Does HPV vaccination change the burden of disease in patients with actinic keratosis?

By Kathryn Schwarzenberger, MD, FAAD, September 1, 2025

In this month’s Clinical Applications column, Physician Editor Kathryn Schwarzenberger, MD, FAAD, talks with Emily Wenande, MD, PhD, about her JAMA Dermatology paper, ‘Human Papillomavirus Vaccination and Actinic Keratosis Burden: The VAXAK Randomized Clinical Trial.’

DermWorld: Your recent paper evaluated whether HPV vaccination (specifically, the 9-valent alphapapillomavirus vaccine) could change the burden of disease in patients with actinic keratosis. Why did you choose to study this topic?

Across North America, Europe, and Australasia, the rising prevalence and treatment burden of actinic keratoses (AKs) and keratinocyte carcinoma (KC) present major challenges for dermatologists and their patients. In the U.S., AKs are among the most diagnosed skin conditions at dermatology visits (J Clin Aesthet Dermatol. 2022. 15(5):E82-E6). So, it’s clear that there’s an urgent need for innovative strategies to address this escalating public health concern.

For decades, dermatologists have been aware of an intriguing association between cutaneous HPVs and AKs/KCs, particularly in immunosuppressed populations. In recent years, our team and others have observed therapeutic and preventative effects of standard HPV vaccination against AK and KC in a small handful of patients (JAMA Dermatol. 2017;153(6):571-4; Dermatol Ther. 2020;33(4):e1345; J Drugs Dermatol. 2022;21(5):526-8). We weren’t content to let these observations remain anecdotal given their potentially game-changing implications. So, prompted by the human and economic cost of AK/KC, the link to HPV, and initial reports indicating benefit of HPV vaccination, we set out to test the hypothesis in a more scientifically rigorous manner.

DermWorld: Can you briefly describe your study protocol?

Dr. Wenande: The VAXAK trial was a 12-month, randomized, double-blind, sham-controlled, non-industry-sponsored trial conducted at the Department of Dermatology at Bispebjerg University Hospital in Copenhagen, Denmark. The study included 70 immunocompetent adults who presented with a high AK burden. Participants were randomized 1:1 to receive three doses of either commercially available 9-valent α-HPV vaccine or saline sham vaccine, administered intramuscularly at months 0, 2, and 6.

During the study, individual AK lesions in a preselected 50-100 cm2 skin area were mapped and tracked across five visits (months 0, 2, 6, 9, 12) and outcomes were measured as percentage change in clinical AK count, as well as number of thick lesions and new AKs. In addition, full-body skin exams were performed at each visit to identify KCs occurring during the study period.

DermWorld: What were your findings?

Dr. Wenande: Over the 12-month observation period, the HPV-vaccinated group showed greater reductions in AK burden compared to sham, reaching statistical significance at multiple time points (e.g., 47% vs. 29% at month six, P = .01). In addition, the HPV-vaccinated group also had fewer thick AK lesions and a lower total AK count, shown at month six and 12. However, we found no significant difference in the number of new AKs or histologically verified incident KC lesions between the groups during the trial.

The blue-sky implication of our findings is that cutaneous HPV-targeted vaccines may, in the future, be used as an adjunctive therapy to reduce AK burden in severely photodamaged patients. It’s important to mention, however, that a long-term effect, including on KC development, remains to be demonstrated.

DermWorld: What is the mechanism by which you believe HPV vaccination leads to a reduction in AK lesions?

Dr. Wenande: Our study certainly raises the question but does not address why a vaccine designed to prevent mucosal α-HPV infection might reduce established actinic skin lesions. Assuming that the in-trial observed effect is true, possible mechanisms include nonspecific immune activation — either by the vaccine or adjuvant — or, as others have proposed, from immunological cross-reactivity due to antigenic similarities in the L1 capsid protein shared across HPV genera. Indeed, there is some clinical evidence of improvement in β-HPV–related skin conditions after α-HPV vaccination. As an example, one study of treatment-resistant plantar warts showed complete clearance rates of 82% and 63% after intralesional and standard intramuscular α-HPV vaccination, respectively (J Am Acad Dermatol. 2020;82(1):94-100).

