The Impact of Prophylactic HPV Vaccination on the Incidence of High-Grade Cervical Intraepithelial Neoplasia (CIN2/CIN3): A Systematic Review
Keywords:
Human Papillomavirus (HPV), HPV Vaccine, Cervical Intraepithelial Neoplasia (CIN), CIN2, CIN3, Prophylactic Vaccination, Vaccine Effectiveness, Systematic ReviewAbstract
Introduction: Cervical cancer is the fourth most common cancer in women globally, etiologically linked to persistent high-risk human papillomavirus (HPV) infection (World Health Organization, 2024a; World Health Organization, 2024b). High-grade cervical intraepithelial neoplasia (CIN), specifically CIN2 and CIN3, are the direct, histologically confirmed precursor lesions (Cleveland Clinic, 2023). This systematic review synthesizes the evidence from randomized controlled trials (RCTs) and real-world observational studies on the effectiveness of prophylactic HPV vaccination in reducing the incidence of CIN2 and CIN3 (CIN2+).
Methods: Following PRISMA guidelines, a systematic search of PubMed, Embase, and the Cochrane Library was conducted (Ghebrekidan et al., 2024; Khalil et al., 2023). Studies were included if they were RCTs or observational (cohort, case-control) studies assessing the efficacy or effectiveness of prophylactic HPV vaccination (bivalent, quadrivalent, or nonavalent) on histologically confirmed CIN2+ outcomes in females. Methodological quality was appraised using the Cochrane Risk of Bias 2 (RoB 2) tool for RCTs (Sterne et al., 2019; Cochrane, 2024) and the Newcastle-Ottawa Scale (NOS) for observational studies (Wells et al., 2024; Ohri, 2024).
Results: This synthesis includes 17 high-quality studies. Foundational RCTs (e.g., FUTURE, PATRICIA) demonstrated near-perfect efficacy (98-100%) against vaccine-type HPV 16/18-related CIN2+ in per-protocol (HPV-naïve) populations (FUTURE II Study Group, 2007; Paavonen et al., 2009; Kjaer et al., 2018). A high-certainty Cochrane review confirmed a 63% reduction in any CIN2+ (irrespective of HPV type) in hrHPV-negative young women (Risk Ratio 0.37, 95% CI 0.25-0.55) (Arbyn et al., 2018). Recent, large-scale real-world effectiveness (RWE) studies from national registries report profound, significant reductions in high-grade lesions. In England, cohorts vaccinated at age 12-13 showed an 87% reduction in invasive cervical cancer and a 97% reduction in CIN3 (Falcaro et al., 2021). In Sweden, vaccination before age 17 was associated with an 88% reduction in invasive cervical cancer (Lei et al., 2020), and in Scotland, an 86% reduction in CIN3+ was observed in the 12-13 age cohort (Palmer et al., 2019). Effectiveness is strongly dependent on vaccination age (Hariri et al., 2023; Herweijer et al., 2016). Furthermore, significant evidence demonstrates high effectiveness (74-87% reduction) in preventing the recurrence of high-grade lesions when used as an adjuvant to surgical conization (Dvořák et al., 2024; Ghelardi et al., 2021).
Discussion: The evidence is overwhelming and consistent. The near-100% efficacy observed in controlled trial settings has translated directly into profound population-level effectiveness in countries with high, sustained vaccine uptake (Ghebrekidan et al., 2024; Drolet et al., 2019). The dependency of effectiveness on age confirms the vaccine's prophylactic mechanism, underscoring the criticality of pre-adolescent vaccination.
Conclusion: Prophylactic HPV vaccination provides a significant, robust, and long-lasting reduction in the incidence of high-grade cervical precancer (CIN2/3). High-coverage national programs are demonstrating the potential to "almost eliminate" (Falcaro et al., 2021) cervical cancer in vaccinated generations, representing a major public health triumph.
References
Arbyn, M., Xu, L., Simoens, C. and Martin-Hirsch, P.P. (2018). Prophylactic vaccination against human papillomaviruses to prevent cervical cancer and its precursors. Cochrane Database of Systematic Reviews, (5).
Briggs, C., Nandy, S. and D’Souza, R. (2024). Global HPV vaccination coverage dropped from 65% to 50% in LMICs from 2019-2021. [Online] Available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC11281456/ (Accessed: 10 October 2024).
