Researchers have demonstrated that standard alphapapillomavirus vaccination can effectively reduce the burden of actinic keratosis lesions in immunocompetent patients with multiple lesions.
The findings from the VAXAK randomized clinical trial, published in JAMA Dermatology, suggested that human papillomavirus (HPV) vaccines may offer a novel approach to managing this common precancerous condition.
In the double-blind, parallel-design, randomized sham-controlled trial, conducted at Copenhagen University Hospital in Denmark between May 2021 and June 2024, the researchers enrolled 70 immunocompetent adults with 15 or more clinical actinic keratosis (AK) lesions in a 50 to 100 cm² test area on the head, trunk, or extremities. Participants received either the 9-valent alphapapillomavirus vaccine (Gardasil-9) or sham vaccine (isotonic sodium chloride solution) administered intramuscularly at 0, 2, and 6 months.
The researchers observed consistently greater reductions in median AK lesion count among the HPV-vaccinated group compared with the sham group, with statistical significance at multiple time points. At month 2, the HPV group showed a 35% reduction (interquartile range [IQR] = 25%–44%) vs 25% (IQR = 18%–33%) in the sham group (P = .03). At month 6, the difference was even more pronounced: a 47% (IQR = 33%–53%) reduction in the HPV group vs 29% (IQR = 16%–44%) in the sham group (P = .01). This effect persisted through month 12, with a 58% (IQR = 47%–69%) reduction in the HPV group vs 47% (IQR = 32%–65%) in the sham group (P = .05).
"In this randomized clinical trial, standard alphapapillomavirus vaccination was found to reduce AK burden in immunocompetent [patients] with multiple lesions," the study authors stated. "HPV-targeted vaccines may be useful for management of AK, a chronic, relapsing disease and the most common precancer in populations [with lighter skin tones]," they added.
Total AK numbers were correspondingly lower in the HPV-vaccinated group at month 6 (median = 14.00, IQR = 11.00–16.00 vs 17.00, IQR = 12.00–23.00, P = .01) and month 12 (median = 10.00, IQR = 6.00–24.00 vs 16.00, IQR = 8.50–21.00, P = .02. Notably, fewer thick AKs (Olsen grade II to III) were observed in the HPV-vaccinated group at month 6 (median = 5.00, IQR = 3.00–7.00 vs 6.50, IQR = 3.75–10.00, P = .02) and month 12 (median = 3.00, IQR = 2.00–5.00 vs 5.00, IQR = 2.50–8.50, P = .049).
However, the researchers found no statistically significant differences in the rates of new AKs (1 to 2 per month) or keratinocyte carcinoma (KC) numbers during the 12-month trial period. KC development was similar between the groups, with tumors detected in 49% of HPV-vaccinated participants and 44% of sham-vaccinated participants (P = .81).
The trial's lead researcher, Emily Wenande, MD, PhD, and colleagues theorized that the mechanism behind these clinical responses could involve boosted T-cell immunity against variant keratinocytes in AK that demonstrate increased viral antigen expression. "Although not their primary mechanism of action, [alphapapillomavirus] vaccine can induce cytotoxic T-cell immunity that may display greater cross-reactive potential than the corresponding antibody response," they noted.
AK is the most prevalent precancer in populations with lighter skin tones, affecting an estimated 14% of individuals worldwide. In the United States, AKs are the most commonly diagnosed skin condition at dermatology visits, with annual management costs exceeding $1 billion. The lesions have a well-known potential to progress to invasive squamous cell carcinoma (SCC).
While multiple treatments exist for AK, including field-directed therapies such as 5-fluorouracil, imiquimod, photodynamic therapy, and lesion-directed approaches like cryotherapy, recurrence rates remain high. "Thicker, hyperkeratotic AKs pose a particular challenge due to their treatment resistance and higher recurrence rate," the study authors wrote.
The VAXAK study indicated that HPV vaccination could potentially serve as an adjunctive therapy in patients with severe photodamage. However, the researchers acknowledged several limitations, including the relatively small population size, the imperfect science of clinical AK assessment, and the lack of histologic confirmation of lesional clearance.
The study could open promising new avenues for AK management, though longer follow-up may be necessary to determine if the observed effects persist over time. The researchers are continuing extended follow-up of their study population for up to 10 years postvaccination using registry-based data outside the RCT framework. The trial is registered on ClinicalTrials.gov (Identifier NCT05202860).
Disclosures can be found in the study.