The Effectiveness of Therapeutic Vaccines for the Treatment of Cervical Intraepithelial Neoplasia 3: A Systematic Review and Meta-Analysis

Abstract

Cervical cancer (CC) is a disease that affects many women worldwide, especially in low-income countries. The human papilloma virus (HPV) is the main causative agent of this disease, with the E6 and E7 oncoproteins being responsible for the development and maintenance of transformed status. In addition, HPV is also responsible for the appearance of cervical intraepithelial neoplasia (CIN), a pre-neoplastic condition burdened by very high costs for its screening and therapy. So far, only prophylactic vaccines have been approved by regulatory agencies as a means of CC prevention. However, these vaccines cannot treat HPV-positive women. A search was conducted in several databases (PubMed, Scopus, Web of Science, and ClinicalTrials.gov) to systematically identify clinical trials involving therapeutic vaccines against CIN 3. Histopathological regression data, immunological parameters, safety, DNA clearance, and vaccine efficacy were considered from each selected study, and from the 102 articles found, 8 were selected based on the defined inclusion criteria. Histopathological regression from CIN 3 to CIN < 1 was 22.1% (95% CI: 0.627−0.967; p-value = 0.024), showing a vaccine efficacy of 23.6% (95% CI; 0.666−0.876; p-value < 0.001). DNA clearance was assessed, and the risk of persistent HPV DNA was 23.2% (95% CI: 0.667−0.885; p-value < 0.001). Regarding immunological parameters, immune responses by specific T-HPV cells were more likely in vaccinated women (95% CI: 1.245−9.162; p-value = 0.017). In short, these studies favored the vaccine group over the placebo group. This work indicated that therapeutic vaccines are efficient in the treatment of CIN 3, even after accounting for publication bias.

Keywords: cervical cancer; clinical trials; meta-analysis; systematic review; therapeutics vaccines.

Figure 1

PRISMA flow-diagram of database search, study selection and included studies in this systematic review with meta-analysis.

Figure 2

Risk of bias graph: review author’s judgments about each risk of bias item presented as percentages across all included studies.

Figure 3

Risk of bias summary: review author’s judgments about each risk of bias item for each included study [35,36,37,38,39,40,41,42].

Figure 4

Forest plot of histopathological downgrading results after vaccination compared with placebo. Downgrading was considered an histological improvement to normal or CIN 1 [35,36,37,38,41,42].

Figure 5

Forest plot of vaccines’ efficacy against high-grade cervical intraepithelial neoplasia (CIN 2/3) in women compared with placebo. Data were obtained by the presence of CIN 2/3 confirmed cases in vaccinated group versus unvaccinated group [35,36,37,39,41].

Figure 6

Forest plot of DNA clearance after vaccination compared with placebo. PCR amplification was utilized to assess HPV DNA in cervical biopsies [35,37,38].

Figure 7

Forest plot of HPV-T cell response after vaccination compared with placebo [38,39,42].

Figure 8

Sensitivity analysis excluding one or more studies from the analysis to see how this affected the results. (A) Histopathological regression to CIN ≤ 1 [35,36,37,38,41,42], (B) efficacy for complete resolution [35,36,37,39,41], (C) DNA clearance [35,37,38], (D) HPV-T cell response [35,38,42].

Figure 9

Funnel plots for the outcomes of this meta-analysis adjusted by Trim and Fill approach. (A) Histological improvement to normal or CIN 1, (B) Vaccine efficacy for complete resolution, (C) DNA clearance, (D) HPV-T cell responses after vaccination.