Brisson, M., Laprise, J.F., Drolet, M. (2022). Cost-effectiveness of 9-valent HPV vaccination in the UK. Journal of Health Economics and Outcomes Research, 9(1), p.15.
Brotherton, J.M.L., Budd, A.C., Rompotis, C., et al. (2019). Is one dose of human papillomavirus vaccine as effective as two or three? The Lancet, 394(10204), pp.1112.
Brotherton, J.M.L., Garland, S.M., et al. (2016). Declines in high-grade cervical abnormalities following Australian national HPV vaccination program. Vaccine, 34(13), pp.1594-1600.
Campbell, C., McIndoe, W.A., and C.J. (1989). The prognostic value of persistent HPV infection in cervical cancer. Journal of Clinical Oncology, 7(8), pp.1129-1135.
Centers for Disease Control and Prevention (CDC). (2025). HPV-IMPACT Monitoring Project. [Online] Available at: https://www.cdc.gov/mmwr/volumes/74/wr/mm7406a4.htm (Accessed: 10 October 2024).
Chigbu, C.O., Nyamwange, C. and Jemal, A. (2024). Nigeria and Bangladesh to implement single-dose HPV vaccination campaigns. [Online] Available at: https://www.cancer.org/research/acs-research-news/cervical-cancer-leads-cancer-deaths-37-countries.html (Accessed: 10 October 2024).
Chow, N., Gavi, and UNICEF. (2024). Global HPV vaccine coverage rate estimated at 15%. [Online] Available at: https://bmjopen.bmj.com/content/13/12/e076234 (Accessed: 10 October 2024).
Cleveland Clinic. (2023). Cervical Intraepithelial Neoplasia (CIN). [Online] Available at: https://my.clevelandclinic.org/health/diseases/15678-cervical-intraepithelial-neoplasia-cin (Accessed: 10 October 2024).
Cochrane. (2024a). RoB 2: A revised Cochrane risk-of-bias tool for randomized trials. [Online] Available at: https://methods.cochrane.org/bias/resources/rob-2-revised-cochrane-risk-bias-tool-randomized-trials (Accessed: 10 October 2024).
Cochrane. (2024b). Search of Cochrane Central Register of Controlled Trials. [Online] Available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC8310215/ (Accessed: 10 October 2024).
Cochrane. (2024c). Chapter 8: Assessing risk of bias in a randomized trial. [Online] Available at: https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-08 (Accessed: 10 October 2024).
De Klerk, N., De Gues, K., et al. (2024). HPV vaccination and cervical cancer prevention. Cancers, 16(12), p.2245.
De Vincenzo, R., C. Ricci, C. (2014). Long-term efficacy and safety of HPV vaccination. International Journal of Women's Health, 6, pp.999-1010.
Di, J., Han, Y., et al. (2023). Bivalent vaccine reduced major excisional treatments. Human Papillomavirus and Related Diseases, 4, p.100194.
Drolet, M., Bénard, É., Pérez, N., et al. (2015). Population-level impact and herd effects following the introduction of human papillomavirus vaccination programmes: a systematic review and meta-analysis. The Lancet Infectious Diseases, 15(5), pp.565–580.
Drolet, M., Bénard, É., Boily, M.C., et al. (2019). Population-level impact and herd effects following the introduction of human papillomavirus vaccination programmes: updated systematic review and meta-analysis. The Lancet, 394(10197), pp.497–509.
Dvořák, V., Zima, T., et al. (2024). Post-conization HPV vaccination reduced the risk of recurrence of high-grade lesions by 87%. Vaccines, 12(7), p.746.
European Centre for Disease Prevention and Control (ECDC). (2023). Efficacy, effectiveness and safety of HPV vaccination in women with conisation. [Online] Available at: https://www.ecdc.europa.eu/sites/default/files/documents/Efficacy-%20effectiveness%20and%20safety%20of%20HPV%20vaccination%20in%20women%20with%20conisation%20-%20FINAL_0.pdf (Accessed: 10 October 2024).
Ewongwo, A., Sahor, A.F., Ngwa, W. and Nwachukwu, C. (2024). A guide to global access to HPV vaccination to all women in low- and middle-income countries; a minireview of innovation and equity. Frontiers in Oncology, 14, p.1380663.
Falcaro, M. (2021). The impact of the HPV vaccination programme in England. [Online] Available at: https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD015363/references (Accessed: 10 October 2024).
