BACKGROUND: The effect of human papillomavirus (HPV) vaccination on cervical intraepithelial neoplasia grade 2 or worse (CIN2+) recurrence with respect to cone margin positivity is unknown. Most studies assessed this effect beyond two months post-conisation. We aimed to determine both the duration and early onset of effect in women who had been prophylactically vaccinated or vaccinated after conisation, considering cone margin status. METHODS: This cohort study used data from one of the central laboratories in the Czech Republic, covering approximately 33% of women undergoing national cervical cancer screening. It included women treated for CIN2+ between 2010 and 2024 who had received either prophylactic HPV vaccination (available through the national immunisation program since 2011) or post-conisation vaccination (recommended by the Czech Gynaecological and Obstetrical Society since 2008). The vaccination effect was estimated using the incidence rate ratio (IRR) from a Poisson regression model, calculated as 100 × (1-IRR). FINDINGS: Of the 10,054 women enrolled, 919 were vaccinated after conisation, 502 prophylactically, and 169 had undetermined timing of vaccination. Throughout the follow-up period, CIN2+ recurrence was observed in 513 unvaccinated women, with a rate of 14·61 per 1000 person-years (py), in 14 prophylactically vaccinated women, with a rate of 5·84 (54% reduction; 95% confidence interval [CI]: 22-73%), and in 15 women vaccinated post-excision, with a rate of 3·37 (74% reduction; 95% CI: 57-85%). The high recurrence rate of 58·59 per 1000 py within six months of conisation was reduced by 80% (95% CI: 19-95%) with prophylactic vaccination and by 89% (95% CI: 57-97%) with incomplete post-excision vaccination. Among a total of 1771 women with a positive cone margin, recurrence was identified in 272 of 1568 unvaccinated women, corresponding to a recurrence rate of 51·62 per 1000 py. A reduction was observed in 84 prophylactically vaccinated and in 119 women vaccinated post-excision, with only 6 recurrence cases documented in each group. This corresponded to recurrence rates of 14·94 (62% reduction; 95% CI: 14-83%) and 9·78 per 1000 py (79% reduction; 95% CI: 52-90%), respectively. INTERPRETATION: Regardless of timing, HPV vaccination has a beneficial long-term effect in lowering the risk of CIN2+ recurrence. Despite the greater reduction in relapse achieved by post-excision vaccination, the difference compared with the prophylactic one was not statistically significant. The most pronounced benefit was observed within the first six months post-conisation, particularly in women with a positive cone margin. FUNDING: Cooperatio 31 fund, Health Sciences, Charles University, Prague, Czech Republic.

Centre of Ambulatory Gynaecology and Primary Care Brno 602 00 Czech Republic

Department of Anaesthesia and Intensive Medicine 1st Faculty of Medicine Charles University and University Military Hospital Prague 100 00 Czech Republic

Department of Epidemiology and Biostatistics 3rd Faculty of Medicine Charles University Prague 100 00 Czech Republic

Department of Health Care and Population Protection Faculty of Biomedical Engineering Czech Technical University Prague Kladno 272 01 Czech Republic

Department of Hygiene 3rd Faculty of Medicine Charles University Prague 100 00 Czech Republic

Department of Medical Biophysics and Informatics 3rd Faculty of Medicine Charles University Prague 100 00 Czech Republic

Department of Obstetrics and Gynaecology Palacký University Olomouc Faculty of Medicine and Dentistry University Hospital Olomouc Olomouc 775 15 Czech Republic

Královské Vinohrady University Hospital Prague 100 00 Czech Republic

Laboratory for Atherosclerosis Research Centre for Experimental Medicine Institute for Clinical and Experimental Medicine Prague 140 21 Czech Republic

Unilabs Pathology k s Prague 160 00 Czech Republic

See more in PubMed

Human papillomavirus vaccines: WHO position paper, December 2022. https://www.who.int/publications/i/item/who-wer9750-645-672

Considerations for human papillomavirus (HPV) vaccine product choice. 1st ed. World Health Organization; Geneva: 2024.

