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Human papillomaviruses (HPVs) are responsible for causing most cervical cancers and also other cancers. Thankfully, safe and highly effective anticancer HPV vaccines have been available for nearly 2 decades, and some countries, notably Australia, are aiming to eliminate cervical cancer by 2035—less than 10 years from now—using HPV vaccines.1 This study asks an important public health question that pediatricians and parents might also ask: do females who originally received 2 doses of HPV vaccine in elementary school need a third dose in high school? That is, are 2 doses noninferior to 2 + 1 doses? HPV vaccines were initially approved on a 3-doses over 6-month schedule. In 2008, the province of Quebec, Canada, started a school-based vaccination program with quadrivalent (4-strain) HPV vaccine recommending 2 doses during the fourth grade and a third dose in the ninth grade, 5 years later. However, in 2013 when the ninth graders were due to receive a third dose, Quebec authorities cancelled the third vaccination based on mathematical modeling studies and other evidence, including emerging herd immunity, but only under the condition that a trial comparing 2 doses to 2 + 1 doses be completed.2 To answer the call of the Quebec public health authorities, investigators completed this large and innovative randomized trial.3 They randomized 3356 females with a mean age of approximately 15 years who had already received 2 doses 5 years earlier, with half receiving an HPV vaccine booster dose during their initial visit and the other half undergoing observation without a placebo. The participants self-collected vaginal swabs every 6 months for at least 5 years. The primary outcome was persistent HPV-16 or HPV-18 DNA detected in consecutive swabs (these 2 genotypes cause 70% of cervical cancers worldwide). One of the innovations implemented midway through the trial was that investigators only tested every other swab for HPV DNA and then tested the swabs immediately before and after only if the initial tested swab was positive. You have to appreciate the cost-effectiveness and efficiency of this approach! After a median follow-up of 10.9 years after the first dose and after collecting more than 36 000 samples, investigators found that almost the exact same proportion of participants in each group had no positive HPV DNA detected, 60.4% in the 2 + 1 booster intervention group and 60.2% in the standard 2-dose control group. When they looked specifically at the persistence of the HPV-16 and HPV-18 genotypes, their primary outcome, only 1 participant (0.1%) in the 2 + 1–dose group had a confirmed time-limited persistent HPV-16 infection, and there were none in the 2-dose control group. Even looking at single positive tests, there were only 8 (0.1%) HPV-16 or HPV-18 types detected in the 2-dose group and 15 (0.2%) in the 2 + 1–dose group. Video Preventing Genital HPV—2 vs 3 Vaccine Doses? Data From a Clinical Trial HPV vaccinations—are all 3 doses needed to protect against cervical HPV infection? JAMA Network Open Editor in Chief Eli Perencevich, MD, MS, discusses his 2025 pick for Editor’s Choice: Clinical Trials of the Year and explains why it highlights how public health decisions should be made. There were not enough persistent infections to test for noninferiority. This was unfortunate for the investigators but great news for the people of Quebec because it shows that the vaccine program was highly successful. It also validates what the mathematical modeling and herd immunity estimates suggested way back in 2013. I hope this cohort is followed up for years since the exact duration of protection is not known, and perhaps the benefits of the booster dose will be seen in future years. But for now, 2 doses (or even a 1-dose schedule, as many countries are implementing) seem to be enough. To me, this trial, this story, highlights how evidence-based public health decisions should be made: with epidemiological studies, mathematical models, and randomized trials like this trial in JAMA Network Open each playing their role. Back to top Article Information Published: September 16, 2026. doi:10.1001/jamanetworkopen.2026.36217Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License, which does not permit alteration or commercial use, including those for text and data mining, AI training, and similar technologies. © 2026 Perencevich EN. JAMA Network Open.Corresponding Author: Eli N. Perencevich, MD, MS, The University of Iowa, Department of Internal Medicine, Carver College of Medicine, CADRE (152), Iowa City VA Medical Center, 601 Hwy 6W, Iowa City, IA 52246 (Eli.Perencevich@jamanetwork.org).Conflict of Interest Disclosures: None reported. References 1.Australia on track to eliminate cervical cancer by 2035. News release. The Hon Rebecca White MP, Assistant Minister for Health and Aged Care, Assistant Minister for Indigenous Health, Assistant Minister for Women. November 19, 2025. Accessed August 7, 2026. https://www.health.gov.au/ministers/the-hon-rebecca-white-mp/media/australia-on-track-to-eliminate-cervical-cancer-by-2035?language=en2.Comité sur l'immunisation du Québec. HPV immunization of Quebec pre-adolescents: two or three doses? Institut national de santé publique du Québec. June 20, 2014. Accessed August 7, 2026. https://www.inspq.qc.ca/en/publications/18373.Sauvageau  C, Mayrand  MH, 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.2025.19095ArticlePubMedGoogle ScholarCrossref