Additional HPV booster found nonsuperior to standard 2-dose regimen

Both a 2-dose quadrivalent human papillomavirus vaccine (4vHPV) and 2+1 dose schedule significantly reduce the incidence of human papillomavirus (HPV)-16 and HPV-18 incidence, according to a recent study published in JAMA Network Open.¹

Background on HPV vaccination

Vaccinations against HPV have been available for decades, with the original regimen of a 3-dose, 6-month schedule recommended in female patients aged 9 to 26 years.² However, alternative schedules have been evaluated, including administration of a booster dose before the age when sexual activity often begins.¹

“No randomized study has compared the effectiveness of the 2-dose (administered at 0 and 6 months) and 2 + 1–dose (administered at 0, 6, and 60 months) schedules for up to 13 years,” wrote investigators.

Comparing vaccine efficacy

To compare the efficacy of a 2-dose 4vHPV schedule with a 2 + 1–dose schedule against persistent HPV-16 and HPV-18 infection for up to 10 years, investigators conducted a 2-arm, parallel, noninferiority randomized controlled trial. Recruitment was accomplished by contacting parents through mail or telephone.

Participants included girls who were aged 9 to 11 years 5 years prior and received the first dose of 4vHPV at this time. Patients also had to receive 2 doses of the regimen 6 months apart, display immunocompetence at first dose, not be pregnant, and reside in one of the recruitment regions.

Randomization 2:1 to the 2-dose or 2 + 1–dose group was performed in the study population. Patients were taught how to perform a self-collected vaginal sample at the recruitment visit. Demographic data, medical history, and sexual and reproductive behaviors were obtained through an online questionnaire.

Sample collection and HPV incidence

Self-sampling kits were provided to patients every 6 months for 5 years, with the exception of a 6-month interruption during the COVID-19 pandemic. Follow-up was extended for up to 13 years after administration of the first dose.

Persistent HPV-16 or HPV-18 infection was reported as the primary outcome, defined by 2 consecutive vaginal samples self-collected 5 to 15 months apart. Rates of HPV-6, -11, -16, -18, -31, -33, -45, -52, and -58 at 60, 90, and 120 months following the first dose were reported as secondary outcomes.

Participant demographics and behavior

There were 3356 participants included in the final analysis, aged a mean 14.8 years at recruitment. Approximately 92% were born in Canada, with 5.7% being English Canadians, 85.4% French Canadians, 4.2% South, Central, or Latin Americans, and 27.5% other ethnicities.

Hormonal contraception was reported in 21.2% of patients, ever smoking in 7.9%, and ever having sex in 16.1%. A median follow-up period after the first dose of 10.9 years was reported.

Of participants, 23.2% sent all scheduled swabs, while 6.4% of swabs were not returned by participants. Additionally, 1.8% of swabs were invalid.

HPV test results

A positive HPV test result was reported in 18.5% of valid swabs obtained from the 2-dose group vs 18% from the 2+1-dose group. No positive test result during the study period was reported in 60.3% and 60.2%, respectively.

When expanding the range of genotypes assessed, an increase in rates was observed in both groups. However, rates of under 1% remained for vaccine-type HPVs, including genotypes 6, 11, 16, and 18.

HPV-16 and HPV-18 were detected in 0.1% of the 2-dose group and 0.2% of the 2+1-dose group. HPV-6 and HPV-11 rates were under 0.1% and 0.1%, respectively. This highlighted no significant differences between groups.

“This finding suggests that a booster dose administered 5 years after the first 2 doses may not provide additional benefit,” wrote investigators. “Nevertheless, HPV vaccination is an exceptionally effective preventive intervention.”

References

1. Sauvageau C, Mayrand M, Ouakki M, et al. Protection against persistent HPV-16/18 infection after different number of doses of quadrivalent vaccine in girls and young women: A randomized clinical trial. JAMA Netw Open. 2025;8(7):e2519095. doi:10.1001/jamanetworkopen.2025.19095
2. Safety of HPV vaccines. World Health Organization. July 14, 2017. Accessed July 15, 2025. https://www.who.int/groups/global-advisory-committee-on-vaccine-safety/topics/human-papillomavirus-vaccines/safety.