Is One Dose of HPV Vaccine Enough? What Does the ESCUDDO Study Published in NEJM Tell Us?

Why Are Fewer Doses of HPV Vaccine Being Discussed?

For many years, HPV vaccines have been administered in schedules of 2 or 3 doses , providing very strong protection. However, particularly in low- and middle-income countries:

• Difficulty returning for appointments,
• Transportation and organizational challenges,
• The cost of vaccination programs

mean that completion rates for these multidose schedules are below the desired level. Observational studies and smaller trials in recent years suggested that even a single dose could provide very strong protection . From 2022 onward, the World Health Organization also began accepting schedules of 1 or 2 doses for certain age groups. :contentReference[oaicite:0]{index=0}

However, the gold standard in this field would be a clear answer from a large, randomized clinical trial. This is exactly what the ESCUDDO trial does: Is one dose inferior to two doses or not? It directly tests this question.

The ESCUDDO Study: Who Received Which Vaccine, and How Many Doses?

The study is a very large randomized clinical trial involving 20,330 girls aged 12–16 years .

• Participants were randomized in a 1:1:1:1 ratio into four arms :
• Bivalent HPV vaccine – one dose
• Bivalent HPV vaccine – two doses
• Nonavalent HPV vaccine – one dose
• Nonavalent HPV vaccine – two doses
• For comparison, 3005 unvaccinated adolescent girls were also enrolled in a separate observational survey group.

The main focus was infection with HPV16 and HPV18 , the two most important HPV types responsible for cervical cancer:

To determine whether one dose was noninferior—no worse than two doses by an acceptable margin— the researchers set a threshold for the difference in infections: It must be no worse than a difference of 1.25 infections per 100 people.

Safety: Fewer Doses Do Not Add Side Effects

Throughout the study, no serious safety concerns were reported. In particular, regarding severe (Grade ≥3) adverse events :

• Rates of severe adverse events in the one-dose and two-dose arms were similar.
• There was also no clear safety difference between the vaccine types (bivalent and nonavalent).

In other words, the single-dose strategy does not require an additional safety trade-off. This offers a major advantage for public health programs: fewer doses + similar protection + similar side-effect profile.

Single-Dose HPV Vaccination: What Could It Change in the Fight Against Cervical Cancer?

HPV vaccination provides individual protection and, when widely used, can establish herd immunity , dramatically reducing cervical cancer incidence. Equivalent protection from one dose and two doses could be transformative in the following areas:

• Vaccine access: Single-dose schedules make vaccination programs more feasible , even in hard-to-reach areas.
• Cost: Fewer doses could reduce countries' vaccination costs and logistical burden substantially reduce.
• Adherence: The pressure of having to return for a second dose decreases, and even one appointment can provide high protection .

The World Health Organization aims to eliminate HPV-related cervical cancer worldwide. The apparent strength of single-dose protection is considered a development that could shorten this process by years . :contentReference[oaicite:2]{index=2}

A Forward-Looking Perspective for Türkiye and Neighboring Countries

Among the most common topics in discussions about HPV vaccination in Türkiye and neighboring countries are cost and program feasibility. The ESCUDDO study tells us:

• Even a single-dose program could provide protection against HPV16/18, the main causes of cervical cancer, that is extremely high protection .
• For countries struggling to plan vaccination programs because of budget and logistical constraints, a simpler, powerful option is emerging.
• Evidence of this quality provides an important scientific foundation for updating and strengthening national immunization programs in the coming years.

Of course, each country's vaccination schedule is shaped by local epidemiology, resources, existing programs, and health authorities' assessments . However, the clinical message is clear: Single-dose HPV vaccination has emerged as a strong and safe strategy, particularly against HPV16 and 18.

Conclusion: Fewer Doses, More Protection?

The ESCUDDO study sends a clear and powerful message: One dose of HPV vaccine is not inferior to two doses in protection, and this conclusion rests on high-quality clinical evidence involving tens of thousands of young people.

In the coming years, HPV vaccination schedules may be reshaped, with more countries considering single-dose strategies. This shift could be an important milestone toward consigning cervical cancer and other HPV-related cancers to history .

Source

Kreimer AR, Porras C, Liu D, et al. Noninferiority of One HPV Vaccine Dose to Two Doses. New England Journal of Medicine. Publication date: December 3, 2025. DOI: 10.1056/NEJMoa2506765.