Wenande Emily, Hastrup Anna, Wiegell Stine, Philipsen Peter A, Thomsen Niels Bech, Demehri Shadmehr, Kjaer Susanne K, Haedersdal Merete
Department of Dermatology, Copenhagen University Hospital-Bispebjerg and Frederiksberg, Copenhagen, Denmark.
Clinic of Dermatology, Naestved, Denmark.
JAMA Dermatol. 2025 Mar 6. doi: 10.1001/jamadermatol.2025.0531.
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).
To investigate the effect of HPV vaccination on burden of disease in immunocompetent patients with high numbers of AK.
DESIGN, SETTING, AND PARTICIPANTS: The VAXAK trial was a parallel-design, double-blind, randomized sham-controlled clinical trial with 12 months' 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 cm2 to 100 cm2 test area on the head, trunk, or extremities.
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.
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.
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%]; P = .03; month 6: 47% [33%-53%] vs 29% [16%-44%]; P = .01; month 9: 58% [37%-63%] vs 42% [33%-56%]; P = .09; month 12: 58% [47%-69%] vs 47% [32%-65%]; P = .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]; P = .01; month 12: 10.00 [6.00-24.00] vs 16.00 [8.50-21.00]; P = .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]; P = .02; month 12: 3.00 [2.00-5.00] vs 5.00 [2.50-8.50]; P = .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.
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.
ClinicalTrials.gov Identifier: NCT05202860.
光化性角化病（AK）治疗所带来的显著发病率和社会经济成本是主要的公共卫生问题。轶事证据表明，人乳头瘤病毒（HPV）疫苗接种可能对AK和角质形成细胞癌（KC）具有治疗和预防作用。
研究HPV疫苗接种对免疫功能正常且AK数量较多患者疾病负担的影响。
设计、地点和参与者：VAXAK试验是一项平行设计、双盲、随机假对照临床试验，随访12个月。该单中心试验于2021年5月至2024年6月在丹麦哥本哈根比斯佩比约格大学医院皮肤科进行。符合条件的参与者是免疫功能正常的成年人，在头部、躯干或四肢50 cm²至100 cm²的测试区域有15个或更多临床AK病变。
参与者按1:1随机分配至盲法9价α乳头瘤病毒疫苗或假疫苗（等渗氯化钠溶液）组，每组均在0、2和6个月时进行肌肉注射。厚的AK（奥尔森II - III级）在第6和9个月接受冷冻治疗；研究期间测试区域的其他部位不进行治疗。
预先选定的主要结局是首次接种疫苗后2、6、9和12个月评估的基线AK减少百分比。次要结局包括AK总数、厚病变、新发AK以及12个月内KC的发病率。
在排除93名因不符合条件或患者退出的个体后，通过对163名筛查患者进行连续抽样选择参与者。在70名入组参与者中（年龄中位数[四分位间距]，75.50[69.00 - 79.00]岁；47名[67%]男性），69名完成了研究。在整个研究期间，HPV疫苗接种组的AK减少中位数（四分位间距）始终高于假疫苗组（第2个月：35%[25% - 44%]对25%[18% - 33%]；P = 0.03；第6个月：47%[33% - 53%]对29%[16% - 44%]；P = 0.01；第9个月：58%[37% - 63%]对42%[33% - 56%]；P = 0.09；第12个月：58%[47% - 69%]对47%[32% - 65%]；P = 0.05）。HPV疫苗接种组的AK总数相应较低（第6个月中位数[四分位间距]：14.00[11.00 - 16.00]对17.00[12.00 - 23.00]；P = 0.01；第12个月：10.00[6.00 - 24.00]对16.00[8.50 - 21.00]；P = 0.02）。同时，HPV疫苗接种组观察到的厚AK较少（第6个月中位数[四分位间距]：5.00[3.00 - 7.00]对6.50[3.75 - 10.00]；P = 0.02；第12个月：3.00[2.00 - 5.00]对5.00[2.50 - 8.50]；P = 0.049）。相比之下，在12个月的试验期间，未发现新发AK（每月1 - 2个AK）率或KC总数及每位参与者的KC数量有显著差异。
在这项随机临床试验中，发现标准的α乳头瘤病毒疫苗接种可减轻免疫功能正常且有多处病变个体的AK负担。针对HPV的疫苗可能有助于治疗AK，AK是一种慢性复发性疾病，也是白皮肤人群中最常见的癌前病变。
ClinicalTrials.gov标识符：NCT05202860。
