Head & Neck. 2019; 41(3): 657-665. doi: 10.1002/hed.25477

MVA E2 therapeutic vaccine for marked reduction in likelihood of recurrence of respiratory papillomatosis

Olga Beltran1, Ricardo Rosales 2

From the 1Department of Otorhinolaryngology, National Institute of Rehabilitation, Mexico City, Mexico, and 2Virolab, S de RL de CV, Cuernavaca, Morelos, Mexico

Correspondence should be addressed to Ricardo Rosales, Department of Molecular Biology, Virolab, S de RL de CV, Cuernavaca, Morelos, Mexico, Email: rrosalesvirolab10@gmail.com

 

Abstract

BACKGROUND:

Recurrent respiratory papillomatosis (RRP) or laryngeal papillomatosis is a disease caused by papillomavirus infection.

METHODS:

In this phase I/II clinical trial, we evaluated the efficacy of the modified vaccinia Ankara (MVA) E2 virus in the treatment of RRP. Twenty-nine patients (18 female and 11 male) underwent injection of MVA E2 directly into the borders of the vocal cords where lesions were seen and were monitored by direct laryngoscopy. The immune response was assessed by the determination of CD3+, CD4+, and CD8+ lymphocytes counts. The presence of papillomavirus was determined by polymerase chain reaction analysis.

RESULTS:

Lesions were completely eliminated in 13 patients (44.8%). In 16 patients (55.2%), lesions recurred between 6 and 18 months after treatment; these patients received a second round of treatment with MVA E2, and they are not seen with new recurrences.

CONCLUSION:

The MVA E2 vaccine has excellent potential for generating complete regression of RRP lesions.

https://doi.org/10.1002/hed.25477

 

Supplement:

Recurrent respiratory papillomatosis (RRP) is a serious and aggressive disease with a significant impact on the quality of life of people suffering from it. The disease is caused by the human papillomavirus (HPV), and it is and characterized by the appearance of papillomatosis lesions in various parts of the aero-digestive tract (1, 2). The disease is classified as juvenile-onset (JRRP) if it develops before the age of 18, and adult-onset (ARRP) when it develops after the age of 18. RRP occurs more frequently in children and young adults. In the case of children, the virus is believed to be acquired by contact with lesions in the birth canal of papilloma-infected mothers. In the case of adults, infection with the virus may occur following oral sex, but this remains unproven (3). Re-activation of a latent HPV infection acquired in childhood is another possible cause (3). Juvenile-onset RRP is generally more aggressive, with multiple papillomatosis lesions typically in the larynx, and has a high recurrence rate (1-3). The adult-onset RRP occurs more commonly in men, with inflammatory lesions tending not to spread. Also, ARRP presents less recurrences than the JRRP. The estimated incidence of RRP is approximately 4 per 100,000 in children and 2 per 100,000 in adults (1-3).

 

Papillomavirus belong to the Papovaviridae family of DNA viruses. These viruses contain a double strand DNA within an icosahedral capsid, composed of 72 capsomeres. More than 180 types of HPV have been identified by DNA sequences, and named sequentially (4). HPV have selective tropism for cutaneous or mucosal epithelia and are classified into two groups: low-risk that cause benign lesions, named papillomas (small wart-like neoplasias); and high-risk that cause malignant transformation and develop into large tumors. High-risk HPV are clearly associated with cancer of the cervix, other tumors in anogenital areas, and tumors of the head and neck (5). The two most common low-risk HPV are HPV-6 and HPV-11. They are responsible for 90% of genital warts and recurrent respiratory papillomas (6). Patients infected with HPV-11 usually progress to more aggressive disease, characterized by proliferation and differentiation of epithelial cells, resulting in cauliflower-likeexophytic growth lesions (1-3).

 

Figure 1. Endoscopic view of laryngeal papilloma lesions in a patient with RRP.

 

In RRP, papillomas may grow as individual or as multiple nodular lesions. These lesions are generally limited to the larynx, but frequently affect the vocal cords (Figure 1), ventricular pleats, subglottis, and laryngeal surface of the epiglottis (2). However, lesions can occur in any part of the aerodigestive tract and even reach to the trachea and lungs (1-2). Clinically, RRP appears with nonspecific symptoms of airway disfunction, including chronic cough, hoarseness, wheezing, voice change, stridor, and chronic dyspnea. In children, progressive hoarseness, stridor, and breathing difficulty usually appear together. In adults, hoarseness is the most common symptom. The evolution of RRP is variable. It can show spontaneous remission in very few cases, but more frequently, in the majority of cases, it is aggressive, requiring multiple surgical treatments due to multiple recurrences (1-3). Thus, RRP exhibits high morbidity with a potentially fatal outcome, as treatment often fail in the long term, and recurrences are the rule.

 

Nowadays there is not a definite curative treatment for RRP. Surgical removal of the papillomas is therefore the main course of action to allow proper functioning of the airway and to preserve the quality of phonation (7). The objective of repeated treatments is to reduce the size of recurrent lesions in the upper airway as much as possible without damaging normal structures. Because, HPV may also be present in mucosa that appears macroscopically healthy, and it is impossible to distinguishing infected cells with normal appearance from uninfected cells, many complications, including respiratory tract burns, severe laryngeal scarring and stenosis, are associated with exceedingly aggressive cold-steel or laser surgery. Hence, micro laryngeal surgery with micro-debrides is becoming the treatment of choice. However, serious surgical complications, such as synechia of the larynx and glottic stenosis, still occur, particularly in patients who undergo multiple procedures (7). The persistence of the viral genome in the remaining tissue is believed to be the principal explanation for such recurrence (1, 2, 6). In addition, to the clinical complications and the decline in quality of life, multiple surgical treatments involve very high health care costs. In the US, it was estimated that treatment just in the first two years of the disease can be as high as $70,000 (8). The total lifetime cost to treat one case of RRP may reach $400,000 in a variable course, ranging from spontaneous remission to multiple recurrences and even malignant transformation.