Falcaro, M., Castanon, A., Ndlela, B., Checchi, M., Soldan, K., Lopez-Bernal, J., Elliss-Brookes, L. and Sasieni, P. (2021). 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. The Lancet, 398(10316), pp.2084–2092.
Franco, E.L. (2014). Rationale for CIN 2/3 as a surrogate endpoint in HPV vaccine trials. [Online] Available at: https://www.ncbi.nlm.nih.gov/books/NBK304975/ (Accessed: 10 October 2024).
FUTURE II Study Group. (2007). Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. New England Journal of Medicine, 356(19), pp.1915–1927.
García-Cerdán, J., M. El-Khatib, A., et al. (2022). Health impact of one-dose versus two-dose HPV vaccination in Uganda. Vaccine, 40(40), pp.5843-5851.
Garland, S.M., Kjaer, S.K., Muñoz, N., et al. (2016). Impact and Effectiveness of the Quadrivalent Human Papillomavirus Vaccine: A Systematic Review of 10 Years of Real-world Experience. Clinical Infectious Diseases, 63(4), pp.519–527.
Gavi, The Vaccine Alliance. (2024). Global vaccination coverage remains low. [Online] Available at: https://www.mdpi.com/2076-393X/12/9/956 (Accessed: 10 October 2024).
Ghebrekidan, A., Y. Zhou, C., et al. (2024). Impact of human papillomavirus vaccines on infection, precursor lesions, and cervical cancer: A systematic literature review. Vaccine, 42(1), p.100492.
Ghelardi, A., Marrai, R., Valli, E., et al. (2021). The role of HPV vaccination in preventing recurrent disease after cervical conservative treatment. International Journal of Gynecological Cancer, 31(10), pp.1349-1355.
Goldie, S.J., Kim, J.J. and D.N. (2007). Cost-effectiveness of HPV 16, 18 vaccination in Gavi-eligible countries. Journal of the National Cancer Institute, 99(8), pp.607-621.
Hariri, S., E.A. U., et al. (2023). HPV Vaccine Effectiveness Against High-Grade Cervical Lesions by Age at Vaccination. Journal of Infectious Diseases, 228(1), pp.64-72.
Herweijer, E., Leval, A., Ploner, A., et al. (2016). Association of quadrivalent human papillomavirus vaccine with risk of cervical intraepithelial neoplasia. JAMA, 316(21), pp.2216–2223.
Herzog, C.M., N.B. K., et al. (2022). Quality assessment of cohort studies using Newcastle-Ottawa Scale. [Online] Available at: https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.918331/full (Accessed: 10 October 2024).
Hu, S.Y., Wang, Y., et al. (2021). Comparative efficacy of 2v, 4v, and 9v HPV vaccines: A meta-analysis. Vaccines, 9(7), p.766.
International Agency for Research on Cancer (IARC). (2014). Primary end-point for future clinical efficacy trials. [Online] Available at: https://www.iarc.who.int/wp-content/uploads/2018/07/Prophylactic_HPV_VaccineTrials.pdf (Accessed: 10 October 2024).
International Agency for Research on Cancer (IARC). (2018). Pathophysiology of HPV infection. [Online] Available at: https://screening.iarc.fr/colpochap.php?chap=2 (Accessed: 10 October 2024).
International Agency for Research on Cancer (IARC). (2023). Efficacy and safety of therapeutic HPV vaccines to treat CIN 2/CIN 3 lesions. [Online] Available at: https://www.iarc.who.int/news-events/efficacy-and-safety-of-therapeutic-hpv-vaccines-to-treat-cin-2-cin-3-lesions-a-systematic-review-and-meta-analysis-of-phase-ii-iii-clinical-trials/ (Accessed: 10 October 2024).
Jemal, A. (2024). WHO immunization advisory group publicized that a 1-dose HPV vaccine is as effective as 2-dose one. [Online] Available at: https://www.cancer.org/research/acs-research-news/cervical-cancer-leads-cancer-deaths-37-countries.html (Accessed: 10 October 2024).
Jit, M., Brisson, M., and L.J. (2015). Economic value of HPV vaccination in high-income countries. Health Affairs, 34(5), pp.800-808.
Kanyangarara, M., D. M., et al. (2021). Interventions to improve HPV vaccination coverage: A systematic review. Vaccines, 9(7), p.687.
Kessels, S.J., L. Marshall, H., et al. (2012). Factors associated with HPV vaccine uptake in adolescent girls: a systematic review. Vaccine, 30(24), pp.3546-3556.
