Towards the elimination of cervical cancer: HPV epidemiology, real-world experiences and the potential impact of the 9-valent HPV vaccine

Objectives: This review aims to describe the biology of human papillo-mavirus (HPV), the development of the related vaccine, real-life experiences from the perspective of the WHO's call on the elimination of cervical cancer, the vaccine's use as an adjuvant to treatments for HPV-related disease, and the international scientific societies' guidelines on HPV vaccination. A systematic review was conducted, also for the specific purpose of assessing the efficacy, immunogenicity and safety of the 9-valent HPV vaccine (the latest to become available). Data sources and study selection methods: PubMed was the primary source of data for this review, while additional information, such as scientific society guidelines, was found by directly searching the web. Publications were eligible if they had at least one result relating to the immunogenicity, safety and efficacy or effectiveness of HPV vaccines. Tabulation, integration and results: The search in the database for this systematic review yielded 266 records, none of which was a duplicate. A first screening procedure excluded 228 publications. Of the remaining 38 potentially eligible publications, 26 were ultimately included in the systematic review. Conclusion: While progress in vaccine development has added more tools to HPV vac-cination programs, real-word studies have started to show the benefits of mass vaccination campaigns using bivalent and quadrivalent vaccines. National vaccination programs have also been a testing ground for gender-neutral vaccination—a strategy on which unanimous consensus may not still be lacking, but which undeniably responds to clinical and ethical needs. Much the same can be said of post-treatment vaccination—a relatively new, but promising practice that will certainly have a role in achieving the elimination of cervical cancer.

Human papillomavirus; Cervical cancer; Genital warts; Vaccination; 9-valent

[1] Harden ME, Munger K. Human papillomavirus molecular biology. Mutation Research/Reviews in Mutation Research. 2017; 772: 3–12.

[2] Doorbar J, Quint W, Banks L, Bravo IG, Stoler M, Broker TR, et al. The biology and life-cycle of human papillomaviruses. Vaccine. 2012; 30: F55–F70.

[3] Chow LT, Broker TR, Steinberg BM. The natural history of human papillomavirus infections of the mucosal epithelia. Acta Pathologica et Microbiologica Scandinavica. 2010; 118: 422–449.

[4] WHO. Human papillomavirus (HPV) and cervical cancer. 2020. Available at: https://www.who.int/news-room/fact-sheets/deta il/human-papillomavirus-(hpv)-and-cervical-cancer (Accessed: 2 March 2021).

[5] CDC. How Many Cancers Are Linked with HPV Each Year? 2020. Available at: https://www.cdc.gov/cancer/hpv/statistics/cases.ht m (Accessed: 2 March 2021).

[6] Majewski S, Jablonska S. Human papillomavirus-associated tumors of the skin and mucosa. Journal of the American Academy of Dermatology. 1997; 36: 659–658.

[7] Serrano B, Brotons M, Bosch FX, Bruni L. Epidemiology and burden of HPV-related disease. Best Practice & Research. Clinical Obstetrics & Gynaecology. 2018; 47: 14–26.

[8] Plummer M, de Martel C, Vignat J, Ferlay J, Bray F, Franceschi S. Global burden of cancers attributable to infections in 2012: a synthetic analysis. The Lancet Global Health. 2016; 4: e609–e616.

[9] HPV Information Center. Human Papillomavirus and Related Diseases Report. 2021. Available at: www.hpvcentre.net (Accessed: 2 March 2021)

[10] Hartwig S, St Guily JL, Dominiak-Felden G, Alemany L, de Sanjosé S. Estimation of the overall burden of cancers, precancerous lesions, and genital warts attributable to 9-valent HPV vaccine types in women and men in Europe. Infectious Agents and Cancer. 2017; 12: 12–19.

[11] AIOM. I numeri del cancro in Italia 2020 AIOM AIRTUM. 2020. Available at: https://www.aiom.it/wp-content/uploads /2020/10/2020_Numeri_Cancro-operatori-web.pdf (Accessed: 24 February 2021). (In Italian)

[12] AIOM. I numeri del cancro in Italia 2019 AIOM AIRTUM. 2019.Available at: https://www.aiom.it/i-numeri-del-cancro-i

n- italia/ (Accessed: 24 February 2021). (In Italian)

[13] WHO. IARC Monographs on the identification of carcinogenic hazards to humans. 2020. Available at: https://monographs.iarc. fr/list-of-classifications (Accessed: 24 February 2021).

