing HPV-induced precancerous lesions, these can cause infertility and menstrual disorders secondary to stenosis of the cervix. In addition, the existing CC prophylactic vaccines are ineffective for HPV-infected women and nontargeted HPV types. Therefore, development of a therapeutic vaccine using immunotherapy as a nonsurgical treatment for CIN is an important strategy for the prevention of CC.

The development of therapeutic vaccines has been mainly targeted for HPV E6 and E7 [90], because these proteins are essential for the malignant transformation of HPV-infected cells and are permanently expressed in CIN. In order to induce an E6 or E7 antigen-specific T cell immune response, several kinds of vaccines have been developed; these include adoptive transfer of tumor-specific T cells, chimeric virus-like particle vaccines, dendritic cell, DNA vaccines, peptide vaccines, protein vaccines, and viral or bacterial vector vaccines. Among these, protein vaccines are the most common therapeutic vaccines for HPV 16 because of the simplicity of the method and the lack of HLA restriction [91]. However, there are currently no available therapeutic HPV vaccines against CIN.

Recently, a randomized, double-blind, placebo-controlled phase 2b trial on CIN2/3 patients showed promising results on the efficacy and safety of VGX-3100, which is a synthetic plasmid targeting human HPV 16 and HPV 18 E6 and E7 proteins (ClinicalTrials. gov Identifier: NCT01304524). In the study, the primary endpoint for efficacy was regression to CIN1 or normal pathology at 36 weeks after the first dose. This study enrolled 167 people who were randomized (3:1) to the VGX-3100 group (n = 125) and the placebo group (n = 42); the rate of histopathologic regression was significantly higher by 18.2% [95% CI 1.3–34.4] in the VGX-3100 group, compared with the placebo group (48.2% vs. 30.0%; p = 0.034). The incidence of erythema at the injection site was significantly higher in the VGX-3100 group than in the placebo group (78.4% vs. 57.1%, p = 0.007). On the other hand, there was no significant increase in the number of severe side effects that could interfere with the performance of vaccine therapy [92]. Therefore, this vaccine might be a nonsurgical therapeutic option for CIN2/3, but further research and development are needed in this field. A clinical trial on HPV therapeutic vaccines was detailed in a recent review [93].
