Intralesional human papillomavirus vaccine for the treatment of recalcitrant cutaneous warts

Human papillomavirus (HPV) is ubiquitously distributed in the population worldwide and its most frequent clinical presentation is cutaneous warts. Despite various treatment options currently available, many patients experience persistent and refractory disease. We sought to evaluate the clinical effectiveness and safety profile of intralesional HPV 9‐valent vaccine for the treatment of recalcitrant warts. A retrospective study was performed for all cases of cutaneous warts treated with intralesional 9‐valent HPV vaccine between January 2017 and March 2021. Epidemiologic, clinical, and treatment data, including safety and effectiveness scores, were reviewed. Our cohort was composed of 20 patients: 13 adults and seven children. Twelve patients (60%) displayed a complete response whereas 8 patients (40%) showed a partial response. Older age was associated with a better response to treatment, while a history of laser therapy was associated with a worse prognosis. Adverse events were local, transient, and negligible. No systemic adverse effects were reported. Intralesional 9‐valent HPV vaccine may be considered for the treatment of recalcitrant cutaneous warts. Controlled studies are required to confirm these results.

We sought to evaluate the clinical effectiveness and safety profile of intralesional HPV 9-valent vaccine for the treatment of recalcitrant warts.A retrospective study was performed for all cases of cutaneous warts treated with intralesional 9-valent HPV vaccine between January 2017 and March 2021.Epidemiologic, clinical, and treatment data, including safety and effectiveness scores, were reviewed.Our cohort was composed of 20 patients: 13 adults and seven children.Twelve patients (60%) displayed a complete response whereas 8 patients (40%) showed a partial response.Older age was associated with a better response to treatment, while a history of laser therapy was associated with a worse prognosis.Adverse events were local, transient, and negligible.No systemic adverse effects were reported.Intralesional 9-valent HPV vaccine may be considered for the treatment of recalcitrant cutaneous warts.Controlled studies are required to confirm these results.In this retrospective case series, we evaluated the clinical effectiveness and safety profile of intralesional HPV 9-valent vaccine in the treatment of recalcitrant warts in healthy and immunocompromised patients.To our knowledge, this is the first description of intralesional 9-valent vaccine as treatment for cutaneous warts.

| MATERIAL S AND ME THODS
We conducted a retrospective case series on recalcitrant cutane- Of the 20 patients in our cohort, 12 (60%) displayed a complete response (PGA score 0 from both assessors), whereas five patients (25%) showed an excellent response (mean PGA score 1-1.5).In contrast, three patients (15%) had moderate or poor response (mean PGA ≥2).In the subjective evaluation using the PGIC scale, 13 patients (65%) reported the highest improvement score of 7. include immunotherapy with diphenylcyclopropenone or squaric acid dibutyl ester, topical/intralesional cidofovir, oral retinoids, and intralesional bleomycin. 6,21,22In persistent cases, CO 2 or pulsed dye lasers, photodynamic therapy, or local hyperthermia can be beneficial.
Intralesional immunotherapy has been tried using a variety of agents such as candida antigen; mumps antigen; combined measles, mumps, and rubella (MMR) vaccine; tuberculin purified protein derivative; and bacille Calmette-Guerin vaccine. 19,20spite the availability of many therapeutic modalities, the management of recalcitrant warts can be challenging.In this report, we sought to evaluate the clinical effectiveness and safety profile of intralesional HPV 9-valent vaccine for the treatment of recalcitrant warts.We observed a good response to intralesional injections of geted by the vaccine. 21In addition, HPV vaccines contain adjuvants enhancing immune responses. 17,22[25] In all the three cases, a routine 9-valent HPV vaccine was given and led to resolution with complete clearance of all the existing warts.
Intralesional injection of HPV vaccines has been found to be beneficial in the treatment of cutaneous warts when compared with the routine intramuscular administration. 18 Th1 such as interleukin 2 and interferon gamma are predominantly increased in response to injection, activating cytotoxic and natural killer cells that help to eradicate HPV infection in both injected and noninjected lesions.In addition, the trauma of injection alone might induce an immune response. 26The injected antigens can provoke a delayed-type hypersensitivity reaction to the antigen and also to the wart virus, thus enabling the immune system to identify and eliminate HPV at distant locations and to prevent recurrences as well. 27Intralesional administration of the 9-valent HPV vaccine injections in our study as well as 2-valent HPV vaccine in a previous report 18 resulted in complete clearance within 10 to 13 weeks, which is significantly lower than the time required for complete response following intramuscular therapy. 13,18x, size, number, and duration of the warts do not seem to affect response to intralesional vaccine therapy.Location did not correlate with better response in contrast to previously reported results by Nofal et al, where plantar warts responded better than warts located elsewhere.In contrast, age has been shown to correlate positively (this study), negatively, 12,13 or not at all 18 with response to vaccine therapy.The only adverse effect seen in our study was transient localized pain at the injection site, as previously reported. 13,15Systemic adverse effects were not observed.
There are several limitations to our study including the small number of participants and the fact that it was a retrospective study.
In addition, the study design did not allow us to control for possible spontaneous resolution, which is known to characterize the clinical behavior of cutaneous warts.A prospective double-blind placebocontrolled study comparing both intralesional and intramuscular vaccination, as well as all three available HPV vaccines, is needed to establish the therapeutic value of this approach and the best treatment regimen.
In conclusion, based on the present results and taking into account its known safety profile, accessibility, and relatively low price, intralesional HPV 9-valent vaccine should be considered as a potential therapeutic solution for the treatment of recalcitrant cutaneous warts.