[14] Ramoz N, Rueda L, Bouadjar B, Montoya L, Orth G, Favre M. Mutations in two adjacent novel genes are associated with epider-modysplasia verruciformis. Nature Genetics. 2002; 32: 579–581.

[15] de Sanjose S, Quint WG, Alemany L, Geraets DT, Klaustermeier JE, Lloveras B, et al. Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional world-wide study. The Lancet Oncology. 2010; 11: 1048–1056.

[16] de Martel C, Plummer M, Vignat J, Franceschi S. Worldwide burden of cancer attributable to HPV by site, country and HPV type. International Journal of Cancer. 2017; 141: 664–670.

[17] Wiley DJ, Douglas J, Beutner K, Cox T, Fife K, Moscicki A, et al. External genital warts: diagnosis, treatment, and prevention. Clinical Infectious Diseases. 2002; 35: S210–S224.

[18] Gilson R, Nugent D, Werner RN, Ballesteros J, Ross J. 2019 IUSTI‐Europe guideline for the management of anogenital warts. Journal of the European Academy of Dermatology and Venereology. 2020; 34: 1644–1653.

[19] Chapman R, Soldan K, Jit M. Modelling borderline and mild dys-plasia associated with HPV 6 and 11 infection. Vaccine. 2011; 29: 2881–2886.

[20] Srodon M, Stoler MH, Baber GB, Kurman RJ. The distribution of low and high-risk HPV types in vulvar and vaginal intraepithelial neoplasia (VIN and VaIN). The American Journal of Surgical Pathology. 2006; 30: 1513–1518.

[21] Vaccarella S, Lortet-Tieulent J, Plummer M, Franceschi S, Bray F. Worldwide trends in cervical cancer incidence: impact of screening against changes in disease risk factors. European Journal of Cancer. 2013; 49: 3262–3273.

[22] McNeil C. Who invented the VLP cervical cancer vaccines? Jour-nal of the National Cancer Institute. 2006; 98: 433.

[23] FDA. Approval Letter—Human Papillomavirus Quadrivalent (Types 6, 11, 16, 18) Vaccine, Recombinant. 2006. Available at: https://www.fda.gov/vaccines-blood-biologics/vaccine s/gardasil (Accessed: 2 March 2021).

[24] EMEA. Scientific Discussion. Document for Reg-istration of Gardasil to EMEA. 2006. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EP AR__Scientific_Discussion/human/000703/WC500021140.pdf (Accessed: 2 March 2021).

[25] EMEA. Scientific discussion, document for regis-tration of Cervarix to EMEA. 2007. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EP AR__Scientific_Discussion/human/000721/WC500024636.pdf (Accessed: 2 March 2021).

[26] Food and Drug Administration. Clinical Review of Biologics Li-cense Application for Human Papillomavirus 16, 18 L1 Virus Like Particle Vaccine, AS04 Adjuvant-Adsorbed (Cervarix). 2009. Available at: http://www.fda.gov/downloads/BiologicsBloodVa ccines/Vaccines/ApprovedProducts/UCM237976.pdf (Accessed: 2 March 2021).

[27] European Medicines Agency. Cervarix. 2009. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/cerv arix#product-information-section (Accessed: 10 March 2021).

[28] European Medicines Agency. Gardasil. 2008. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/gardasil (Ac-cessed: 10 March 2021).

[29] Petrosky E, Bocchini JA, Hariri S, Chesson H, Curtis CR, Saraiya M, et al. Use of 9-valent human papillomavirus (HPV) vaccine: up-dated HPV vaccination recommendations of the advisory committee on immunization practices. MMWR. Morbidity and Mortality Weekly Report. 2015; 64: 300–304.

[30] European Medicines Agency. Gardasil 9. Authorisation Details. 2015. Available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/003852/human_med_ 001863.jsp&mid=WC0b01ac058001d124 (Accessed: 10 March 2021).

