Impact of HPV Vaccine on CIN2+ Recurrence After Conization: A Systematic Review and Meta-Analysis of Vaccination Timing, Valency and Surgical Margins

Mauro Francesco Pio Maiorano^1*Ambrogio Cazzolla²Brigida Anna Maiorano³Vera Loizzi^2,4Gennaro Cormio^1,2Giuseppe Colonna²Salvatore Lopez²

• ¹Unit of Obstetrics and Gynecology, Department of Interdisciplinary Medicine (DIM), University of Bari Aldo Moro, Bari, Italy
• ²Unit of Oncologic Gynecology, Istituto Tumori Bari Giovanni Paolo II IRCCS, Bari, Italy
• ³Department of Medical Oncology, Universita Vita Salute San Raffaele, Milan, Italy
• ⁴Translational Biomedicine and Neuroscience Department (DiBraiN), University of Bari Aldo Moro, Bari, Italy

Background: Prophylactic Human Papillomavirus (HPV) vaccines prevent high-grade cervical lesions, but their role as adjuvant therapy after conization for high-grade cervical intraepithelial neoplasia (CIN2+) remains uncertain, particularly regarding vaccine type, timing, and margin status. This review aimed to quantify the effect of adjuvant HPV vaccination on CIN2+ recurrence after conization and to determine whether vaccine valency, timing of administration (before vs after surgery), and cone margin status modify this effect. Methods: We performed a PROSPERO-registered (CRD420251042109) systematic review and meta-analysis of randomized trials and cohort studies comparing HPV vaccination versus no vaccination in women treated with conization and/or loop electrosurgical excision procedure (LEEP) for histologically confirmed CIN2+. The primary outcome was recurrent CIN2+; secondary outcomes were HPV persistence/ reinfection and vaccine-related adverse events. Random-effects models were used to pool risk ratios (RRs), with preplanned subgroup analyses by vaccine valency (bivalent, quadrivalent, nonavalent), timing of vaccination (before vs after conization), and cone margin status (positive vs negative), alongside sensitivity and GRADE certainty assessments. Results: Seventeen studies (four randomized controlled trials [RCTs], thirteen cohorts), including 33,181 women (6,665 vaccinated; 26,516 unvaccinated), met inclusion criteria. Overall, adjuvant HPV vaccination was associated with a 62% relative reduction in CIN2+ recurrence (pooled RR 0.38, 95% confidence interval [CI] 0.29-0.51; I² = 58.6%). Subgroup analyses showed similar benefit across valencies (bivalent RR 0.50, quadrivalent RR 0.37, nonavalent RR 0.41; p for subgroup difference = 0.94), vaccination before versus after conization (RR 0.57 vs 0.72; p = 0.35), and in both margin-negative (RR 0.34) and margin-positive (RR 0.40) women (p = 0.63). Data on HPV persistence suggested a predominantly prophylactic mechanism (prevention of new/re-infection rather than clearance), and no new safety signals emerged. Conclusions: Adjuvant prophylactic HPV vaccination meaningfully lowers CIN2+ recurrence after conization across vaccine types and clinical subgroups, supporting its integration into routine post-excisional care for eligible women as a low-burden strategy to reduce repeat procedures, preserve reproductive potential, and help avert progression to cervical cancer.