Immunotherapy: No warts about it
Therapeutic use of the HPV vaccine shows promise as a treatment for stubborn warts.
Feature
By Emily Margosian, Assistant Editor, September 1, 2024
Warts are one of the most common skin disorders worldwide. They can also be among the most challenging to treat.
“Warts are stubborn. They often take months to resolve and may involve multiple therapies at the same time for effective results,” said Washington dermatologist Margit Juhasz, MD, FAAD, AACMS.
“Warts can be resistant to treatment in more than a third of cases,” agreed Hagar Nofal, MD, MSc, DM, consultant dermatologist at School of Medicine at Zagazig University in Egypt. “Others may be recurrent or spread to non-infected sites which adds to the challenge and increases the virus load. Likewise, success rates vary significantly across patients and different therapeutic interventions.”
Additionally, despite a variety of options, conventional treatments for warts can be uncomfortable for patients and potentially result in significant adverse events.
However, a new treatment option is beginning to emerge, showing potential as a valuable tool in physicians’ arsenal against common cutaneous warts. While the human papilloma virus (HPV) vaccine is typically used as a preventative measure rather than a treatment for existing infections, versions of the vaccine have shown promise for the treatment of warts. This month, dermatologists discuss the latest research, with practical considerations for patients and physicians.
Short on time?
Key takeaways from this article:
While available remedies for warts abound, some can present significant challenges in terms of efficacy and patient discomfort.
Use of the HPV vaccine as a potential treatment for warts joins a growing trend in dermatology involving the use of therapeutic vaccines to fight existing disease.
The mechanism of action regarding the HPV vaccine’s use as a destructive agent against warts is not fully understood. However, it potentially involves the induction of a long-term immune response against targeted HPV types, and enhancement of virus recognition and production of cross-reactive antibodies.
So far, research has found that use of the HPV vaccine for immune stimulation as a preventative measure or treatment option for cutaneous warts is promising. Research has also found the HPV vaccine to be just as effective, or in some cases, more effective than other intralesional treatments for warts, such as Candida antigen.
Adverse events observed during studies have been mild and well-tolerated. They include pain during injection, localized itching, mild erythema, and edema. However, more research is needed to fully evaluate potential adverse events.
The HPV vaccine is currently not FDA-approved for treatment of cutaneous warts. This may pose a financial hurdle as the vaccine may not be covered by insurance. Implementation also involves a multi-dose, strict vaccine schedule.
Drawbacks of traditional treatments
While remedies for warts abound, some can present significant challenges in terms of efficacy and patient discomfort.
“Aside from ineffectiveness in some patients, and recurrence with non-immunotherapeutic treatment options, physical destructive maneuvers carry the risk of pain, scarring, and pigmentary changes,” according to Dr. Nofal.
“Traditional treatment options take a long time to work and may need to be combined for clinical efficacy,” added Dr. Juhasz. “For instance, liquid nitrogen and over-the-counter topical salicylic acid — probably the most common therapies utilized — can take multiple rounds of treatment over months for resolution.”
The HPV vaccine as a treatment for warts
Use of the HPV vaccine as a potential treatment for warts joins a growing trend in dermatology involving the use of therapeutic vaccines to fight existing disease.
Therapeutic vaccines are administered after an individual is already infected with a disease. This differs from preventative vaccines, which are administered as a precautionary measure to avoid an infection or disease. Their mechanism of action involves the activation of the immune system and targets specific antigens related to the condition being treated. Types of therapeutic vaccines include peptide-based vaccines, DNA vaccines, RNA vaccines, and viral vector-based vaccines.
“Our results present fortnightly intralesional quadrivalent and bivalent HPV vaccines as a promising, safe, and effective treatment option for existing warts.”
While the mechanism of action regarding the HPV vaccine’s use as a destructive agent against warts is not fully understood, it potentially involves the induction of a long-term immune response against targeted HPV types, and enhancement of virus recognition and production of cross-reactive antibodies. “The exact mechanisms by which immunotherapy treats warts are still undefined,” explained Dr. Nofal. “Immunotherapy is proposed to enhance virus recognition by cell-mediated immunity, which allows the clearance of both injected and distant noninjected warts and helps to prevent recurrences through induction of a long-term acquired immunity to HPV. Mechanisms underlying the therapeutic role of HPV vaccine in existing warts can — similar to other immunotherapeutic antigens — be attributed to enhancement of virus recognition by cell-mediated immunity, or to the production of cross-reactive antibodies. Cross reactivity was reported with both bivalent and quadrivalent HPV vaccines. This added cross reactivity characteristic of HPV vaccines supports their therapeutic potential against genital and non-genital warts. This proposed widespread, activated immune response against HPV helps eliminate distant noninjected warts in most patients as well.”
The route of administration of the HPV vaccine for the treatment of warts can be intralesional or intramuscular, although recent studies have found intralesional injection to be more effective in terms of treating existing warts, prevention of new warts, and reduction of recurrences.
What does the literature say?
“Most research on the use of the HPV vaccine for cutaneous warts has focused on the quadrivalent vaccine, which is available in the United States,” said Dr. Juhasz, who recently published a review of the HPV vaccine as a treatment for related conditions, including warts. “So far, use of the HPV vaccine for immune stimulation as a preventative measure or treatment option for cutaneous warts is promising; however, it is not yet FDA-approved.”
