{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T00:55:13Z","timestamp":1792716913099,"version":"4.5.0"},"reference-count":73,"publisher":"American Medical Association (AMA)","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Dermatol"],"published-print":{"date-parts":[[2025,6,1]]},"abstract":"<jats:sec><jats:title>Importance<\/jats:title><jats:p>The substantial morbidity and socioeconomic costs associated with actinic keratosis (AK) management represent major public health concerns. Anecdotal evidence suggests that human papillomavirus (HPV) vaccination may offer therapeutic and preventive effects against AK and keratinocyte carcinomas (KCs).<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>To investigate the effect of HPV vaccination on burden of disease in immunocompetent patients with high numbers of AK.<\/jats:p><\/jats:sec><jats:sec><jats:title>Design, Setting, and Participants<\/jats:title><jats:p>The VAXAK trial was a parallel-design, double-blind, randomized sham-controlled clinical trial with 12 months\u2019 follow-up. This single-center trial was conducted at the Department of Dermatology, Bispebjerg University Hospital in Copenhagen, Denmark, between May 2021 and June 2024. Eligible participants were immunocompetent adults with 15 or more clinical AK lesions in a 50 cm<jats:sup>2<\/jats:sup> to 100 cm<jats:sup>2<\/jats:sup> test area on the head, trunk, or extremities.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interventions<\/jats:title><jats:p>Participants were randomized 1:1 to blinded, 9-valent alphapapillomavirus vaccine or sham vaccine (isotonic sodium chloride solution), each administered intramuscularly at 0, 2, and 6 months. Thick AKs (Olsen grade II-III) received cryotherapy at months 6 and 9; test areas were otherwise untreated during the study.<\/jats:p><\/jats:sec><jats:sec><jats:title>Main Outcomes and Measures<\/jats:title><jats:p>The preselected primary outcome was the percentage reduction in baseline AKs assessed 2, 6, 9, and 12 months after first vaccination. Secondary outcomes included total AK number, thick lesions, new AKs, and rate of incident KCs over 12 months.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Participants were selected by consecutive sampling of 163 screened patients following exclusion of 93 individuals due to ineligibility or patients opting out. Among 70 enrolled participants (median [IQR] age, 75.50 [69.00-79.00] years; 47 [67%] male), 69 completed the study. Median (IQR) AK reductions were higher in the HPV-vaccinated vs sham group, shown consistently over the study period (month 2: 35% [25%-44%] vs 25% [18%-33%]; <jats:italic>P<\/jats:italic>\u2009=\u2009.03; month 6: 47% [33%-53%] vs 29% [16%-44%]; <jats:italic>P<\/jats:italic>\u2009=\u2009.01; month 9: 58% [37%-63%] vs 42% [33%-56%]; <jats:italic>P<\/jats:italic>\u2009=\u2009.09; month 12: 58% [47%-69%] vs 47% [32%-65%]; <jats:italic>P<\/jats:italic>\u2009=\u2009.05). Total AK numbers were correspondingly lower in the HPV-vaccinated group (median [IQR] at month 6: 14.00 [11.00-16.00] vs 17.00 [12.00-23.00]; <jats:italic>P<\/jats:italic>\u2009=\u2009.01; month 12: 10.00 [6.00-24.00] vs 16.00 [8.50-21.00]; <jats:italic>P<\/jats:italic>\u2009=\u2009.02). Coincidingly, fewer thick AKs were observed in the HPV-vaccinated group (median [IQR] at month 6: 5.00 [3.00-7.00] vs 6.50 [3.75-10.00]; <jats:italic>P<\/jats:italic>\u2009=\u2009.02; month 12: 3.00 [2.00-5.00] vs 5.00 [2.50-8.50]; <jats:italic>P<\/jats:italic>\u2009=\u2009.049). In contrast, no significant differences in rates of new AKs (1-2 AK[s] per month) or KC numbers overall or per participant were identified during the 12-month trial.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Relevance<\/jats:title><jats:p>In this randomized clinical trial, standard alphapapillomavirus vaccination was found to reduce AK burden in immunocompetent individuals with multiple lesions. HPV-targeted vaccines may be useful for management of AK, a chronic, relapsing disease and the most common precancer in fair-skinned populations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Trial Registration<\/jats:title><jats:p>ClinicalTrials.gov Identifier: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.clinicaltrials.gov\/study\/NCT05202860\">NCT05202860<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1001\/jamadermatol.2025.0531","type":"journal-article","created":{"date-parts":[[2025,3,6]],"date-time":"2025-03-06T15:30:26Z","timestamp":1741275026000},"page":"605","source":"Crossref","is-referenced-by-count":13,"title":["Human Papillomavirus Vaccination and Actinic Keratosis Burden"],"prefix":"10.1001","volume":"161","author":[{"given":"Emily","family":"Wenande","sequence":"first","affiliation":[{"name":"Department of Dermatology, Copenhagen University Hospital\u2013Bispebjerg and Frederiksberg, Copenhagen, 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Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shadmehr","family":"Demehri","sequence":"additional","affiliation":[{"name":"Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Boston"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne K.","family":"Kjaer","sequence":"additional","affiliation":[{"name":"Unit of Virus, Lifestyle and Genes, Danish Cancer Institute, Copenhagen, Denmark"},{"name":"Department of Obstetrics and Gynecology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark"},{"name":"Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merete","family":"Haedersdal","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Copenhagen University Hospital\u2013Bispebjerg and Frederiksberg, Copenhagen, Denmark"},{"name":"Department 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