[31] European Medicines Agency. Gardasil 9. 2015. Available at: https: //www.ema.europa.eu/en/medicines/human/EPAR/gardasil-9 (Accessed: 10 March 2021).

[32] Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. The British Medical Journal. 2021; 372: n71.

[33] Joura EA, Giuliano AR, Iversen O, Bouchard C, Mao C, Mehlsen J, et al. A 9-valent HPV vaccine against infection and intraepithelial neoplasia in women. The New England Journal of Medicine. 2015; 372: 711–723.

[34] Kosalaraksa P, Mehlsen J, Vesikari T, Forstén A, Helm K, Van Damme P, et al. An open-label, randomized study of a 9-valent human papillomavirus vaccine given concomitantly with diphtheria, tetanus, pertussis and poliomyelitis vaccines to healthy adolescents 11- 15 years of age. The Pediatric Infectious Disease Journal. 2015; 34: 627–634.

[35] Vesikari T, Brodszki N, van Damme P, Diez-Domingo J, Icardi G, Petersen LK, et al. A Randomized, Double-Blind, Phase III Study of the Immunogenicity and Safety of a 9-Valent Human Papillo-mavirus L1 Virus-Like Particle Vaccine (V503) Versus Gardasil® in 9-15-Year-Old Girls. The Pediatric Infectious Disease Journal. 2015; 34: 992–998.

[36] Van Damme P, Olsson SE, Block S, Castellsague X, Gray GE, Herrera T, et al. Immunogenicity and Safety of a 9-Valent HPV Vaccine. Pediatrics. 2015; 136: e28–e39.

[37] Castellsagué X, Giuliano AR, Goldstone S, Guevara A, Mogensen O, Palefsky JM, et al. Immunogenicity and safety of the 9-valent HPV vaccine in men. Vaccine. 2015; 33: 6892–6901.

[38] Schilling A, Parra MM, Gutierrez M, Restrepo J, Ucros S, Herrera T, et al. Coadministration of a 9-Valent Human Papillomavirus Vaccine with Meningococcal and Tdap Vaccines. Pediatrics. 2015; 136: e563–e572.

[39] Garland SM, Cheung T, McNeill S, Petersen LK, Romaguera J, Vazquez-Narvaez J, et al. Safety and immunogenicity of a 9-valent HPV vaccine in females 12-26 years of age who previously received the quadrivalent HPV vaccine. Vaccine. 2015; 33: 6855–6864.

[40] Van Damme P, Meijer CJLM, Kieninger D, Schuyleman A, Thomas S, Luxembourg A, et al. A phase III clinical study to compare the immunogenicity and safety of the 9-valent and quadrivalent HPV vaccines in men. Vaccine. 2016; 34: 4205–4212.

[41] Iversen O, Miranda MJ, Ulied A, Soerdal T, Lazarus E, Chokephaibulkit K, et al. Immunogenicity of the 9-Valent HPV Vaccine Using 2-Dose Regimens in Girls and Boys vs a 3-Dose Regimen in Women. Journal of the American Medical Association. 2016; 316: 2411–2421.

[42] Iwata S, Murata S, Rong Han S, Wakana A, Sawata M, Tanaka Y. Safety and Immunogenicity of a 9-Valent Human Papillomavirus Vaccine Administered to 9- to 15-Year-Old Japanese Girls. Japanese Journal of Infectious Diseases. 2017; 70: 368–373.

[43] Guevara A, Cabello R, Woelber L, Moreira ED, Joura E, Reich O, et al. Antibody persistence and evidence of immune memory at 5 years following administration of the 9-valent HPV vaccine. Vaccine. 2016; 35: 5050–5057.

[44] Huh WK, Joura EA, Giuliano AR, Iversen O, de Andrade RP, Ault KA, et al. Final efficacy, immunogenicity, and safety analyses of a nine-valent human papillomavirus vaccine in women aged 16–26 years: a randomised, double-blind trial. The Lancet. 2017; 390: 2143–2159.

[45] Landazabal CS, Moro PL, Lewis P, Omer SB. Safety of 9-valent human papillomavirus vaccine administration among pregnant women: Adverse event reports in the Vaccine Adverse Event Reporting System (VAERS), 2014–2017. Vaccine. 2019; 37: 1229–1234.

