Protection Against Persistent HPV-16/18 Infection After Different Number of Doses of Quadrivalent Vaccine in Girls and Young Women: A Randomized Clinical Trial

Abstract

Importance: There are no randomized studies comparing the long-term effectiveness of a 2-dose schedule (administered at 0 and 6 months) of quadrivalent human papillomavirus vaccine (4vHPV) with a 2 + 1-dose schedule (administered at 0, 6, and 60 months) given to preadolescents for the prevention of persistent HPV-16 and HPV-18 infection.

Objective: To evaluate whether a 2-dose 4vHPV schedule is noninferior to a 2 + 1-dose schedule for preventing persistent HPV-16 and HPV-18 infection up to 13 years after the first dose.

Design, setting, and participants: This 2-arm, parallel, noninferiority, randomized clinical trial (RCT), called ICI-VPH (Impact of HPV Immunization Schedules Against HPV), was conducted in Québec, Canada, from 2013 to 2021. Eligible participants were girls who had received 2 doses of 4vHPV, 6 months apart when they were aged 9 to 11 years, 5 years prior to trial recruitment. Efficacy-evaluable population analysis was conducted between April 2023 and June 2024.

Interventions: Participants were randomized 1:1 to the 2-dose or 2 + 1-dose groups. The 2 + 1-dose group received a booster dose of 4vHPV at the recruitment visit. Both groups were instructed on how to self-collect a vaginal sample, provided an initial vaginal swab, and completed an online questionnaire.

Main outcomes and measures: The primary outcome was persistent HPV-16 and HPV-18 infection, defined as the presence of HPV-16 or HPV-18 DNA in 2 consecutive vaginal samples self-collected 5 to 15 months apart.

Results: Among the 3356 participants, the mean (SD) age at enrollment was 14.8 (0.4) years, and 2867 (85.4%) were French Canadian individuals. Of the 3364 participants initially randomized, 8 (0.2%) withdrew immediately after randomization, 1675 (49.8%) were assigned to the 2-dose group, and 1681 (50.0%) were assigned to the 2 + 1-dose group. Of the 16 989 genotyping tests analyzed, 31 (0.2%) detected vaccine-type HPV-6, -11, -16, and -18. Only 1 participant in the 2 + 1-dose group (0.1%) had a time-limited persistent HPV-16 infection.

Conclusions and relevance: This clinical trial found that the incidence of HPV-16 and HPV-18 infection was low with both the 2-dose and 2 + 1-dose 4vHPV schedules. A 2-dose schedule provided robust protection against persistent HPV-16 and HPV-18 infection for up to 13 years, suggesting that a booster dose administered at 60 months would not provide additional benefit.

Trial registration: ClinicalTrials.gov Identifier: NCT02009800.

Figure 1.. Impact of HPV Immunization Schedules Against HPV (ICI-VPH) Study Procedures

HPV indicates human papillomavirus. ^aParticipants provided the initial vaginal swabs and were instructed on how to self-collect vaginal samples. ^bParticipants started self-sampling every 6 months from visit 2 through visit 11. Study staff tested samples at even-numbered time points (eg, visit 2, visit 4). If a sample tested positive for HPV, previous and subsequent swabs were tested. Participants completed yearly questionnaires at odd-numbered time points (eg, visit 3, visit 5). ^cSome participants continued follow-up and completed questionnaires at odd-numbered time points.

Figure 2.. CONSORT Flow Diagram

Figure 3.. Human Papillomavirus (HPV) Positivity in Participants With 2-Dose vs 2 + 1–Dose Quadrivalent Vaccine Schedule at Even-Numbered Time Points During Follow-Up

The extension period was optional, with some participants continuing follow-up for an additional 3 years. HR indicates high risk and LR indicates low risk.