For years, many have believed that cutaneous HPVs act as a carcinogenic cofactor in KC development. However, new research is reshaping our understanding of skin cancer pathogenesis, particularly the role of the commensal skin virome, host immune surveillance, and tissue homeostasis. I’d like to highlight a seminal study by our co-author, Dr. Shawn Demehri, and his team, which demonstrated that T-cell–mediated immune responses targeting skin-tropic papillomaviruses play a protective role in suppressing skin cancer development in immunocompetent hosts (Nature. 2019;575(7783):519-22; Son HG, Ha DT, Xia Y, et al. Cancer Cell. 2024). Such findings raise an important question: Could the clinical responses observed in our trial reflect enhanced T-cell–mediated immunity against variant keratinocytes in AK with upregulated expression of viral antigens? The jury is still out on that one.

DermWorld: You also saw a decrease in AKs in the sham-treated group. Do you have a good explanation, and does it weaken your conclusion?

Dr. Wenande: That finding was not entirely unexpected, since spontaneous regression of clinical AKs is a known phenomenon. Illustratively, a recent systematic review of 18 RCTs found a lesion-specific regression rate of 23% in placebo group populations, ranging from 13% to 33% (Sci Rep. 2022;12(1):5884). In our study, decreases in AKs in the sham-treated group were most pronounced following month six, potentially driven by cryotherapy (initiated for thick lesions in both groups after month six). However, the observation does underscore that further studies are needed to confirm the reproducibility of our findings.

DermWorld: Do you believe your findings justify changing treatment protocols now, or do we need more studies?

Dr. Wenande: While certainly thought-provoking, our findings do not yet justify routine use of HPV vaccination for AK outside of a research setting. The observed reduction in AK burden, though consistent, was modest (~10-18%), and the trial involved a relatively small study population of severely photodamaged patients. Importantly, no significant impact on KC incidence was observed within the 12-month follow-up period, although few of the trial’s participants developed squamous cell carcinoma in that time. To further explore potential long-term effects on KC development, our team, headed by Professor Merete Haedersdal, will continue to follow the study population.

DermWorld: If you were to redo this study or perform additional ones, what would you do differently?

Dr. Wenande: Naturally, we would have preferred a larger trial population, as the small, 70-patient sample size remains the primary limitation of our study. Additional analyses such as assessing vaccinated patients’ skin for HPV presence or T-cell infiltration could also have further substantiated our clinical findings. It moreover remains unclear whether the observed effects on AK are specific to the HPV vaccine. Future studies comparing HPV vaccination to an alternative vaccine, such as MMR or adjuvant alone, may help clarify that question. Another key question is whether similar efficacy can be demonstrated in immunosuppressed patients, a group with a significant unmet clinical need. Although many important questions remain unanswered, the results from this trial provide a launchpad of sorts for future research, offering a potential glimpse of novel HPV-targeted approaches to managing a common and burdensome skin disease.

Emily Wenande, MD, PhD, is in the department of dermatology at Copenhagen University Hospital Bispebjerg and Frederiksberg, in Copenhagen, Denmark.

Her paper appeared in JAMA Dermatology.

Dr. Wenande has received grants from Region Hovedstadens Forskningsfond til Sundhedsforskning (A7173) (2021-0112206), Bispebjerg og Frederiksberg Hospitaler Frie Forskningsmidler 2021, and Fonden af Fam. Kjarsgaard, Sunds (DAHL-A.FID3424431), funding from the Danish Research Center for Skin Cancer during the study, and personal fees from Sanofi (speaker honorarium). Dr. Wenande is currently a full-time employee of Novo Nordisk A/S since September 2024 (after the trial’s conclusion and unrelated to the study).

Disclaimer: The views and opinions expressed in this article do not necessarily reflect those of DermWorld.

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