[46] Donahue JG, Kieke BA, Lewis EM, Weintraub ES, Hanson KE, McClure DL, et al. Near Real-Time Surveillance to Assess the Safety of the 9-Valent Human Papillomavirus Vaccine. Pediatrics. 2019; 144: e20191808.

[47] Olsson S, Restrepo JA, Reina JC, Pitisuttithum P, Ulied A, Varman M, et al. Long-term immunogenicity, effectiveness, and safety of nine-valent human papillomavirus vaccine in girls and boys 9 to 15 years of age: Interim analysis after 8 years of follow-up. Papillomavirus Research. 2020; 10: 100203.

[48] Kjaer SK, Nygård M, Sundström K, Munk C, Berger S, Dzabic M, et al. Long-term effectiveness of the nine-valent human papillomavirus vaccine in Scandinavian women: interim analysis after 8 years of follow-up. Human Vaccines & Immunotherapeutics. 2020; 17: 943–949.

[49] Boey L, Curinckx A, Roelants M, Derdelinckx I, Van Wijngaerden E, De Munter P, et al. Immunogenicity And Safety Of The Nine-Valent Human Papillomavirus Vaccine In Solid Organ Transplant Recipients And Hiv-Infected Adults. Clinical Infectious Diseases. 2021; 73: e661–e671.

[50] Bornstein J, Roux S, Kjeld Petersen L, Huang L, Dobson SR, Pitisuttithum P, et al. Three-Year Follow-up of 2-Dose Versus 3-Dose HPV Vaccine. Pediatrics. 2021; 147: e20194035.

[51] Yih WK, Kulldorff M, Dashevsky I, Maro JC. A Broad Safety Assessment of the 9-Valent Human Papillomavirus Vaccine. American Journal of Epidemiology. 2021; 190: 1253–1259.

[52] Joura EA, Ulied A, Vandermeulen C, Rua Figueroa M, Seppä I, Hernandez Aguado JJ, et al. Immunogenicity and safety of a nine-valent human papillomavirus vaccine in women 27–45 years of age compared to women 16–26 years of age: an open-label phase 3 study. Vaccine. 2021; 39: 2800–2809.

[53] NCIRS. HPV vaccination. 2020. Available at: https://www.ncirs. org.au/public/hpv-vaccination (Accessed: 3 March 2021).

[54] Hall MT, Simms KT, Lew J, Smith MA, Brotherton JM, Saville M, et al. The projected timeframe until cervical cancer elimination in Australia: a modelling study. The Lancet Public Health. 2019; 4: e19–e27.

[55] Brotherton JM, Fridman M, May CL, Chappell G, Saville AM, Gertig DM. Early effect of the HPV vaccination programme on cervical abnormalities in Victoria, Australia: an ecological study. The Lancet. 2011; 377: 2085–2092.

[56] Crowe E, Pandeya N, Brotherton JML, Dobson AJ, Kisely S, Lambert SB, et al. Effectiveness of quadrivalent human papillomavirus vaccine for the prevention of cervical abnormalities: case- control study nested within a population based screening programme in Australia. British Medical Journal. 2014; 348: g1458–g1458.

[57] Robertson G, Robson SJ. Excisional Treatment of Cervical Dys-plasia in Australia 2004–2013: a Population-Based Study. Journal of Oncology. 2016; 2016: 1–5.

[58] Cornall AM, Saville M, Pyman J, Callegari ET, Tan FH, Broth-erton JML, et al. HPV16/18 prevalence in high-grade cervical lesions in an Australian population offered catch-up HPV vaccination. Vaccine. 2020; 38: 6304–6311.

[59] Ali H, Donovan B, Wand H, Read TRH, Regan DG, Grulich AE, et al. Genital warts in young Australians five years into national human papillomavirus vaccination programme: national surveillance data. British Medical Journal. 2013; 346: f2032.

[60] Chow EPF, Read TRH, Wigan R, Donovan B, Chen MY, Bradshaw CS, et al. Ongoing decline in genital warts among young heterosexuals 7 years after the Australian human papillomavirus (HPV) vaccination programme. Sexually Transmitted Infections. 2015; 91: 214–219.