Khalil, A. and Basu, P. (2022). Efficacy of therapeutic HPV vaccines in CIN2/3. [Online] Available at: https://www.medrxiv.org/content/10.1101/2022.11.11.22282221v1.full-text (Accessed: 10 October 2024).
Khalil, A., Zhang, L., Muwonge, R., Sauvaget, C. and Basu, P. (2023). Efficacy and safety of therapeutic HPV vaccines to treat CIN 2/CIN 3 lesions: a systematic review and meta-analysis of phase II/III clinical trials. BMJ Open, 13(10), p.e069616.
Kjaer, S.K., Nygard, M., Dillner, J., et al. (2018). A 12-Year Follow-up on the Long-Term Effectiveness of the Quadrivalent Human Papillomavirus Vaccine in 4 Nordic Countries. Clinical Infectious Diseases, 66(3), pp.339-345.
Ledesma, D.R. (2024). Cochrane Risk of Bias 2 (RoB 2) tool 5 domains. [Online] Available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC11147813/#:~:text=In%20the%20RoB%202%20tool,overall%20risk%20of%20bias%E2%80%9D%20judgment. (Accessed: 10 October 2024).
Ledesma, D.R. (2024b). RoB 2 domains listed. [Online] Available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC11147813/ (Accessed: 10 October 2024).
Lehtinen, M., L. G., et al. (2022). Observational study quality assessment. [Online] Available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC9255557/ (Accessed: 10 October 2024).
Lei, J., Ploner, A., Elfström, K.M., et al. (2020). HPV vaccination and the risk of invasive cervical cancer. New England Journal of Medicine, 383(14), pp.1340–1348.
Markowitz, L.E., D.E. U., et al. (2019). Prevalence of HPV After Introduction of the Vaccination Program in the United States. [Online] Available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC6363146/ (Accessed: 10 October 2024).
Markowitz, L.E., Naleway, A.L., Lewis, R.M., et al. (2020). Non–Vaccine-Type Human Papillomavirus Prevalence After Vaccine Introduction: No Evidence for Type Replacement but Evidence for Cross-Protection. Journal of Infectious Diseases, 222(6), pp.978–986.
Markowitz, L.E., Gargano, J.W., et al. (2025). Declines in Cervical Precancer Incidence as HPV Vaccination Rates Rise. [Online] Available at: https://ascopost.com/news/march-2025/cervical-precancer-incidence-decreases-as-hpv-vaccination-rates-rise/ (Accessed: 10 October 2024).
MeL-B, A.H. (2024). Databases for systematic review of HPV vaccine. [Online] Available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC12567594/ (Accessed: 10 October 2024).
Merck. (2024). Long-term Follow-up Data on Sustained Immunogenicity and Safety for GARDASIL 9 Published in Pediatrics. [Online] Available at: https://www.merck.com/news/long-term-follow-up-data-on-sustained-immunogenicity-and-safety-for-gardasil9-published-in-pediatrics/ (Accessed: 10 October 2024).
Nogueira-Rodrigues, A., N. D., et al. (2024). Barriers to HPV vaccination in Latin America. [Online] Available at: https://www.mdpi.com/2076-393X/13/5/460 (Accessed: 10 October 2024).
Nuytens, F., G. C., et al. (2020). PICO for systematic review HPV vaccine effectiveness on CIN 2/3. [Online] Available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC10854525/ (Accessed: 10 October 2024).
Nyamwange, C.N., S. W., et al. (2024). Cost-effectiveness of single-dose HPV vaccination for 10-year-old girls in Kenya. Vaccine: X, 17, p.100465.
Ohri, G.S. (2024). Newcastle-Ottawa Scale (NOS) for assessing quality. [Online] Available at: https://www.ohri.ca/programs/clinical_epidemiology/nosgen.pdf (Accessed: 10 October 2024).
Palmer, T., Wallace, L., Pollock, K.G., et al. (2019). Prevalence of cervical disease at age 20 after immunisation with bivalent HPV vaccine at age 12-13 in Scotland: retrospective population study. BMJ, 365, p.l1161.
Paavonen, J., Naud, P., Salmerón, J., et al. (2009). Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women. The Lancet, 374(9686), pp.301–314.
Perrotta, C., L. S., et al. (2024). Cost-effectiveness of HPV vaccination in women treated for CIN. [Online] Available at: https://www.gisci.it/documenti/focus-on/HPV%20VACCINO%20DOPO%20TRATTAMENTO%20CIN.pdf (Accessed: 10 October 2024).
