Safety, Efficacy, and Immunogenicity of Therapeutic Vaccines for Patients with High-Grade Cervical Intraepithelial Neoplasia (CIN 2/3) Associated with Human Papillomavirus: A Systematic Review

Simple Summary We conducted a systematic review using 16 trials (RCTs and NRCTs) across eight countries and three continents; which included 672 patients with high-grade CIN associated with HPV. To the best of our knowledge, this is the first synthesis related to the safety, efficacy, and immunogenicity of therapeutic vaccines for the treatment of patients with high-grade CIN associated with HPV. The findings from the trials revealed that therapeutic vaccines can be considered promising for these injuries. However, there are still only a few phase III RCTs, and a better understanding of the specificities of different vaccine compositions and delivery systems and pathways to prevent viral escape mechanisms are needed. Overall, the results of this systematic review indicate that the therapeutic vaccines that are being developed for the treatment of CIN 2/3 are safe and well tolerated and that most trigger only systemic symptoms classified as mild or moderate that improve spontaneously in a short period of time. Considering the inconsistent results among phase I and II trials involving different therapeutic vaccines, our findings provide some clarification and have implications for multiple stakeholders. Abstract Despite the knowledge that HPV is responsible for high-grade CIN and cervical cancer, little is known about the use of therapeutic vaccines as a treatment. We aimed to synthesize and critically evaluate the evidence from clinical trials on the safety, efficacy, and immunogenicity of therapeutic vaccines in the treatment of patients with high-grade CIN associated with HPV. A systematic review of clinical trials adhering to the PRISMA 2020 statement in MEDLINE/PubMed, Embase, CENTRAL Cochrane, Web of Science, Scopus, and LILACS was undertaken, with no data or language restrictions. Primary endpoints related to the safety, efficacy, and immunogenicity of these vaccines were assessed by reviewing the adverse/toxic effects associated with the therapeutic vaccine administration via histopathological regression of the lesion and/or regression of the lesion size and via viral clearance and through the immunological response of individuals who received treatment compared to those who did not or before and after receiving the vaccine, respectively. A total of 1184 studies were identified, and 16 met all the criteria. Overall, the therapeutic vaccines were heterogeneous regarding their formulation, dose, intervention protocol, and routes of administration, making a meta-analysis unfeasible. In most studies (n = 15), the vaccines were safe and well tolerated, with clinical efficacy regarding the lesions and histopathological regression or viral clearance. In addition, eleven studies showed favorable immunological responses against HPV, and seven studies showed a positive correlation between immunogenicity and the clinical response, indicating promising results that should be further investigated. In summary, therapeutic vaccines, although urgently needed to avoid progression of CIN 2/3 patients, still present sparse data, requiring greater investments in a well-designed phase III RCT.