Czech Gynecological and Obstetrical Society of the Czech Medical Association of J. E. Purkyně (ČGPS ČLS JEP) Recommendations for HPV vaccination in women treated for cervical precancerous lesions. https://www.hpvguide.eu/ockovani-konizovanych-zen?utm_source=chatgpt.com

Bizzarri N., Kyrgiou M., De Vincenzo R., et al. Prophylactic HPV vaccination in HPV -related gynecologic cancers: European Society of Gynecological Oncology (ESGO) prevention committee opinion. Intl J Gynecol Obste. 2024;169(2):597–604. PubMed PMC

Khieu M., Butler S.L. StatPearls. StatPearls Publishing; Treasure Island (FL): 2025. High-grade squamous intraepithelial lesion of the cervix.http://www.ncbi.nlm.nih.gov/books/NBK430728/ PubMed

Grzes B., Heimrath J., Ciszek M. Minimally invasive surgery with the complementing immunotherapy in the treatment of intraepithelial neoplasia of cervix in women of child-bearing age. Onkol Pol. 2011;14:125–130.

Joura E.A., Garland S.M., Paavonen J., et al. Effect of the human papillomavirus (HPV) quadrivalent vaccine in a subgroup of women with cervical and vulvar disease: retrospective pooled analysis of trial data. BMJ. 2012;344 PubMed PMC

Petráš M., Dvořák V., Lomozová D., et al. Timing of HPV vaccination as adjuvant treatment of CIN2+ recurrence in women undergoing surgical excision: a meta-analysis and meta-regression. Sex Transm Infect. 2023;99:561–570. PubMed PMC

Dvořák V., Petráš M., Dvořák V., et al. Reduced risk of CIN2+ recurrence in women immunized with a 9-valent HPV vaccine post-excision: retrospective cohort study. Hum Vaccines Immunother. 2024;20 PubMed PMC

Kang W.D., Choi H.S., Kim S.M. Is vaccination with quadrivalent HPV vaccine after loop electrosurgical excision procedure effective in preventing recurrence in patients with high-grade cervical intraepithelial neoplasia (CIN2–3)? Gynecol Oncol. 2013;130:264–268. PubMed

Hejcmanová K., Ambrožová M., Chloupková R., Ngo O., Májek O. Ministry of Health of the Czech Republic and Institute of Health Information and Statistics of the Czech Republic; Prague: 2024. Number of performed cervicovaginal cytologies. National Health information portal.http://www.nzip.cz/data/2095-cervix-cytologie-pocet-otevrena-data 2025; published online March 15.

Chovanec J., Náležinská M. Overview of the diagnostics and treatment of the cervical cancer. Onkologie. 2014;8:269–274.

Liu Y., Alqatari M., Sultan K., et al. Using p16 immunohistochemistry to classify morphologic cervical intraepithelial neoplasia 2: correlation of ambiguous staining patterns with HPV subtypes and clinical outcome. Hum Pathol. 2017;66:144–151. PubMed PMC

Ellingson M.K., Sheikha H., Nyhan K., Oliveira C.R., Niccolai L.M. Human papillomavirus vaccine effectiveness by age at vaccination: a systematic review. Hum Vaccines Immunother. 2023;19 PubMed PMC

Zhao S., Hu S., Xu X., et al. Impact of HPV-16/18 AS04-adjuvanted vaccine on preventing subsequent infection and disease after excision treatment: post-hoc analysis from a randomized controlled trial. BMC Infect Dis. 2020;20:846. PubMed PMC

Hildesheim A., Gonzalez P., Kreimer A.R., et al. Impact of human papillomavirus (HPV) 16 and 18 vaccination on prevalent infections and rates of cervical lesions after excisional treatment. Am J Obstet Gynecol. 2016;215:212.e1–212.e15. PubMed PMC

Garland S.M., Paavonen J., Jaisamrarn U., et al. Prior human papillomavirus-16/18 AS04-adjuvanted vaccination prevents recurrent high grade cervical intraepithelial neoplasia after definitive surgical therapy: post-hoc analysis from a randomized controlled trial. Intl Journal of Cancer. 2016;139:2812–2826. PubMed PMC