ous warts treated with intralesional 9 -
Photographs were ascertained by two independent dermatologists using a Physician Global Assessment (PGA) scale: 4 = poor response (0%-24% improvement); 3 = moderate response (25%-49%, improvement); 2 = good response (50%-74%); 1 = excellent response (75%-99% improvement); and 0 = complete response.The Patient's Global Impression of Change (PGIC) was generated using a scale of 1 to 7, with 1 representing no change or worsening and 7 representing a significant improvement.All adverse effects were reported and documented over a follow-up period of up to 14 months (average, 7.1 months).All statistical tests were two-sided.A p-value <0.05 was considered statistically significant.SPSS version 26 (IBM) was used for all statistical analyses.This case series was conducted following the tenets of the Declaration of Helsinki.As the vaccine used in this study is not registered for intralesional treatment of cutaneous warts, the hospital safety and ethic board approved the treatment of each case in advance.As part of this procedure, the patients and the parents/legal guardians for participants younger than 18 years gave their consent for the treatment after being informed about the nature of the procedure and possible side effects.In addition, written informed consent to publish the cases including nonrecognizable pictures was obtained from all adult participants and from parents/legal guardians for all participants younger than 18 years.

Figures 1 through 8
Figures 1 through 8 demonstrate complete clearance in two patients and Figure 9 represents an excellent response in an immunocompromised patient.Histograms showing the results are also presented (Figure 10).In order to control for a number of parameters likely to assist predicting the mean PGA score, a multivariate stepwise linear regression model was used, including age, sex, number of treatments, immune status, wart location, duration of condition, and past therapies.Past laser treatment was associated with a worse score (p < 0.01, β of 2.05 [confidence interval, 1.08-3.02]),whereas older age was associated with a better score (p < 0.05, β of −0.044 [confidence interval, −0.083 to −0.004]).The adjusted r 2 was 0.54.

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valent HPV vaccine with complete response in 60% of the cases with no evidence of recurrence.HPV vaccines contain noninfectious HPV-like small particles of the L1 capsid found specifically in each HPV subtype.Three HPV vaccines are in use for the prevention of HPV diseases: a 2-valent vaccine against HPV-16 and -18, a 4-valent vaccine against HPV-6, -11, -16, -18, and a new 9-valent vaccine that, in addition, confers protection against subtypes -31, -33, -45, -52, and -58.There is homology between the L1 capsid proteins of the HPV subtypes responsible for common warts, namely HPV subtypes 1-4, and the ones found in the HPV vaccines, possibly resulting in cross-immunity F I G U R E 2 Complete clearance of multiple cutaneous warts in a 20-year-old woman.Multiple recalcitrant warts on the left sole before (a) and after (b) four treatments with intralesional injection of 9-valent human papillomavirus vaccine.Complete clearance of multiple cutaneous warts in a 26-year-old woman.Multiple recalcitrant warts on the right sole before (a) and after (b) four treatments with intralesional injection of 9-valent human papillomavirus vaccine.Complete clearance of a cutaneous wart in a 22-yearold woman.Recalcitrant wart on the right fifth finger right foot before (a) and after (b) six treatments with intralesional injection of 9-valent human papillomavirus vaccine.and enabling elicitation of immune response to a wide range of HPV subtypes.Some cutaneous warts are caused by the HPV types tar-

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Nofal et al reported the use of 2-valent HPV vaccine in a comparative study of two groups, each containing 22 adult patients.The first group was treated with an intralesional injection of 0.1 to 0.3 mL of 2-valent HPV vaccine into the largest wart at 2-week intervals until complete clearance or for a maximum of six sessions.The second group was treated with the intramuscular conventional HPV vaccine regimen.The abovementioned treatment resulted in complete clearance of 81.8% and 63.3% in the two groups, respectively, without recurrence during the follow-up period.The higher complete clearance rate in the intralesional group as compared with our study (81.8% vs 60%) may be attributed, in part, to the fact that two participants in our study had immunologic impairment and to the longer mean disease duration in our study (5 years in adults and 2.7 years in children as compared with 2.4 years in the study of Nofal et al).Nevertheless, bothof these studies demonstrate a significant complete clearance rate in patients with recalcitrant warts.In addition, Yang et al15 and Kuan et al13 reported meaningful results, yet with lower complete clearance rates of 46.6% and 30.8%, respectively, using intramuscular 4-valent HPV vaccine.The long-term immunity response induced by HPV vaccines might be the reason that no recurrences were recorded in the present study or in the study by Nofal et al,18 and only one recurrence was reported in the study by Yang et al.15 HPV clearance and wart resolution depends on cell-mediated immune response.Intralesional immunotherapy introduces antigens at the wart site and induces a T cell-mediated systemic response.Complete clearance of multiple cutaneous warts in a 12-year-old girl.Recalcitrant warts on the forehead (a) and after (b) six treatments with intralesional injection of 9-valent human papillomavirus vaccine.Complete clearance of multiple cutaneous warts in a 31-year-old man.Multiple recalcitrant warts on the right sole before (a) and after (b) six treatments with intralesional injection of 9-valent human papillomavirus vaccine.

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Complete clearance of a cutaneous wart in a 26-yearold man.A recalcitrant wart on the right foot before (a) and after (b) five treatments with intralesional injection of 9-valent human papillomavirus vaccine.Complete clearance of multiple cutaneous warts in a 22-year-old man.Multiple recalcitrant warts on the left sole before (a) and after (b) four treatments with intralesional injection of 9-valent human papillomavirus vaccine.Excellent response in an immune compromised 11-year-old girl.Multiple recalcitrant warts on the right dorsal palm before (a) and after (b) five treatments with intralesional injection of 9-valent human papillomavirus vaccine.