Reference: N Engl J Med 2025 Dec 18;393(24):2421
Practice Point: A single dose of an HPV vaccine may be good enough for near-perfect protection against HPV16 and 18.
EBM Pearl: Noninferiority studies don’t prove that treatments are equal but test whether a simpler strategy is “good enough” within a prespecified margin that preserves meaningful clinical benefit.
Vaccination against human papillomavirus (HPV) is one of medicine’s most effective cancer-prevention strategies, but nearly 2 decades in, global uptake remains low. HPV16 and HPV18 are responsible for > 77% of cervical cancers worldwide, and when you include HPV31, 33, 45, 52, and 58, this percentage goes up to about 95%. This doesn’t even account for other HPV-related cancers, such as anal, oropharyngeal, vaginal, vulvar, and penile cancers. Access to vaccines remains the key challenge, as multidose regimens don’t often mix well with real life, especially in limited-resource settings. The most common HPV vaccine schedules are 2 doses given 6-12 months apart for individuals who start vaccination before age 15 and 3 doses at 0, 1-2, and 6 months for those who begin at age 15 or older, or who are immunocompromised. The ESCUDDO trial, published in the New England Journal of Medicine, asks a practical question: Can we simplify the schedule without sacrificing protection? In other words, is 1 dose of an HPV vaccine enough to get the job done?
In most situations, the answer appears to be a resounding YES. In this double-blind, randomized, noninferiority trial, more than 20,000 girls aged 12-16 years in Costa Rica were assigned to receive either 1 or 2 doses of either a bivalent or nonavalent HPV vaccine and followed for 5 years. The primary endpoint was new, persistent HPV16 or HPV18 infections at 12-60 months. One dose was found to be noninferior to two doses for preventing HPV16 or HPV18 in both vaccines. The rate difference was -0.13 infections per 100 participants for the bivalent vaccine and 0.21 per 100 participants for the nonavalent vaccine, both comfortably within the prespecified noninferiority margin of ≤ 1.25 infections per 100 participants.
Effectiveness analyses drove the point home. When compared with an unvaccinated survey cohort of 3,005 similar young females aged 16-21 years, vaccine effectiveness against persistent HPV16/18 infection was about 98% across all groups, regardless of whether participants received 1 or 2 doses. Protection was long-lasting, showing no meaningful evidence of decreased efficacy over 5 years. As a secondary endpoint, a single dose of the nonavalent vaccine was also noninferior to 2 doses for preventing infection with the larger set of 7 high-risk HPV types, with a vaccine effectiveness of around 95%.
For clinicians, the implications are tough to ignore. The strategy of providing a single-dose HPV vaccine could dramatically improve vaccination coverage by simplifying schedules, reducing missed opportunities, lowering costs, and easing delivery, particularly in populations where the HPV-related cancer risk is high and screening is not as accessible. While one-dose vaccination may not be appropriate for all populations, the call to action is simple. As guidance evolves, clinicians should champion HPV vaccination early and often and be set to embrace one-dose protection when it removes barriers to prevention. Because when one shot can prevent multiple cancers with lasting protection, “one and done” isn’t a shortcut; it’s maximizing public health impact.
For more information, see the topic Human Papillomavirus (HPV) Vaccine in DynaMed.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by Rich Lamkin, MPH, MPAS, PA-C, Senior Clinical Writer at DynaMed. Edited by Katharine DeGeorge, MD, MS, Executive Editor at DynaMed and Associate Professor of Family Medicine at the University of Virginia; Alan Ehrlich, MD, FAAFP, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School; McKenzie Ferguson, PharmD, BCPS, Senior Clinical Writer at DynaMed; Claire Symanski, PhD, Medical Editor and Team Lead for ENT at DynaMed; Michael Butler, PhD, Medical Writer at DynaMed; Matthew Lavoie, BA, Senior Medical Copyeditor at DynaMed; Hannah Ekeh, MA, Senior Associate Editor II at DynaMed; and Jennifer Wallace, BA, Senior Associate Editor at DynaMed.