Efficacy and safety of therapeutic HPV vaccines to treat CIN 2/CIN 3 lesions: a systematic review and meta-analysis of phase II/III clinical trials

Abstract

Objectives: We aims to assess the efficacy and safety of therapeutic HPV vaccines to treat cervical intraepithelial neoplasia of grade 2 or 3 (CIN2/3). Design: This study is a systematic review and meta-regression that follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses recommendations. Data sources: PubMed, Embase, Web of Science, Global Index Medicus and CENTRAL Cochrane were searched up January 31, 2022. Eligibility criteria: Phase II/III studies reporting the efficacy of therapeutic vaccines to achieve regression of CIN2/3 lesions were included. Data extraction and synthesis: Two independent reviewers extracted data, evaluated study quality. A random-effect model was used to pool the proportions of regression and/or HPV clearance. Results: 12 trials met the inclusion criteria. Out of the total 734 women receiving therapeutic HPV vaccine for CIN 2/3, 414 regressed to normal/CIN1 with the overall proportion of regression of 0.54 (95%CI: 0.39, 0.69) for vaccinated group. Correspondingly, 166 women receiving placebo only achieving the pooled normal/CIN1 regression of 0.27 (95%CI: 0.20, 0.34). When only including two-arm studies, the regression proportion of the vaccine group was higher than that of control group (relative risk (RR): 1.52, 95%CI: 1.14, 2.04). Six studies reported the efficacy of the therapeutic vaccines to clear high-risk human papillomavirus (hrHPV) with the pooled proportion of hrHPV clearance of 0.42 (95%CI: 0.32, 0.52) for the vaccine group and 0.17 (95%CI: 0.11, 0.26) for the control group and the RR of 2.03 (95%CI: 1.30, 3.16). Similar results were found regarding HPV16/18 clearance. No significant unsolicited adverse events have been consistently reported. Conclusions: The efficacy of the therapeutic vaccines in the treatment of CIN2/3 was modest. Besides, the implementation issues like feasibility, acceptability, adoption, and cost-effectiveness need to be further studied. PROSPERO registration number: CRD42020189617

Elimination of human papillomavirus 16-induced tumors by a mucosal rAd5 therapeutic vaccination in a pre-clinical study

“…Non-invasive treatments, like the one examined here, may even used at the point of infection identification prior to diagnosis with CIN2/3 to prevent the progression to from CIN1 to cervical cancer. 27 In this report, we evaluated a novel HPV16 E6/E7 vaccine that contains previously described mutations that inhibit E6 and E7 oncogenic properties or contains only the predicted immunodominant epitopes to increase safety. 25 We demonstrate that mucosal vaccination via an intranasal route in mice was able to reduce tumor burden in a subcutaneous model of HPV tumorigenesis.…”

“…A review of different vaccine modalities using variations of HPV16 and HPV18 E6 and E7 as antigens, observed a total overall proportion of regression from CIN2/3 to CIN1 at 0.54 compared a placebo group at 0.27. 27 These numbers represent a meaningful reduction in advancement to cervical cancer, yet room for improvement remains. Studies with an electroporated DNA vaccine candidate suggested that the ability to elicit potent antigen-specific T cell responses correlated with histopathological regression and a reduction in HPV viral DNA detection.…”

Understanding the key determinants of an HPV therapeutic vaccine: a modeling analysis

“…In the absence of trial data on effectiveness of a therapeutic vaccine product, we conducted robust exploration around therapeutic vaccine properties, varying effectiveness against productive infections from 50 to 100% and against high-grade lesions from 0 to 50%. An upper-bound of 50% effectiveness at regressing high-grade lesions was imposed based upon modest results of previous therapeutic vaccines that have targeted high-grade lesions and cervical cancer and the expectation that the microenvironment would be less conducive for stimulating a response that would effectively regress high-grade lesions ( 25 ).…”

Human Papillomavirus and Associated Cancers: A Review

“…These are entirely new medications and similar to currently available vaccines only insofar as they are delivered via injection. A systematic review and meta-analysis completed in 2023 by Ibrahim Khalil et al analyzed the effectiveness of a variety of newly developed therapeutic HPV vaccines in treating cervical cancer [66]. The therapeutic vaccines used in this study were peptide-based, protein-based, viral-vectored, bacterial-vectored, DNA-based, and cell-based vaccines [66].…”

“…A systematic review and meta-analysis completed in 2023 by Ibrahim Khalil et al analyzed the effectiveness of a variety of newly developed therapeutic HPV vaccines in treating cervical cancer [66]. The therapeutic vaccines used in this study were peptide-based, protein-based, viral-vectored, bacterial-vectored, DNA-based, and cell-based vaccines [66]. The targets of many therapeutic vaccines are E6 and E7 proteins, which are the main proteins that influence infection and carcinogenesis [66].…”