[61] Smith MA, Liu B, McIntyre P, Menzies R, Dey A, Canfell K. Fall in genital warts diagnoses in the general and indigenous Australian population following implementation of a national human papil-lomavirus vaccination program: analysis of routinely collected na-tional hospital data. The Journal of Infectious Diseases. 2015; 211: 91–99.

[62] Herrero R, Wacholder S, Rodríguez AC, Solomon D, González P, Kreimer AR, et al. Prevention of persistent human papillomavirus infection by an HPV16/18 vaccine: a community-based randomized clinical trial in Guanacaste, Costa Rica. Cancer Discovery. 2011; 1: 408–419.

[63] Porras C, Tsang SH, Herrero R, Guillén D, Darragh TM, Stoler MH, et al. Efficacy of the bivalent HPV vaccine against HPV 16/18-associated precancer: long-term follow-up results from the Costa Rica Vaccine Trial. The Lancet Oncology. 2020; 21: 1643–1652.

[64] Baldur-Felskov B, Dehlendorff C, Munk C, Kjaer SK. Early impact of human papillomavirus vaccination on cervical neoplasia–nationwide follow-up of young Danish women. Journal of the Na-tional Cancer Institute. 2014; 106: djt460.

[65] Thamsborg LH, Napolitano G, Larsen LG, Lynge E. Impact of HPV vaccination on outcome of cervical cytology screening in Denmark—a register‐based cohort study. International Journal of Cancer. 2018; 143: 1662–1670.

[66] Thamsborg LH, Napolitano G, Larsen LG, Lynge E. High‐grade cervical lesions after vaccination against human papillomavirus: a Danish cohort study. Acta Obstetricia Et Gynecologica Scandinavica. 2020; 99: 1290–1296.

[67] Mascaro V, Pileggi C, Currà A, Bianco A, Pavia M. HPV vaccination coverage and willingness to be vaccinated among 18–30 year-old students in Italy. Vaccine. 2019; 37: 3310–3316.

[68] Repvbblica Italiana. Piano nazionale prevenzione vaccinale 2017–2019. 2017. Available at: http://www.salute.gov.it/imgs/C_17_ pubblicazioni_2571_allegato.pdf (Accessed: 3 March 2021).

[69] Mennini FS, Fabiano G, Marcellusi A, Sciattella P, Saia M, Cocchio S, et al. Burden of Disease of Human Papillomavirus (HPV): Hospitalizations in the Marche and Veneto Regions. an observational study. Clinical Drug Investigation. 2018; 38: 173–180.

[70] Cocchio S, Prandi GM, Furlan P, Bertoncello C, Fonzo M, Saia M, et al. Timetrend of hospitalizations for anogenital warts in Veneto region in the HPV vaccination era: a cross sectional study (2007–2018). BMC Infectious Diseases. 2020; 20: 857.

[71] Lei J, Ploner A, Elfström KM, Wang J, Roth A, Fang F, et al. HPV Vaccination and the Risk of Invasive Cervical Cancer. New England Journal of Medicine. 2020; 383: 1340–1348.

[72] Mesher D, Soldan K, Howell-Jones R, Panwar K, Manyenga P, Jit M, et al. Reduction in HPV 16/18 prevalence in sexually active young women following the introduction of HPV immunisation in England. Vaccine. 2013; 32: 26–32.

[73] Mesher D, Panwar K, Thomas SL, Beddows S, Soldan K. Continuing reductions in HPV 16/18 in a population with high coverage of bivalent HPV vaccination in England: an ongoing cross-sectional study. BMJ Open. 2016; 6: e009915.

[74] Mesher D, Panwar K, Thomas SL, Edmundson C, Choi YH, Bed-dows S, et al. The Impact of the National HPV Vaccination Program in England Using the Bivalent HPV Vaccine: Surveillance of Type-Specific HPV in Young Females, 2010-2016. The Journal of Infectious Diseases. 2018; 218: 911–921.

[75] Kavanagh K, Pollock KGJ, Potts A, Love J, Cuschieri K, Cubie H, et al. Introduction and sustained high coverage of the HPV bivalent vaccine leads to a reduction in prevalence of HPV 16/18 and closely related HPV types. British Journal of Cancer. 2014; 110: 2804–2811.

