Source: Kreimer AR, Porras C, Liu D, et al. Noninferiority of one HPV vaccine dose to two doses. N Engl J Med. 2025;393(24):2421-2433; doi: 10.1056/NEJMoa2506765.Investigators from multiple institutions conducted a randomized controlled trial to compare the effectiveness of 1 or 2 doses of human papillomavirus (HPV) vaccine in girls. Both a bivalent (HPV16, HPV18) and nonavalent (HPV6, HPV11, HPV16, HPV18, HPV31, HPV33, HPV45, HPV52, and HPV58) vaccine were evaluated. Study participants were girls 12–16 years old enrolled at multiple locations in Costa Rica. At enrollment, participants were randomized to receive a dose of the bivalent or nonavalent vaccine. Six months later, they were randomized to receive a second dose of their assigned vaccine, or a tetanus, diphtheria, pertussis vaccine (to maintain blinding). Girls enrolled in the trial subsequently were followed on a semi-annual or annual basis. At each follow-up visit, cervicovaginal specimens were obtained and assayed for 46 HPV types. The primary outcome was an incident, persistent infection with HPV16 or HPV18. The rate of infection was compared in girls receiving 1 or 2 doses of the bivalent vaccine, and in those receiving 1 or 2 doses of the nonavalent vaccine. If the upper limit of the 95% confidence interval (CI) of the difference in rate of infection was <1.25 infections per 100 participants, 1 dose was considered noninferior to 2 doses. For participants receiving the nonavalent vaccine, the difference in infection rate from 7 carcinogenic HPV types included in the vaccine among those receiving 1 or 2 doses were compared. If the upper limit of the 95% CI of the difference was <2.55 infections per 100 participants, 1 dose was considered noninferior to 2. To assess vaccine effectiveness, cervicovaginal specimens were obtained in a second, non-randomized sample of females 16 to 21 years old, and HPV16 or HPV18 infections were identified. The infection rate in these participants was compared to that of females in each of the 4 vaccine groups.A total of 4,880 participants were randomized to the 1 dose of bivalent vaccine group and 4,880 to 2 doses and 4,851 and 4,851, respectively, assigned to 1 or 2 doses of nonavalent vaccine. Vaccine effectiveness was assessed in 83.8%. Among those receiving bivalent vaccine, the difference in rate of HPV16 or HPV18 infections in participants receiving 1 or 2 doses was -0.13 per 100 participants (95% CI, -0.45, 0.15). For those receiving nonavalent vaccine the difference was 0.21 (95% CI, -0.09, 0.51). The difference in rate of infection with a carcinogenic HPV type in nonavalent vaccine recipients receiving 1 or 2 doses was 0.56 infections per 100 participants (95% CI, 0.01, 1.11). Compared with the infection rate among 3,005 unvaccinated females, the effectiveness of HPV vaccine against HPV16 or HPV18 was ≥97.1% in each of the 4 trial groups.The authors conclude that 1 dose of HPV vaccine was noninferior to 2 doses in preventing infection with HPV16 or HPV18.Dr Brady has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.HPV infection is responsible for genital warts, penile, anal, and head and neck cancers, and more than 90% of cervical cancers.1,2 A recent review of 225 studies, including 132 million women across multiple countries, found that girls who received the HPV vaccine before 16 years had an 80% lower risk of cervical cancer compared with those who were not vaccinated.3 In addition, HPV vaccination prevented 56% of head and neck cancers in men in a recent US study.4Despite HPV vaccine’s effectiveness in preventing cancers, global uptake remains low due to cost, dosing challenges, and vaccine hesitancy.3 The results from the current study and a similar study (See AAP Grand Rounds. 2023;505:52.)5 were used in support of the WHO alternative recommendation for single-dose HPV vaccination6 to achieve higher coverage (fewer doses, less cost) while maintaining high effectiveness.Even with a 1-dose schedule, there still are significant barriers to overcoming misinformation and addressing HPV vaccine hesitancy. An established medical home can, however, provide a foundation of trust of patients and their families in the provider’s recommendation. The vaccine is safe and not associated with infertility or promoting the initiation of sexual activity.7 Most importantly, HPV vaccine prevents cancer.One dose of HPV vaccine is noninferior to 2 doses in preventing infection with HPV types most often associated with cancer.1
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