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The Role of Immunotherapy in Wart Treatment: A Review

By Nina Mbonu, BS, and Sandra Marchese Johnson, MD, FAAD

Abstract

Warts, benign growths on the skin caused by the human papillomavirus (HPV), remain a therapeutic challenge due to their persistence and recurrence. Traditional therapies, such as cryotherapy and topical agents, often provide incomplete resolution, calling for the need for alternative treatment options. Immunotherapy has become a worthwhile option, using the body’s immune system to target and clear treated and untreated HPV-infected cells. This review explores the efficacy, mechanisms, and clinical application of intralesional immunotherapy, highlighting antigens such as Candida albicans, measles-mumps-rubella (MMR) vaccine, and purified protein derivative (PPD). Special emphasis is placed on Candida antigen as an efficacious and cost-effective option for recalcitrant warts. The findings support immunotherapy as a transformative option in dermatology, with promising outcomes across different wart types.

 

 

Introduction

Warts are a common dermatologic condition caused by HPV, a DNA virus with more than 100 genotypes that infect keratinocytes. These lesions vary in morphology and include types such as common, plantar, periungual, and anogenital warts. Although warts are benign, they can significantly impact quality of life by causing physical discomfort, cosmetic concerns, and psychosocial distress. Traditional therapies, including cryotherapy and topical agents, focus on local destruction of wart tissue but often fail to address the underlying HPV infection, leading to high recurrence rates.

Immunotherapy for treating all warts, and especially recalcitrant warts, by using the immune system to target and remove HPV-infected cells, has garnered favor over the past 20 years and is often considered first-line treatment now. With intralesional immunotherapy, antigens are injected into the wart to trigger an immune response that can clear both the treated and nearby untreated warts. This review evaluates the mechanisms, efficacy, and safety of immunotherapy, with a particular focus on Candida antigen.

Overview of Immunotherapy


Immunotherapy is a breakthrough in wart treatment, using the body’s immune system to rid HPV infections throughout the body. Unlike traditional destructive methods, which focus on localized tissue destruction, immunotherapy induces a delayed-type hypersensitivity reaction that activates immune cells, including T lymphocytes, against HPV-infected cells. This systemic effect allows for the resolution of both injected and distant untreated warts, making immunotherapy particularly effective for patients with multiple or recalcitrant lesions.

The broad scope of intralesional immunotherapy includes agents such as the Candida albicans antigen, MMR vaccine, PPD, and quadrivalent HPV vaccine. These agents vary in their mechanisms of action but share the common goal of stimulating an immune response to eradicate HPV-infected cells.

Types of Intralesional Immunotherapy

MMR Vaccine

The MMR vaccine has demonstrated efficacy in inducing an immune response against HPV-infected cells through cross-reactive antigenic stimulation. Studies report clearance rates of 62.5–73% for warts treated with intralesional MMR vaccine, making it an option for recalcitrant warts. Its ability to stimulate systemic immunity provides benefits for clearing untreated distant lesions. However, mild side effects, such as erythema and pain at the injection site, are common.1,2

PPD

PPD, traditionally used for tuberculosis testing, has shown promising results as an intralesional therapy for warts. It induces a Th1-mediated immune response, leading to increased cytokine production and wart clearance. Clearance rates range from 55% to 70%, with efficacy varying by wart type and patient population. Despite its effectiveness, PPD may cause localized swelling and discomfort during treatment.2,3

Quadrivalent HPV Vaccine

The quadrivalent HPV vaccine targets specific HPV genotypes and has been evaluated as an intralesional treatment for warts. Its systemic immune activation has shown clearance rates of approximately 50–70% in some studies. While effective, its high cost and limited availability in low-resource settings pose significant challenges to widespread use.2,3

Other Agents

Other intralesional therapies include Mycobacterium w vaccine, Bacillus Calmette–Guérin (BCG), and Trichophyton antigens. These agents have been explored for their immunostimulatory effects, with varying degrees of efficacy. While these therapies provide additional options for resistant warts, more extensive studies are needed to establish standardized protocols and comparative efficacy.1,2

Candida Antigen Immunotherapy

Candida antigen immunotherapy has emerged as one of the most effective and well-tolerated options for intralesional wart treatment. This therapy involves injecting Candida albicans antigen into the wart, which triggers a delayed-type hypersensitivity response, recruiting immune cells to clear HPV-infected keratinocytes. This approach not only resolves treated lesions but also frequently clears distant untreated warts due to its systemic immunomodulatory effects.4,5

Efficacy

Studies consistently report high clearance rates with Candida antigen, ranging from 63% to 82.5%, depending on the patient population and wart type.4,6 Johnson et al. demonstrated that 74% of patients receiving Candida antigen immunotherapy experienced complete clearance of treated warts, with distant untreated warts resolving in 78% of responders.4 A pivotal study comparing Candida antigen to cryotherapy and the quadrivalent HPV vaccine found that Candida antigen achieved superior clearance rates for multiple recalcitrant warts, particularly those resistant to prior treatments.7,8

In pediatric populations, Candida antigen immunotherapy has proven to be particularly effective for managing recalcitrant warts. Clifton et al. evaluated 47 children with resistant warts and reported that 47% of patients experienced complete clearance of treated warts after an average of 3.78 treatments.6 Furthermore, 68% of participants with multiple warts observed at least partial resolution of untreated, distant warts, with 34% achieving complete clearance of all lesions. These findings emphasize the systemic immunologic response induced by Candida antigen, which extends beyond the site of injection to distant lesions.