[76] Pollock KGJ, Kavanagh K, Potts A, Love J, Cuschieri K, Cubie H, et al. Reduction of low- and high-grade cervical abnormalities associated with high uptake of the HPV bivalent vaccine in Scotland. British Journal of Cancer. 2014; 111: 1824–1830.

[77] CDC. Human Papillomavirus (HPV) ACIP Vaccine Recommendations. 2014. Available at: https://www.cdc.gov/vaccines/hcp/a cip-recs/vacc-specific/hpv.html (Accessed: 10 March 2021).

[78] Hariri S, Bennett NM, Niccolai LM, Schafer S, Park IU, Bloch KC, et al. Reduction in HPV 16/18-associated high grade cervical lesions following HPV vaccine introduction in the United States 2008-2012. Vaccine. 2015; 33: 1608–1613.

[79] Hariri S, Unger ER, Powell SE, Bauer HM, Bennett NM, Bloch KC, et al. The HPV vaccine impact monitoring project (HPV-IMPACT): assessing early evidence of vaccination impact on HPV-associated cervical cancer precursor lesions. Cancer Causes & Control. 2012; 23: 281–288.

[80] Silverberg MJ, Leyden WA, Lam JO, Gregorich SE, Huchko MJ, Kulasingam S, et al. Effectiveness of catch-up human papillomavirus vaccination on incident cervical neoplasia in a us healthcare setting: a population-based case-control study. The Lancet Child & Adolescent Health. 2018; 2: 707–714.

[81] Mix JM, Van Dyne EA, Saraiya M, Hallowell BD, Thomas CC. Assessing Impact of HPV Vaccination on Cervical Cancer Incidence among Women Aged 15–29 Years in the United States, 1999–2017: an Ecologic Study. Cancer Epidemiology Biomarkers & Prevention. 2021; 30: 30–37.

[82] WHO. Weekly epidemiological record. 2009. Available at: ht tps://www.who.int/wer/2009/wer8415.pdf?ua=1 (Accessed: 17 February 2021).

[83] WHO. Weekly epidemiological record. 2014. Available at: ht tps://www.who.int/wer/2014/wer8943.pdf?ua=1 (Accessed: 17 February 2021).

[84] WHO. Weekly epidemiological record. 2017. Available at: https://apps.who.int/iris/bitstream/handle/10665/255353/WE R9219.pdf;jsessionid=F2CC5ABBCA74F69704DDC4E3F152B F64?sequence=1 (Accessed: 17 February 2021).

[85] WHO. WHO Director-General calls for all countries to take ac-tion to help end the suffering caused by cervical cancer. 2018. Available at: https://www.who.int/reproductivehealth/call-to-a ction-elimination-cervical-cancer/en/ (Accessed: 17 February 2021).

[86] WHO. A cervical cancer-free future: First-ever global commitment to eliminate a cancer. 2020. Available at: https: //www.who.int/news/item/17-11-2020-a-cervical-cancer-fre

e- future-first-ever-global-commitment-to-eliminate-a-cancer (Accessed: 17 February 2021).

[87] European Cancer Organisation. Resolution on HPV-Related Cancer Elimination. 2019. Available at: https://www.europeancancer.org/resources/112:resolution

- hpv-related-cancer-elimination.html (Accessed: 10 March 2021).

[88] WHO. Immunization coverage. 2021. Available at: https://www. who.int/news-room/fact-sheets/detail/immunization-coverage (Accessed: 17 February 2021).

[89] Mitchell MF, Tortolero-Luna G, Cook E, Whittaker L, Rhodes-Morris H, Silva E. A randomized clinical trial of cryotherapy, laser vaporization, and loop electrosurgical excision for treatment of squamous intraepithelial lesions of the cervix. Obstetrics and Gynecology. 1998; 92: 737–744.

[90] Kocken M, Helmerhorst TJM, Berkhof J, Louwers JA, Nobbenhuis MAE, Bais AG, et al. Risk of recurrent high-grade cervical intraepithelial neoplasia after successful treatment: a long-term multicohort study. The Lancet Oncology. 2011; 12: 441–450.