 

To improve the situation various adjuvant methods of treatment have been used in a small fraction (20 %) of patients (1-2). The current criteria for adjuvant therapy are the requirement for more than four surgical procedures annually, rapid recurrence of papillomas with airway compromise, and distal multisite spread of the disease (1, 2, 6). Adjuvants used include interferon and antiviral agents, such as acyclovir and cidofovir. Interferon treatment resulted in better disease evolution with reduction of lesion growth in some patients. However, the intravenous administration of interferon leads to severe systemic toxicity (2, 7). Common side effects include transient fever, fatigue, nausea, arthralgia, and headache. Cidofovir, an analog of cytosine, is currently the most commonly used antiviral in treatment for RRP. Cidofovir administration has led to variable, sometimes promising, results (2, 7). The introduction of vaccines against HPV offers potential for prevention of this disease in the future, by reducing the incidence of the virus. The quadrivalent vaccine is indicated for the prevention of cervical and anogenital cancers and pre-carcinogenetic lesions associated with HPV types 6,11,16, and 18 (9). Nevertheless, the impact of the vaccination is not yet fully determined (10).

 

Considering the severity of RRP, the negative impact on patients’ quality of life, and the high cost to health systems for repetitive interventions, it is unfortunate that surgery remains the mainstay of treatment for this disease. A novel very promising alternative is described in the present publication. Patients with RRP were treated with the recombinant modified vaccinia Ankara (MVA) E2 vaccine, and found to be free of recurrent lesions for more than two years. Thus, the MVA E2 vaccine has excellent potential for generating complete regression of RRP lesions.

 

The recombinant MVA E2 vaccine contains the bovine papilloma virus E2 protein (10). This recombinant therapeutic vaccine has been shown to induce a strong immune response involving the generation of antibodies and a cytotoxic activity against HPV-infected cells (11). In clinical trials, MVA E2 completely eliminated precancerous lesions in 94 % of patients, while reducing the severity of lesions from CIN 3 to CIN 1 grade in the rest of treated patients (12). Also, 50 % of patients completely eliminated the HPV, and in the remaining 50 % of patients, HPV DNA was reduced to only 10% of the original viral load (12). In addition, specific cytotoxic activity against cancer cells correlated with clinical outcome (13). MVA E2 treatment was also effective in eliminating lesions in HPV-infected men presenting intraurethral flat condylomas (14). More recently, in a phase Ⅲ clinical trial, female patients with ano-genital intraepithelial lesions were treated with MVA E2 directly into the uterus, vulva, or anus lesions. In 1045 women (89 % out of the 1176 treated patients) a complete elimination of lesions was found. These patients also generated a specific cytotoxic response against papilloma transformed cells (15). Thus, because the local application of the MVA E2 vaccine has shown to be an excellent therapy for stimulating the immune system and creating regression of HPV-induced intraepithelial lesions, we decide to evaluate the therapeutic potential of MVA E2 in patients with RRP.

 

 

Figure 2. Twenty-nine patients with recurrent respiratory papillomatosis (RRP), who have had several recurrences were treated with the modified vaccinia Ankara (MVA) E2 therapeutic vaccine after surgery. A) Percentage of patients with recurrences after one or two rounds of treatment with MVA E2. B) Recurrent index X= number of patients with recurrences within 18 months after surgery, before and after one or two rounds of treatment with MVAE2.

 

Figure 3. Endoscopic view of larynx of a representative patient treated with modified vaccinia Ankara (MVA) E2 therapeutic vaccine. The patient was free of lesions after MVA E2 treatment for more than five years.

 

In the present report, 29 patients with RRP who underwent surgical elimination of papilloma lesions, received adjuvant treatment with MVA E2 directly injected into the larynx mucosa at the site of lesions. Patients, ranging from 3 to 70 years and involving both sexes, had multiple recurrences and some of them had undergone more than 10 surgical interventions before enrollment in the study. All patients developed new lesions within 6 months after surgery before treatment with the MVA E2 vaccine. In order to compare the recurrence rate in patients before and after treatment, a recurrent index (designated X) was defined as the number of patients with recurrences during an 18-month period. All patients had an X=1 patient/month, before treatment (Figure 2). After, surgery and treatment with MVA E2, 13 patients (45 %) did not present any recurrences for 3 to 5 years. Thus, they had an X=0 patient/month (Figure 2). The other 16 patients (55 %) presented recurrent lesions within 18 months after surgery, with and X=0.88 patient/month (Figure 2). This suggested that a single round of recombinant vaccine injections was ineffective. Therefore, these patients received a second round of MVA E2 injections. After a second treatment, none of the patients in this group presented new lesions in the subsequent months or years. Thus, they had an X = 0 patient/month (Figure 2). Most patients also presented a normal healthy tissue after treatment (Figure 3). Importantly, no adverse events (involving skin and body in general, or musculoskeletal, gastrointestinal, urogenital, nervous, and respiratory systems) were detected in any patient involved in this study.

 

In conclusion, the data presented in this report suggests that the MVA E2 therapeutic vaccine is a promising adjuvant treatment for RRP.

 

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