Highlights
– A large randomized trial (ESCUDDO; NCT03180034) compared one versus two doses of bivalent and nonavalent HPV vaccines in girls 12–16 years and found one dose was noninferior to two doses for preventing persistent HPV16/18 infection over 5 years.
– Rate differences between one and two doses were small and within the prespecified noninferiority margin (bivalent: -0.13 per 100; nonavalent: 0.21 per 100). Vaccine effectiveness relative to an unvaccinated survey exceeded 97% in each group.
– No safety concerns were identified. Findings have major implications for global vaccine delivery, equity, and cervical cancer prevention strategies, while longer-term disease and population-level impacts require further study.
Background and Disease Burden
Human papillomavirus (HPV) types 16 and 18 cause the majority of cervical cancers worldwide. Prophylactic HPV vaccines (bivalent, quadrivalent, and nonavalent formulations) are highly effective against vaccine-type infection and precancerous cervical lesions when given in multidose schedules. Despite proven efficacy, vaccine uptake remains suboptimal in many countries due to cost, logistical challenges of delivering multi-dose schedules, and limited health-system capacity. Simplified schedules that maintain effectiveness could increase coverage, reduce program costs, and accelerate reductions in HPV-related cancers, particularly in low- and middle-income countries (LMICs).
Study Design
The ESCUDDO trial (ClinicalTrials.gov NCT03180034) is a randomized, controlled, multicentre noninferiority study reported by Kreimer et al. (N Engl J Med. 2025). Girls aged 12–16 years were randomized in a 1:1:1:1 ratio to receive either one or two doses of a bivalent HPV vaccine or one or two doses of a nonavalent HPV vaccine. The primary outcome was incident infection with HPV type 16 or 18 occurring between month 12 and month 60 that persisted for at least 6 months. The prespecified noninferiority margin was 1.25 infections per 100 participants (i.e., an allowable absolute difference up to 1.25 per 100). A nonrandomized contemporaneous survey of unvaccinated girls and women (n = 3005) was used to estimate vaccine effectiveness relative to unvaccinated populations.
Key Findings
Enrollment and follow-up: A total of 20,330 participants were randomized into the four trial arms and followed for up to 5 years (60 months). The separate unvaccinated survey enrolled 3005 participants to provide contextual background incidence for effectiveness comparisons.
Primary noninferiority analysis
One dose was noninferior to two doses for prevention of persistent HPV16 or HPV18 infection.
- Bivalent vaccine: rate difference (one dose minus two doses) = -0.13 infections per 100 participants (95% CI, -0.45 to 0.15). P < 0.001 for noninferiority.
- Nonavalent vaccine: rate difference = 0.21 infections per 100 participants (95% CI, -0.09 to 0.51). P < 0.001 for noninferiority.
Interpretation: The point estimates are very close to zero, and the 95% confidence intervals lie wholly within the prespecified noninferiority margin of 1.25 per 100, supporting noninferiority of a single dose compared with two doses for the prespecified endpoint.
Vaccine effectiveness compared with unvaccinated survey
Across all four trial groups (bivalent one dose, bivalent two doses, nonavalent one dose, nonavalent two doses), vaccine effectiveness against HPV16 or HPV18 infection was reported to be at least 97% relative to the unvaccinated survey cohort. This large magnitude of protection underscores the clinical relevance of the prevention of persistent infection.
Safety
No safety concerns were identified in the trial. Adverse event rates did not indicate any new or unexpected safety signals associated with the single-dose schedules.
Strengths of the Trial
- Large sample size and randomized design reduce bias and increase precision for the noninferiority comparison.
- Clinically meaningful primary endpoint (persistent infection with high-risk types 16/18), measured over five years, is a valid intermediate outcome on the causal pathway to cervical precancer and cancer.
- Head-to-head evaluation of bivalent and nonavalent formulations enhances generalizability across vaccine platforms.
- Concurrent unvaccinated survey allowed estimation of vaccine effectiveness against background incidence.
Limitations and Considerations
- Endpoint versus disease: The primary endpoint was persistent HPV16/18 infection (≥6 months). While persistent infection is a necessary precursor to cervical intraepithelial neoplasia and cancer, the trial did not report clinical disease endpoints such as CIN2+ or cancer; such outcomes require longer follow-up to assess the full clinical impact of single-dose vaccination.
- Duration of protection: Follow-up was 5 years. Longer-term follow-up will be essential to determine durability of protection and whether waning occurs beyond the observation window.
- Age and sex generalizability: The trial enrolled girls 12–16 years. Extrapolation to older adolescents, young adults, or males requires caution. Immune responses and epidemiology may differ in other populations.