Henere C., Torné A., Llupià A., et al. HPV vaccination in women with cervical intraepithelial neoplasia undergoing excisional treatment: insights into unsolved questions. Vaccines. 2022;10:887. PubMed PMC

Del Pino M., Martí C., Torras I., et al. HPV vaccination as adjuvant to conization in women with cervical intraepithelial neoplasia: a study under real-life conditions. Vaccines. 2020;8:245. PubMed PMC

Bogani G., Raspagliesi F., Sopracordevole F., et al. Assessing the long-term role of vaccination against HPV after loop electrosurgical excision procedure (LEEP): a propensity-score matched comparison. Vaccines. 2020;8:717. PubMed PMC

Pieralli A., Bianchi C., Auzzi N., et al. Indication of prophylactic vaccines as a tool for secondary prevention in HPV-linked disease. Arch Gynecol Obstet. 2018;298:1205–1210. PubMed

Karimi-Zarchi M., Allahqoli L., Nehmati A., Kashi A.M., Taghipour-Zahir S., Alkatout I. Can the prophylactic quadrivalent HPV vaccine be used as a therapeutic agent in women with CIN? A randomized trial. BMC Public Health. 2020;20:274. PubMed PMC

Ghelardi A., Parazzini F., Martella F., et al. SPERANZA project: HPV vaccination after treatment for CIN2+ Gynecol Oncol. 2018;151:229–234. PubMed

Gómez De La Rosa A.G., Quesada López-Fe A., Vilar Chesa M., et al. Efficacy of human papillomavirus vaccination 4 Years after conization for high-grade cervical neoplasia. J Low Genit Tract Dis. 2021;25:287–290. PubMed

Chen M., Li C., Cui Q., Zhou C., Chen P., Yao S. The efficacy of human papillomavirus prophylactic vaccination after conization in preventing cervical intraepithelial neoplasia recurrence: a prospective observational study in China. Eur J Obstet Gynecol Reprod Biol. 2023;286:10–15. PubMed

Casajuana-Pérez A., Ramírez-Mena M., Ruipérez-Pacheco E., et al. Effectiveness of prophylactic human papillomavirus vaccine in the prevention of recurrence in women conized for HSIL/CIN 2-3: the VENUS study. Vaccines. 2022;10:288. PubMed PMC

Shiravani Z., Nazari Z., Yazdani F., et al. Evaluation of the therapeutic effect of quadrivalent human papillomavirus (HPV) vaccination on cervical intraepithelial neoplasia lesions. Indian J Surg Oncol. 2023;14:504–509. PubMed PMC

Sand F.L., Kjaer S.K., Frederiksen K., Dehlendorff C. Risk of cervical intraepithelial neoplasia grade 2 or worse after conization in relation to HPV vaccination status. Intl J Cancer. 2020;147:641–647. PubMed

Rykkelid M., Wennberg H.M., Richardsen E., Sørbye S.W. Post-Conization HPV vaccination and its impact on viral status: a retrospective cohort study in troms and finnmark, 2022. Pathogens. 2024;13:381. PubMed PMC

Paradkar P.H., Joshi J.V., Mertia P.N., Agashe S.V., Vaidya R.A. Role of cytokines in genesis, progression and prognosis of cervical cancer. Asian Pac J Cancer Prev. 2014;15:3851–3864. PubMed

Mortezaee K. Immune escape: a critical hallmark in solid tumors. Life Sci. 2020;258 PubMed

Saftlas A.F., Spracklen C.N., Ryckman K.K., et al. Influence of a loop electrosurgical excision procedure (LEEP) on levels of cytokines in cervical secretions. J Reprod Immunol. 2015;109:74–83. PubMed

Zhuang C.-L., Lin Z.-J., Bi Z.-F., et al. Inflammation-related adverse reactions following vaccination potentially indicate a stronger immune response. Emerg Microb Infect. 2021;10:365–375. PubMed PMC

Wu S., Ploner A., Astorga Alsina A.M., Deng Y., Ask Schollin L., Lei J. Effectiveness of quadrivalent human papillomavirus vaccination against high-grade cervical lesions by age and doses: a population-based cohort study. Lancet Reg Health Eur. 2025;49 PubMed PMC