{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T16:48:55Z","timestamp":1785775735596,"version":"3.56.0"},"reference-count":34,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathogens"],"abstract":"<jats:p>Background: Women treated for cervical intraepithelial neoplasia grade 2 (CIN2) face an increased risk of disease recurrence due to persistent or newly acquired human papillomavirus (HPV) infections, suggesting a potential role for adjuvant HPV vaccination. While a growing body of literature evaluates the outcomes of HPV vaccination following a large loop excision of the transformation zone (LLETZ) for high-grade squamous intraepithelial lesions (CIN2\u20133), data specifically focused on isolated CIN2 remain limited. This study aims to evaluate the clinical efficacy of the nonavalent HPV vaccine (9vHPV) as an adjuvant strategy to reduce CIN2+ recurrence in women undergoing LLETZ for histologically confirmed, isolated CIN2. Methods: Between November 2017 and November 2024, women undergoing LLETZ for histologically confirmed CIN2 received their first dose of adjuvant 9vHPV within one month of surgery. Patients who achieved double-negative co-testing (Pap test and high-risk HPV DNA test) at the 6-month post-LLETZ follow-up were included in the study group. Conversely, patients with at least one positive test result at 6 months were excluded to rule out residual disease. The study group underwent a subsequent Pap smear at 12 months and a full co-test at 18 months post-surgery; upon achieving negative results through the 18th month, patients returned to the organized screening program. The primary outcome was the recurrence rate, defined as histologically confirmed CIN2+ occurring more than 6 months post-treatment. It was compared against an unvaccinated historical control group treated with LLETZ prior to the study period. The secondary outcome evaluated the prevalence of HPV genotypes at baseline and at the time of recurrence. Results: In the vaccinated group, 3 women (2.03%) experienced CIN2+ recurrence compared to 6 women (5.71%) in the unvaccinated control group. This represents an absolute risk difference of 3.69% and a relative risk reduction of 64.6%, though the difference did not reach statistical significance via Fisher\u2019s exact test (p = 0.165). In the study group, two recurrences were detected at 18 months (associated cytologies: ASC-H and LSIL; genotypes: HPV 51\/53 and 16, respectively) and one at four years (cytology: HSIL; genotype: HPV 33\/58). In the control group, recurrences occurred at 12 months (n = 3), 18 months (n = 2), and four years (n = 1). Associated cytology revealed HSIL in three cases, ASC-H in one case, LSIL in one case, and ASCUS in the final case. The corresponding HPV genotypes were 16 (two cases), 18, 51, 31 and 56 (co-infection), and one case of high-risk HPV, not further genotyped. Conclusions: Adjuvant 9vHPV administration after LLETZ for isolated CIN2 was associated with a clinically substantial lower absolute recurrence rate (2.03% vs. 5.71%, corresponding to a 64.6% relative risk reduction). Although this reduction did not achieve statistical significance (p=0.165) due to our small sample size and a low baseline recurrence rate in this isolated cohort, the effect size is highly comparable to broader CIN2+ studies. The study was likely underpowered to prove statistical significance, and larger multi-center studies are required to confirm the statistical value of adjuvant vaccination specifically in isolated CIN2 lesions.<\/jats:p>","DOI":"10.3390\/pathogens15080814","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T15:51:23Z","timestamp":1785772283000},"page":"814","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Role of Adjuvant Nonavalent HPV Vaccination After LLETZ in Patients with Isolated CIN2: A Controlled Cohort Study"],"prefix":"10.3390","volume":"15","author":[{"given":"Vincenzo","family":"Pinto","sequence":"first","affiliation":[{"name":"Department of Interdisciplinary Medicine (DIM), Obstetrics and Gynecology Unit, University of Bari \u201cAldo Moro\u201d, Piazza Giulio Cesare 11, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Dellino","sequence":"additional","affiliation":[{"name":"Department of Interdisciplinary Medicine (DIM), Obstetrics and Gynecology Unit, University of Bari \u201cAldo Moro\u201d, Piazza Giulio Cesare 11, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Cerbone","sequence":"additional","affiliation":[{"name":"Department of Interdisciplinary Medicine (DIM), Obstetrics and Gynecology Unit, University of Bari \u201cAldo Moro\u201d, Piazza Giulio Cesare 11, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7675-7171","authenticated-orcid":false,"given":"Edoardo","family":"Di Naro","sequence":"additional","affiliation":[{"name":"Department of Interdisciplinary Medicine (DIM), Obstetrics and Gynecology Unit, University of Bari \u201cAldo Moro\u201d, Piazza Giulio Cesare 11, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Achiropita","family":"Lepera","sequence":"additional","affiliation":[{"name":"Department of Interdisciplinary Medicine (DIM), Obstetrics and Gynecology Unit, University of Bari \u201cAldo Moro\u201d, Piazza Giulio Cesare 11, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4194-0210","authenticated-orcid":false,"given":"Silvio","family":"Tafuri","sequence":"additional","affiliation":[{"name":"Department of Interdisciplinary Medicine (DIM), Public Health Unit, University of Bari \u201cAldo Moro\u201d, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0325-4316","authenticated-orcid":false,"given":"Gerardo","family":"Cazzato","sequence":"additional","affiliation":[{"name":"Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), Pathology Unit, University of Bari \u201cAldo Moro\u201d, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2390-4582","authenticated-orcid":false,"given":"Ettore","family":"Cicinelli","sequence":"additional","affiliation":[{"name":"Department of Interdisciplinary Medicine (DIM), Obstetrics and Gynecology Unit, University of Bari \u201cAldo Moro\u201d, Piazza Giulio Cesare 11, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1038\/nrmicro2872","article-title":"Understanding and Learning from the Success of Prophylactic Human Papillomavirus Vaccines","volume":"10","author":"Schiller","year":"2012","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Cerbone, M., De Vincenzo, R., Auriola, A., Dellino, M., Cascardi, E., Carriero, C., Pinto, V., Maiorano, M.F.P., Baldini, G.M., and Ricci, C. (2026). Colposcopy \u201cUnder the Loupe\u201d: Diagnostic Accuracy of Colposcopic Examination of CIN2+ Lesions: Systematic Review and Meta-Analysis of 141,355 Cases. Cancers, 18.","DOI":"10.3390\/cancers18142239"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1016\/S1470-2045(22)00334-5","article-title":"Comparative Effectiveness and Risk of Preterm Birth of Local Treatments for Cervical Intraepithelial Neoplasia and Stage IA1 Cervical Cancer: A Systematic Review and Network Meta-Analysis","volume":"23","author":"Athanasiou","year":"2022","journal-title":"Lancet Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2048","DOI":"10.1002\/ijc.21604","article-title":"Long-term Risk of Invasive Cervical Cancer after Treatment of Squamous Cervical Intraepithelial Neoplasia","volume":"118","author":"Soutter","year":"2006","journal-title":"Int. J. Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e070135","DOI":"10.1136\/bmj-2022-070135","article-title":"Role of Human Papillomavirus (HPV) Vaccination on HPV Infection and Recurrence of HPV Related Disease after Local Surgical Treatment: Systematic Review and Meta-Analysis","volume":"378","author":"Kechagias","year":"2022","journal-title":"BMJ"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/S1470-2045(11)70078-X","article-title":"Risk of Recurrent High-Grade Cervical Intraepithelial Neoplasia after Successful Treatment: A Long-Term Multi-Cohort Study","volume":"12","author":"Kocken","year":"2011","journal-title":"Lancet Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1177\/09691413231175630","article-title":"The 5-Year Risk of Recurrence of Grade 2\/3 Cervical Intraepithelial Neoplasia after Treatment in a Population Screening Programme by Human Papillomavirus Status: A Cohort Study in Central Italy","volume":"30","author":"Visioli","year":"2023","journal-title":"J. Med. Screen."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1097\/LGT.0000000000000287","article-title":"Loop Electrosurgical Excision Procedure Instead of Cold-Knife Conization for Cervical Intraepithelial Neoplasia in Women with Unsatisfactory Colposcopic Examinations: A Systematic Review and Meta-Analysis","volume":"21","author":"Shazly","year":"2017","journal-title":"J. Low. Genit. Tract. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2084","DOI":"10.1016\/S0140-6736(21)02178-4","article-title":"The Effects of the National HPV Vaccination Programme in England, UK, on Cervical Cancer and Grade 3 Cervical Intraepithelial Neoplasia Incidence: A Register-Based Observational Study","volume":"398","author":"Falcaro","year":"2021","journal-title":"Lancet"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1980","DOI":"10.1111\/aogs.70027","article-title":"Survey of Practices in the European Federation for Colposcopy: HPV Vaccination after Treatment for Cervical Precancerous Lesions","volume":"104","author":"Heinonen","year":"2025","journal-title":"Acta Obstet. Gynecol. Scand."},{"key":"ref_11","first-page":"26","article-title":"Cytological And Histopathological Aspects Concerning Preinvasive Squamous Cervical Lesions","volume":"36","author":"Muntean","year":"2010","journal-title":"Curr. Health Sci. J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1093\/ajcp\/aqae029","article-title":"Interobserver Reproducibility of Cervical Histology Interpretation with and without P16 Immunohistochemistry","volume":"162","author":"Tao","year":"2024","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"k499","DOI":"10.1136\/bmj.k499","article-title":"Clinical Course of Untreated Cervical Intraepithelial Neoplasia Grade 2 under Active Surveillance: Systematic Review and Meta-Analysis","volume":"360","author":"Tainio","year":"2018","journal-title":"BMJ"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1097\/LGT.0000000000000604","article-title":"The Natural History of Cervical Intraepithelial Neoplasia Grades 1, 2, and 3: A Systematic Review and Meta-Analysis","volume":"25","author":"Loopik","year":"2021","journal-title":"J. Low. Genit. Tract. Dis."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Di Donato, V., Caruso, G., Petrillo, M., Kontopantelis, E., Palaia, I., Perniola, G., Plotti, F., Angioli, R., Muzii, L., and Benedetti Panici, P. (2021). Adjuvant HPV Vaccination to Prevent Recurrent Cervical Dysplasia after Surgical Treatment: A Meta-Analysis. Vaccines, 9.","DOI":"10.3390\/vaccines9050410"},{"key":"ref_16","first-page":"CD016121","article-title":"Human Papillomavirus (HPV) Vaccination in Women with Conisation","volume":"2025","author":"Kapp","year":"2025","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Maiorano, M.F.P., Cazzolla, A., Maiorano, B.A., Loizzi, V., Cormio, G., Colonna, G., and Lopez, S. (2026). Impact of HPV Vaccine on CIN2+ Recurrence after Conization: A Systematic Review and Meta-Analysis of Vaccination Timing, Valency and Surgical Margins. Front. Oncol., 16.","DOI":"10.3389\/fonc.2026.1748972"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.ygyno.2018.08.033","article-title":"SPERANZA Project: HPV Vaccination after Treatment for CIN2+","volume":"151","author":"Ghelardi","year":"2018","journal-title":"Gynecol. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"212.e1","DOI":"10.1016\/j.ajog.2016.02.021","article-title":"Impact of Human Papillomavirus (HPV) 16 and 18 Vaccination on Prevalent Infections and Rates of Cervical Lesions after Excisional Treatment","volume":"215","author":"Hildesheim","year":"2016","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e37","DOI":"10.1016\/j.lanogw.2025.100007","article-title":"Adjuvant Prophylactic Human Papillomavirus Vaccination for Prevention of Recurrent High-Grade Cervical Intraepithelial Neoplasia Lesions in Women Undergoing Lesion Surgical Treatment (VACCIN): A Multicentre, Phase 4 Randomised Placebo-Controlled Trial in the Netherlands","volume":"1","author":"Hofhuis","year":"2025","journal-title":"Lancet Obstet. Gynaecol. Women\u2019s Health"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1111\/1471-0528.16081","article-title":"Conservative Management of Women with Cervical Intraepithelial Neoplasia Grade 2 in Denmark: A Cohort Study","volume":"127","author":"Skorstengaard","year":"2020","journal-title":"BJOG"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1111\/aogs.70128","article-title":"HPV Vaccination Following Cervical Intraepithelial Neoplasia Grade 2 Diagnosis and Risk of Progression","volume":"105","author":"Eriksen","year":"2026","journal-title":"Acta Obstet. Gynecol. Scand."