Advances in Therapeutic Vaccines Against HPV: A Review of Human Clinical Trials

Cervical cancer remains a major public health concern, particularly in low- and middle-income countries (LMICs) where access to preventive measures is limited. Persistent infection with high-risk human papillomavirus (HPV) types, mainly HPV16 and HPV18, is the key cause of cervical cancer. While prophylactic HPV vaccines effectively prevent new infections, they offer no therapeutic benefit for individuals with established lesions. This review evaluates the clinical evidence on therapeutic HPV vaccines, focusing on their ability to promote viral clearance. A bibliographic search was conducted in PubMed, selecting human studies reporting outcomes on HPV clearance. Seventeen clinical trials were identified, including DNA-based (VGX-3100, GX-188E), viral-vector (MVA E2, TG4001), peptide-based (Pepcan), and bacterial-vector (GLT 001) vaccines. Among them, DNA-based vaccines, particularly VGX-3100, showed the most consistent results, whereas several protein- or vector-based approaches demonstrated variable outcomes. Early therapeutic HPV vaccine trials faced setbacks due to limited efficacy, delivery approaches, and study design challenges, preventing progression to late-phase development. Recent DNA-based candidates, however, are advancing through phase II/III trials. While none have yet to be approved for commercial use, these vaccines elicit virus-specific T-cell responses and can induce regression of precancerous lesions, offering a promising addition to prophylactic vaccination and screening. Variability in study designs and endpoints underlines the need for standardized protocols and further phase III trials. Overall, therapeutic HPV vaccines represent a rapidly advancing field with the potential to complement prophylactic vaccination and screening, thereby strengthening global cervical cancer control efforts, particularly in LMICs.