Recurrent respiratory papillomatosis: Recent advances in HPV-6/HPV-11-targeted immunotherapy

Recurrent respiratory papillomatosis (RRP) is caused by human papillomavirus (HPV) types 6 and 11. Juvenile-onset RRP (JoRRP), typically acquired during birth, and adult-onset RRP (AoRRP), commonly associated with sexual transmission, are both predominantly caused by HPV-6, followed by HPV-11. HPV-11 infection, more frequent in children, is associated with more severe disease, increased risk of tracheobronchial and pulmonary spread, and, rarely, RRP-related mortality. Local immune tolerance within the airway mucosa is thought to impair clearance of HPV-6/11-infected cells, resulting in persistent infection and recurrent papilloma growth. Surgical debulking remains the cornerstone of management; however, JoRRP requires substantially more procedures than AoRRP (4-8 vs 1-2 per year), leading to cumulative morbidity, including vocal fold scarring, anterior commissure webbing, glottic or subglottic stenosis, and pulmonary dissemination. Defective innate immune activation and impaired HPV-specific cellular immunity contribute to viral persistence, with the papilloma microenvironment characterized by ineffective antiviral T-cell responses. To reduce surgical burden, immunotherapeutic strategies targeting HPV-6/11 antigens have been developed. Three platforms have advanced into phase 1-2 clinical trials: a gorilla adenoviral vector (gAdeno)-based therapy, a DNA plasmid vaccine, both encoding HPV-6/HPV-11 E6/E7 oncoproteins, and a Modified Vaccinia Ankara (MVA)-based bovine papillomavirus E2 vaccine. These approaches aim to elicit robust E6/E7-specific cellular immunity, particularly CD8+ T-cell responses, to overcome local immune tolerance and eradicate HPV-infected cells. The gAdeno-based therapy is the first FDA-approved immunotherapy for RRP; however, with annual treatment costs exceeding USD 300,000, ensuring equitable access remains a critical challenge.