Dr. Nofal co-authored a recent JAAD study comparing the efficacy of intralesional quadrivalent (qHPV) and intralesional bivalent (bHPV) HPV vaccines. “There are three versions of the HPV vaccine: the bivalent, quadrivalent, and 9-valent vaccines. For prophylaxis against HPV virus infection, vaccines are injected intramuscularly at zero, two, and six months. However, as a treatment option for already present disease, both intralesional and intramuscular treatment options were investigated in the literature. The intralesional schedule differs since it occurs at more frequent intervals (fortnightly). The intradermal injection of qHPV and bHPV showed equal immunogenicity and more reactogenicity compared to the regular intramuscular injections.”
While both the intralesional quadrivalent and bivalent vaccines showed promise as treatments for common warts, the study found the quadrivalent option superior. “The quadrivalent vaccine showed higher efficacy with up to 90% of the treated cohort showing complete clearance,” Dr. Nofal noted. “Our results present fortnightly intralesional quadrivalent and bivalent HPV vaccines as a promising, safe, and effective treatment option for existing warts specifically for multiple, recalcitrant, or recurrent ones with significant superiority of the quadrivalent vaccine.”
Other research has produced similar findings. A 2023 study observed 60% total clearance and 40% partial clearance among patients with recalcitrant cutaneous warts following the administration of an intralesional 9-valent HPV vaccine. However, literature indicates that general vaccination against HPV has not been associated with spontaneous clearance of warts.
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Practical considerations for dermatologists
As research continues to support the HPV vaccine’s potential utility as a treatment option for warts, what do these findings mean in practical terms for dermatologists and their patients?
According to Dr. Juhasz, research supports certain criteria that make a patient a good candidate for treatment. “A patient who has multiple cutaneous warts that are resistant to traditional therapies would make me consider using the HPV vaccine as an adjuvant, barring the patient has no contraindications for the vaccine’s use,” she said.
Research also supports the efficacy of the HPV vaccine when integrated into existing treatment plans. “There have been multiple small studies that show that the HPV vaccine, given as either an intramuscular vaccine or intralesionally, is an effective adjuvant therapeutic option to traditional therapies and can increase overall clinical efficacy,” said Dr. Juhasz.
Compared to other intralesional treatments for warts, the HPV vaccine approach showed similar or in some cases, greater efficacy. A 2022 JAAD study demonstrated no significant difference in efficacy between Candida antigen and bivalent HPV vaccine administration when injected directly into the wart. A more recent study reported that the quadrivalent HPV vaccine was more effective than Candida antigen in the treatment of recalcitrant non-genital warts. “However, it is important to note that in both these studies the HPV vaccine was injected intralesionally into the wart itself and did not use the vaccine on its FDA-approved vaccine schedule as an intramuscular injection,” said Dr. Juhasz.
The HPV vaccine’s use as a therapeutic for the treatment of warts is not without potential side effects. “During our study, adverse events were mild, transient, and well-tolerated, and included pain during injection, localized itching, mild erythema, and edema,” said Dr. Nofal. “Systemic adverse effects — flu-like symptoms such as headache, fever, and nausea — were much less frequent than reported with intramuscular vaccination in clinical trials.”
“The lack of FDA-approval for treatment of cutaneous warts is definitely a hurdle because depending on the patient’s age, the vaccine may not be covered by insurance. In addition, the vaccine is multi-dose, and the vaccine schedule must be followed.”
According to Dr. Juhasz, further research needs to be completed to fully evaluate potential adverse events related to use of the HPV vaccine as a treatment of cutaneous warts. “We know from use of the HPV vaccines for routine cervical cancer protection they have long-term safety data,” she said. “Based on the current literature, there is no evidence against the use of HPV vaccines as a therapeutic option for cutaneous warts. However, we currently lack robust, multicenter clinical trials. Of course, if a patient has a reported prior adverse reaction to the HPV vaccine, it should be avoided.”
Another unknown is whether a patient’s vaccination status may interfere with the efficacy of the HPV vaccine as a therapeutic treatment for warts. “This is a great question. We really don’t know if a patient’s previous vaccination status will cause them to respond differently to subsequent HPV vaccination,” said Dr. Juhasz. “In studies, younger children (age 9-11 years) demonstrate increased clinical response to the vaccine for cutaneous warts than adolescents and adults, which could suggest prior vaccination status does play a role.”
As the HPV vaccine is not currently approved for use as a treatment in warts, dermatologists may find it challenging to implement as a treatment at this time. “The lack of FDA-approval for treatment of cutaneous warts is definitely a hurdle because depending on the patient’s age, the vaccine may not be covered by insurance. In addition, the vaccine is multi-dose, and the vaccine schedule must be followed,” said Dr. Juhasz.
However, as further research continues to be underway, the HPV vaccine may soon become a routine tool in dermatologists’ arsenal against stubborn warts, suggested Dr. Nofal. “I believe intralesional HPV vaccines can be added to the armamentarium against warts,” she said. “It is important to take into consideration that some patients who show resistance to certain immunotherapeutic modalities are responsive to others. That’s why it is important to widen the pool available for both physicians and patients to choose from.”
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