Highlights
- HPV vaccination significantly lowers the risk of high-grade cervical intraepithelial neoplasia (CIN2+) in females aged 15–25, especially for vaccine-matched HPV types.
- Gardasil-9 shows the highest probability of reducing anogenital warts in young women.
- No major safety concerns were identified across more than 97,000 participants.
- Evidence for cancer prevention is currently lacking due to limited follow-up duration.
Background
Cervical cancer remains a major cause of cancer-related mortality among women globally, ranking as the fourth leading cause. Persistent infection with high-risk human papillomavirus (HPV) is the primary etiological factor, with multiple HPV types implicated in cervical, vulvar, vaginal, anal, penile, and oropharyngeal cancers. Preventive vaccination aims to elicit protective antibodies against HPV to avert infection and its downstream oncogenic consequences. Despite decades of vaccination programs, clarity remains needed on relative vaccine performance, optimal scheduling, and population-specific benefits.
Study Design
This comprehensive Cochrane network meta-analysis synthesized data from 60 randomized controlled trials (RCTs), encompassing 157,414 participants, with follow-up periods ranging from 7 months to 11 years. Vaccines assessed were World Health Organization (WHO) prequalified products: Cervarix, Gardasil, Gardasil-9, and Cecolin. The analysis incorporated pairwise and network meta-analysis (NMA) approaches, ranking vaccine efficacy using surface under the cumulative ranking curve (SUCRA). Outcomes focused on precancerous lesions (e.g., CIN2+), other HPV-related intraepithelial neoplasias, anogenital warts, treatment rates for pre-invasive disease, and serious adverse events. Risk of bias was assessed via the Cochrane RoB 2 tool, and certainty of evidence graded using GRADE methodology.
Key Findings
Precancerous Outcomes
Across all studies, no cervical cancer cases were detected during follow-up, reflecting the relatively short observation window. In females aged 15–25 years:
- CIN2+ (irrespective of HPV type) incidence was reduced by 30% after six years (RR 0.70, 95% CI 0.56–0.88; moderate certainty).
- For vaccine-matched HPV types, CIN2+ risk dropped by 60% (RR 0.40, 95% CI 0.30–0.54; moderate certainty).
In females over 25 years, Cervarix and Gardasil offered little to no protection against CIN2+ compared with controls.
No CIN2+ data were available for Cecolin.
Vulvar and Vaginal Lesions
Young women receiving Gardasil or Gardasil-9 saw slight reductions in high-grade VIN/VaIN. NMA estimates indicated:
- Gardasil: RR 0.21 (95% CI 0.10–0.45), translating to ~1 case avoided per 1000 participants.
- Gardasil-9: RR 0.16 (95% CI 0.05–0.51), ~0 cases avoided per 1000 participants.
No substantial difference was found between Gardasil, Gardasil-9, and Cervarix in direct comparisons.
Anal and Penile Lesions
In men who have sex with men, Gardasil reduced high-grade anal intraepithelial neoplasia (RR 0.75, 95% CI 0.53–1.07; low certainty). For penile intraepithelial neoplasia, Gardasil showed little to no benefit over controls (RR 1.00, 95% CI 0.20–4.93; low certainty).
Anogenital Warts
Pairwise meta-analysis of three studies (21,271 participants) revealed 25 fewer cases of anogenital warts per 1000 vaccinated participants (RR 0.38, 95% CI 0.32–0.46; high certainty). In NMA, Gardasil-9 ranked highest for wart prevention in females aged 15–25.
Need for Treatment
Five studies (38,606 participants) showed vaccinees required treatment for HPV-related pre-invasive disease 12 fewer times per 1000 participants compared to controls (RR 0.76, 95% CI 0.65–0.89; moderate certainty).
Safety
Across 39 studies (97,272 participants), serious adverse event rates were indistinguishable between vaccine and control groups (RR 0.99, 95% CI 0.94–1.04; high certainty). No signal for vaccine-related safety concerns emerged.
Expert Commentary
These findings reinforce the efficacy of HPV vaccines in preventing high-grade cervical lesions and anogenital warts, with Gardasil-9 performing best for wart prevention in young women. The lack of observed cancers reflects insufficient follow-up time, not ineffectiveness. Importantly, large trial populations and consistent safety signals bolster confidence in widespread vaccination, especially before HPV exposure.
Clinically, prioritizing vaccination in adolescents and young adults — ideally before sexual debut — remains critical. The absence of benefit in women over 25 years suggests immunization efforts should target younger cohorts.
Conclusion
HPV vaccination provides substantial protection against pre-cancerous lesions and anogenital warts, with robust safety data. While cancer prevention evidence is indirect and long-term data are awaited, current results strongly support existing public health recommendations to vaccinate adolescents, particularly females aged 9–14. Future studies should explore efficacy in males under 15 and evaluate Cecolin’s performance.
Funding and ClinicalTrials.gov
Trials were registered across ClinicalTrials.gov, WHO ICTRP, and other registries, with manufacturer support for some RCTs. Data extraction included Clinical Study Reports from the European Medicines Agency.
References
Bergman H, Henschke N, Arevalo-Rodriguez I, Buckley BS, Crosbie EJ, Davies JC, Dwan K, Golder SP, Loke YK, Probyn K, Petkovic J, Villanueva G, Morrison J. Human papillomavirus (HPV) vaccination for the prevention of cervical cancer and other HPV-related diseases: a network meta-analysis. Cochrane Database Syst Rev. 2025 Nov 24;11(11):CD015364. doi: 10.1002/14651858.CD015364.pub2. PMID: 41276263; PMCID: PMC12640750.