Additionally, intralesional Candida immunotherapy has proven particularly beneficial for individuals living with HIV, as it helps overcome the immune system deficiencies typically seen in this population. Wong and Crawford found that Candida antigen immunotherapy significantly improved wart treatment outcomes in patients with HIV, offering an effective therapeutic approach for managing warts in immunocompromised individuals.9

Advantages

Candida antigen immunotherapy offers several advantages over traditional therapies. It is minimally invasive, cost-effective, and associated with a low recurrence rate. Unlike destructive methods, which often target individual warts, Candida antigen provides systemic benefits by clearing both injected and non-injected warts. These attributes make it particularly valuable for patients with multiple lesions or recalcitrant warts unresponsive to standard treatments.4,5

This combination of systemic efficacy and minimal invasiveness is especially advantageous in pediatric patients, who often struggle with the pain and discomfort associated with destructive treatments like cryotherapy. By offering a less invasive yet highly effective alternative, Candida antigen immunotherapy reduces the physical and emotional burden of wart treatment in children. Clifton et al. further emphasized its value in pediatric populations, noting its ability to achieve significant clearance rates while improving treatment adherence.6

Safety and Limitations

Although generally well-tolerated, Candida antigen therapy is not without risks. Common side effects include localized erythema, swelling, and mild flu-like symptoms, which typically resolve without intervention.4,6 Rare complications, such as fingertip ischemia and uveitis, have been reported, emphasizing the need for careful patient selection and monitoring during treatment. Despite these limitations, the benefits of Candida antigen immunotherapy outweigh its drawbacks, particularly for patients with refractory warts.10,11

Discussion

Intralesional immunotherapy has redefined the management of warts. Its systemic immune activation enables the clearance of both treated and untreated lesions, offering a significant advantage for patients with recalcitrant or multiple warts. Candida antigen has emerged as a leading immunotherapeutic agent, demonstrating high efficacy, favorable safety profiles, and cost-effectiveness. Its ability to elicit a robust immune response, combined with its accessibility, positions it as a first-line option for resistant warts.

While other agents such as the MMR vaccine and PPD also show promise, Candida antigen’s superior efficacy and systemic effects make it a preferred choice in many clinical settings. Biomarkers such as elevated TLR4 expression and IFN-a levels provide valuable insight into predicting therapeutic response and optimizing treatment protocols.12,13

Although most studies focus on immunocompetent patients, the potential of Candida antigen in immunocompromised populations warrants further attention. While Candida antigen has demonstrated consistent efficacy in the general population, its role in individuals with altered immune responses, such as those with HIV, has not been extensively studied. A recent case series in HIV-positive patients with long-standing warts showed mixed results, with some achieving clearance and others not responding to treatment.9 This study emphasizes the need for further research to understand how immunocompromised states impact treatment efficacy and whether adjustments to the treatment regimen are required.

To build on these observations, future research should not only investigate the specific impact of immune status but also focus on large-scale comparative trials. These trials would help establish standardized dosing regimens, identify optimal combinations of immunotherapeutic agents, and enhance our understanding of the immunological mechanisms driving wart clearance. Additionally, exploring how patient-specific factors—such as age, immune status, and viral subtype—affect therapeutic outcomes will be essential in refining treatment strategies, ensuring that equitable and personalized care can be delivered to diverse populations.

In conclusion, Candida antigen immunotherapy represents a highly effective and practical solution for managing resistant warts. As research progresses, its potential to be integrated with other immunotherapeutic strategies and applied to a wider range of clinical scenarios is likely to enhance its value further. Further investigation into its mechanisms and patient-specific factors will be essential in optimizing its use and maximizing its impact in dermatology and beyond.

REFERENCES

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  2. Fawzy MM, Nofal A, Alakad R. Intralesional antigen immunotherapy for the treatment of plane warts: A comparative study. Dermatol Ther. 2020;33(6):e13807.https://doi.org/10.1111/dth.13807
  3. Nofal A, Alakad R, Fouda I, Fawzy MM. Intralesional antigen immunotherapy in the treatment of periungual warts. J Cutan Med Surg. 2021;25(3):286–292. https://doi.org/10.1177/1203475420988859
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  13. Sabry HH, Hamed AM, Salem RM, Marei AM, El Sebaey RM. Peripheral blood toll-like receptor 4 correlates response to Candida immunotherapy of warts. Dermatol Ther. 2018;31(5):e12691. https://doi.org/10.1111/dth.12691

 

ABOUT THE AUTHORS
Nina Mbonu, BS, is a Medical Student at the Meharry Medical College School of Medicine and an Incoming Resident at the University of Tennessee Health Science Center in Memphis, TN.
Sandra Marchese Johnson, MD, FAAD, is the Founder of Johnson Dermatology in Fort Smith, AR.

DISCLOSURES
Nina Mbonu, BS, and Sandra Marchese Johnson, MD, FAAD, report no disclosures.

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