- HPV type coverage: The nonavalent vaccine covers additional oncogenic HPV types beyond 16/18; this trial’s primary endpoint focused on 16/18, so effects on non-16/18 types require separate consideration.
- Contextual implementation: Effectiveness comparisons relied on a nonrandomized unvaccinated survey; differences in behavior or exposure between groups may influence absolute effectiveness estimates, although randomized comparisons internally validate the one-dose versus two-dose question.
Biological Plausibility and Supporting Evidence
Immunologic data from prior studies indicate that a single dose of HPV vaccine can elicit robust antibody responses and immunologic memory in adolescents and young adults. Observational analyses from earlier vaccine trials and programmatic data suggested sustained antibody levels and reduced infection rates after a single dose, prompting randomized evaluations. The ESCUDDO trial provides the most definitive randomized evidence to date that a single dose can prevent persistent vaccine-type infection over several years.
Clinical and Public Health Implications
Policy and programmatic implications of a validated single-dose HPV schedule are profound, particularly for LMICs where cervical cancer burden is highest and vaccine access is limited by cost and delivery constraints. Potential advantages include:
- Increased coverage: Removing the requirement for a second clinic visit can substantially improve completion rates.
- Cost savings: Single-dose schedules reduce the per-person cost of vaccine procurement and delivery, allowing reallocation of resources toward expanding age cohorts or including boys.
- Simplified logistics: Lower cold chain needs, reduced administrative burden, and easier integration into existing school-based or single-contact campaigns.
- Equity gains: Faster scale-up in resource-limited settings could narrow disparities in cervical cancer prevention.
Nevertheless, policymakers should balance these potential benefits against remaining uncertainties (durability beyond 5 years, disease endpoints, and applicability to other populations). Where feasible, national immunization technical advisory groups may consider phased implementation with robust surveillance for infection, precancerous lesions, and programmatic outcomes.
Expert Commentary and Guideline Context
Leading vaccine scientists and public health authorities have closely followed accumulating evidence about single-dose regimens. The ESCUDDO trial provides randomized, high-quality evidence that can inform guideline updates. Any change in global recommendations will weigh randomized trial data together with immunologic studies, programmatic feasibility, cost-effectiveness analyses, and equity considerations. Continued dialogue between national programs, WHO, and non-governmental partners will be needed to translate these findings into policy.
Research Gaps and Next Steps
- Long-term follow-up: Extend surveillance to 10–15 years to determine durability of protection and impact on CIN2+ and cancer incidence.
- Broader populations: Trials or observational studies in older adolescents, young adults, and males will clarify generalizability.
- Non-16/18 outcomes: Evaluate protection against additional oncogenic HPV types, especially with nonavalent formulations.
- Programmatic studies: Real-world implementation research to evaluate coverage, adherence, cost-effectiveness, and health-system impacts.
- Immunologic correlates: Work to identify robust correlates of protection that can support licensure and policy decisions in diverse populations.
Conclusion
The ESCUDDO randomized trial demonstrates that a single dose of either a bivalent or nonavalent HPV vaccine is noninferior to two doses for prevention of persistent HPV16/18 infection over five years in girls aged 12–16. Vaccine effectiveness relative to unvaccinated participants exceeded 97% in trial groups, and no safety concerns were identified. These findings create an evidence-based opportunity to reconsider HPV vaccination schedules to expand access and accelerate reductions in cervical cancer, especially in settings where logistical or financial barriers have limited uptake. Implementation should proceed thoughtfully, informed by longer-term follow-up, disease outcome data, and local programmatic considerations.
Funding and ClinicalTrials.gov
Funding: National Cancer Institute and others (see original publication for full list). ClinicalTrials.gov: NCT03180034 (ESCUDDO).
References
1. Kreimer AR, Porras C, Liu D, Hildesheim A, Carvajal LJ, Ocampo R, Romero B, Gail MH, Cortes B, Sierra MS, Coronado K, Sampson J, Coto C, Dagnall CL, Mora D, Kemp TJ, Zuniga M, Pinto LA, Barrientos G, Schussler J, Estrada Y, Montero C, Avila C, Ruggieri D, Cyr JT, Chanock S, Lowy DR, Schiller JT, Herrero R. Noninferiority of One HPV Vaccine Dose to Two Doses. N Engl J Med. 2025 Dec 3. doi: 10.1056/NEJMoa2506765. Epub ahead of print. PMID: 41337735.
2. World Health Organization. Human papillomavirus (HPV) vaccines: WHO position paper. Weekly Epidemiological Record. 2017;92(19):241–268. (Position papers and technical guidance available at www.who.int)
Note: For full details of trial methods, secondary analyses, and supplementary data, consult the original NEJM publication and clinicaltrials.gov registry.