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"430.e1","DOI":"10.1016\/j.ajog.2023.11.1235","article-title":"Risk of Progression of Cervical Intraepithelial Neoplasia Grade 2 in Human Papillomavirus-Vaccinated and Unvaccinated Women: A Population-Based Cohort Study","volume":"230","author":"Krog","year":"2024","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1177\/030089160208800609","article-title":"Recurrence after Treatment by Loop Electrosurgical Excision Procedure (LEEP) of High-Grade Cervical Intraepithelial Neoplasia","volume":"88","author":"Cecchini","year":"2002","journal-title":"Tumori"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1002\/ijgo.14340","article-title":"Risk Factors Analysis of Recurrent Disease after Treatment with a Loop Electrosurgical Excision Procedure for High-grade Cervical Intraepithelial Neoplasia","volume":"160","author":"Ding","year":"2023","journal-title":"Intl J. Gynecol. Obs."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Henere, C., Torn\u00e9, A., Llupi\u00e0, A., Aldea, M., Mart\u00ed, C., Glickman, A., Saco, A., Marimon, L., Manzotti, C., and Rakislova, N. (2022). HPV Vaccination in Women with Cervical Intraepithelial Neoplasia Undergoing Excisional Treatment: Insights into Unsolved Questions. Vaccines, 10.","DOI":"10.3390\/vaccines10060887"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2343552","DOI":"10.1080\/21645515.2024.2343552","article-title":"Reduced Risk of CIN2+ Recurrence in Women Immunized with a 9-Valent HPV Vaccine Post-Excision: Retrospective Cohort Study","volume":"20","author":"Pilka","year":"2024","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Anton, E.T.-T., Matasariu, D.R., Ursache, A., Anton, G.-I., Balan, R.A., Ursu, R.-G., Scripcariu, I.-S., C\u0103r\u0103uleanu, A., Pintilescu, C., and Socolov, D.G. (2026). Integrating Adjuvant HPV Vaccination into Cervical Dysplasia Management After LLETZ\/Conization. J. Clin. Med., 15.","DOI":"10.3390\/jcm15093424"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Bruno, M.T., Valenti, G., Ruggeri, Z., Incognito, G.G., Coretti, P., Montana, G.D., Panella, M.M., and Mereu, L. (2024). Correlation of the HPV 16 Genotype Persistence in Women Undergoing LEEP for CIN3 with the Risk of CIN2+ Relapses in the First 18 Months of Follow-Up: A Multicenter Retrospective Study. Diagnostics, 14.","DOI":"10.3390\/diagnostics14050509"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"You, D., Han, L., Li, L., Hu, J., Zimet, G.D., Alias, H., Danaee, M., Cai, L., Zeng, F., and Wong, L.P. (2020). Human Papillomavirus (HPV) Vaccine Uptake and the Willingness to Receive the HPV Vaccination among Female College Students in China: A Multicenter Study. Vaccines, 8.","DOI":"10.3390\/vaccines8010031"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Kiamba, E.W., Goodier, M.R., and Clarke, E. (2025). Immune Responses to Human Papillomavirus Infection and Vaccination. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1591297"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"102913","DOI":"10.1016\/j.jogoh.2025.102913","article-title":"Predictors for Negative Large Loop Excision of the Transformation Zone (LLETZ) in a Primary HPV Screened Population","volume":"54","author":"Parker","year":"2025","journal-title":"J. Gynecol. Obstet. Hum. Reprod."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1186\/s13027-023-00547-2","article-title":"Can Prophylactic HPV Vaccination Reduce the Recurrence of Cervical Lesions after Surgery? Review and Prospect","volume":"18","author":"Han","year":"2023","journal-title":"Infect. Agents Cancer"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Facciol\u00e0, A., Visalli, G., Lagan\u00e0, A., and Di Pietro, A. (2022). An Overview of Vaccine Adjuvants: Current Evidence and Future Perspectives. Vaccines, 10.","DOI":"10.3390\/vaccines10050819"}],"container-title":["Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-0817\/15\/8\/814\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T16:11:24Z","timestamp":1785773484000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-0817\/15\/8\/814"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,1]]},"references-count":34,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["pathogens15080814"],"URL":"https:\/\/doi.org\/10.3390\/pathogens15080814","relation":{},"ISSN":["2076-0817"],"issn-type":[{"value":"2076-0817","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,1]]}}}