[91] Joura EA, Garland SM, Paavonen J, Ferris DG, Perez G, Ault KA, 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. British Medical Journal. 2012; 344: e1401.

[92] Kang WD, Choi HS, Kim SM. 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)? Gynecologic Oncology. 2013; 130: 264–268.

[93] Ghelardi A, Parazzini F, Martella F, Pieralli A, Bay P, Tonetti A, et al. SPERANZA project: HPV vaccination after treatment for CIN2+. Gynecologic Oncology. 2018; 151: 229–234.

[94] Sand FL, Kjaer SK, Frederiksen K, Dehlendorff C. Risk of cervical intraepithelial neoplasia grade 2 or worse after conization in relation to HPV vaccination status. International Journal of Cancer. 2020; 147: 641–647.

[95] Petrillo M, Dessole M, Tinacci E, Saderi L, Muresu N, Capobianco G, et al. Efficacy of HPV Vaccination in Women Receiving LEEP for Cervical Dysplasia: A Single Institution’s Experience. Vac-cines. 2020; 8: 45.

[96] Bogani G, Raspagliesi F, Sopracordevole F, Ciavattini A, Ghe-lardi A, Simoncini T, et al. Assessing the Long-Term Role of Vac-cination against HPV after Loop Electrosurgical Excision Proce-dure (LEEP): A Propensity-Score Matched Comparison. Vaccines. 2020; 8: 717.

[97] Del Pino M, Martí C, Torras I, Henere C, Munmany M, Marimon L, et al. HPV Vaccination as Adjuvant to Conization in Women with Cervical Intraepithelial Neoplasia: A Study under Real-Life Conditions. Vaccines. 2020; 8: 245.

[98] Lichter K, Krause D, Xu J, Tsai SHL, Hage C, Weston E, et al. Adjuvant Human Papillomavirus Vaccine to Reduce Recurrent Cervical Dysplasia in Unvaccinated Women: A Systematic Review and Meta-analysis. Obstetrics & Gynecology. 2020; 135: 1070–1083.

[99] Jentschke M, Kampers J, Becker J, Sibbertsen P, Hillemanns P. Prophylactic HPV vaccination after conization: a systematic review and meta-analysis. Vaccine. 2020; 38: 6402–6409.

[100] Jenco M. Study: Physicians make stronger HPV vaccination recommendations for older children. AAP News. 2019. Available at: https://www.aappublications.org/news/2019/09/16/hp vrecommendation091619 (Accessed: 2 August 2021).

[101] American Cancer Society. Recommendations for Human Papillomavirus (HPV) Vaccine Use. 2020. Available at: https://www.cancer.org/cancer/cancer-causes/infectious-a gents/hpv/acs-recommendations-for-hpv-vaccine-use.html

(Accessed: 2 August 2021).

[102] American Cancer Society. Prevent 6 Cancers with the HPV Vaccine. 2021. Available at: https://www.cancer.org/healthy/hpv-v accine.html (Accessed: 2 August 2021).

[103] Bhatla N, Berek JS, Cuello Fredes M, Denny LA, Grenman S, Karunaratne K, et al. Revised FIGO staging for carcinoma of the cervix uteri. International Journal of Gynecology & Obstetrics. 2019; 145: 129–135.

[104] Arrossi S, Temin S, Garland S, Eckert LO, Bhatla N, Castellsagué X, et al. Primary Prevention of Cervical Cancer: American Society of Clinical Oncology Resource-Stratified Guideline. Journal of Global Oncology. 2017; 3: 611–634.

[105] Verheijen RHM, Mahmood T, Donders G, Redman CWE, Wood P. EBCOG position statement: Gender neutral HPV vac-cination for young adults. European Journal of Obstetrics & Gynecology and Reproductive Biology. 2020; 246: 187–189.

[106] SNLG-ISS. Linee guida condivise per la prevenzione del carcinoma della cervice uterine. Follow-up post trattamento CIN2 e CIN3. 2020. Available at: https://snlg.iss.it/wp-content/uploads/2020/07/LLGG-197-GIS Ci_et_al-vaccino-HPV-20luglio_Racc1.pdf (Accessed: 2 August 2021).