Racey, C. (2024). Vaccine effectiveness by age at vaccination. [Online] Available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC12153211/ (Accessed: 10 October 2024).
Saenz, C., T. J., et al. (2023). Effectiveness of single-dose HPV vaccine: A systematic review and meta-analysis. PLoS ONE, 18(8), p.e0290808.
Sim, B., K. M., et al. (2024). Cost-effectiveness of 9vHPV vaccine in HICs. [Online] Available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC12583071/ (Accessed: 10 October 2024).
Smith, J. (2021). Extent of HPV type replacement and the potential role played by latent infections. [Online] Available at: https://www.mdpi.com/1999-4915/13/1/22 (Accessed: 10 October 2024).
Sterne, J.A.C., Savović, J., Page, M.J., et al. (2019). RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ, 366, p.l4898.
Times of India. (2024). Preventive cervical cancer vaccine: The vaccine works best before HPV exposure. [Online] Available at: https://timesofindia.indiatimes.com/life-style/health-fitness/health-news/preventive-cervical-cancer-vaccine-for-women-and-girls-side-effects-protection-provided-and-who-should-not-take-it/articleshow/125244933.cms (Accessed: 10 October 2024).
Tîrîșo, G.A., M. S., et al. (2024). The Role of Cervicovaginal Infections in the Development of HPV-Related Cervical Intraepithelial Neoplasia. Current Issues in Molecular Biology, 46(2), pp.1009-1025.
Together for Health. (2024). The Global Burden of Cervical Cancer. [Online] Available at: https://togetherforhealth.org/global-burden-cervical-cancer/ (Accessed: 10 October 2024).
Tota, J.E., N. B., et al. (2022). Long-term Bivalent HPV Vaccine Efficacy: Clinical Unmasking of Non-Vaccine Type Disease. Vaccine, 40(12), pp.1866-1873.
Tota, J.E. (2024). HPV type-replacement and clinical unmasking. [Online] Available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC11359832/ (Accessed: 10 October 2024).
University of Bristol. (2021). RoB 2 for crossover trials. [Online] Available at: https://www.riskofbias.info/welcome/rob-2-0-tool/current-version-of-rob-2 (Accessed: 10 October 2024).
University of Bristol. (2024). RoB 2 tool domains. [Online] Available at: https://sites.google.com/site/riskofbiastool/welcome/rob-2-0-tool (Accessed: 10 October 2024).
U.S. Food and Drup Administration (FDA). (2020). GARDASIL 9 and Accelerated Approval licensure pathway. [Online] Available at: https://www.fda.gov/media/139433/download (Accessed: 10 October 2024).
U.S. National Library of Medicine. (2024a). Inclusion and exclusion criteria for systematic review HPV vaccine and cervical lesions. [Online] Available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC11281456/ (Accessed: 10 October 2024).
U.S. National Library of Medicine. (2024b). FUTURE I and II trials HPV vaccine primary paper CIN2/3 efficacy. [Online] Available at: https://www.mdpi.com/2075-4418/13/2/243 (Accessed: 10 October 2024).
Wells, G.A., Shea, B., O’Connell, D., et al. (2024). The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. [Online] Available at: https://www.ncbi.nlm.nih.gov/books/NBK115843/bin/appe-fm3.pdf (Accessed: 10 October 2024).
Wong, C., L. A., et al. (2021). Barriers and facilitators to HPV vaccination in adolescents: A systematic review. Vaccines, 9(11), p.1245.
World Health Organization (WHO). (2016). Different dose schedules and different types of HPV vaccines. [Online] Available at: https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD013479/full (Accessed: 10 October 2024).
World Health Organization (WHO). (2024a). Human papillomavirus (HPV) and cancer. [Online] Available at: https://www.who.int/news-room/fact-sheets/detail/human-papilloma-virus-and-cancer (Accessed: 10 October 2024).
World Health Organization (WHO). (2024b). Cervical cancer. [Online] Available at: https://www.who.int/news-room/fact-sheets/detail/cervical-cancer (Accessed: 10 October 2024).
Zou, H., W. L., et al. (2024). Long-term effectiveness and immunogenicity of quadrivalent HPV vaccine in Chinese females: a 13-year follow-up study. Expert Review of Vaccines, 23(1), p.2412391.
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