Abstract
This review provides an overview of current therapeutic human papillomavirus (HPV) vaccination approaches. We examine crucial development criteria and present vaccines currently in clinical trials for precursor lesions or established cancers. Subsequently, we list approaches that were abandoned after reaching clinical trial stage. We also discuss promising preclinical studies. We conclude with a brief overview of novel in silico tools developed to enhance vaccine design.
Introduction
Human papillomaviruses and cancer
Human papillomaviruses (HPV) comprise over 200 known double-stranded DNA viruses that infect the basal keratinocytes of squamous epithelia in the skin and mucosae. While most HPV types cause no disease or only benign skin and anogenital warts, at least 12 types are considered oncogenic and termed high-risk types (hrHPV). These include HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59 (https://monographs.iarc.who.int/list-of-classifications). Notably, HPV6 and HPV11, two low-risk types, are associated with the development of recurrent respiratory papillomatosis (RRP) (1). In most cases, HPV infections, even high-risk infections, resolve spontaneously within two years, highlighting HPV's susceptibility to immune attack. This has been recently demonstrated by the FDA's approval of the first therapeutic HPV vaccine, targeting HPV6 and HPV11 in the context of RRP (https://www.fda.gov/news-events/press-announcements/fda-approves-first-immunotherapy-recurrent-respiratory-papillomatosis). Persistent infections with high-risk HPV types are a prerequisite for developing multiple malignancies, including cervical, other anogenital, and a subset of head and neck cancers, accounting for approximately 5% of all cancer cases worldwide, i.e., around 730,000 cases in 2022 (2). HPV16 is the most prevalent hrHPV, responsible for ~60% of cervical cancers and over 85% of HPV-induced head and neck cancers (3, 4). HPV18 ranks second, causing ~15% of cervical cancer cases (3, 5).
Before advancing to advanced cancer stages, hrHPV are involved in the development of precursor lesions, known as intraepithelial neoplasia (e.g., Cervical Intraepithelial Neoplasia - CIN). In Germany, for instance, it is estimated that approximately 6,250 women are diagnosed with HPV-related cancers annually, while around 56,000 women are treated for precursor lesions within the same period (https://www.rki.de/DE/Aktuelles/Publikationen/RKI-Ratgeber/Ratgeber/Ratgeber_HPV.html).
Prevention, detection, and treatment of HPV-related cancers
It is estimated that almost all sexually active individuals will be exposed to HPV during their lifetime (6). Prophylactic vaccines are based on viral-like particles (VLPs) consisting of the type-specific capsid protein L1, aiming to protect individuals who have not been exposed to the targeted HPV types from future infections. Prophylactic HPV vaccines (e.g., Gardasil™, Cervarix™, and Cecolin™) have been integrated into national immunization programs in 125 countries for girls, while 47 countries have also included boys (7, 8). However, only 28% of girls received their first dose of an HPV prophylactic vaccine in 2023 (https://www.who.int/data/gho/data/indicators/indicator-details/GHO/girls-aged-15-years-old-that-received-the-recommended-doses-of-hpv-vaccine), a figure far below the 90% global coverage goal set for 2030 in the WHO strategy to accelerate the eradication of cervical cancer (7). While effective in individuals naive to HPV, prophylactic vaccines do not protect against the development of lesions in individuals already infected with hrHPV. Regular screening with Papanicolaou (Pap) smears and HPV DNA testing enable early detection of HPV.