Abstract
The human papillomaviruses (HPVs) are a family of small DNA tumor viruses including over 200 genotypes classified by phylogeny into several genera. Different genera of HPVs cause ano-genital and oropharyngeal cancers, skin cancers, as well as benign diseases including skin and genital warts. Licensed vaccines composed of L1 virus-like particles (VLPs) confer protection generally restricted to the ≤9 HPV types targeted. Here, we examine approaches aimed at broadening the protection against diverse HPV types by targeting conserved epitopes of the minor capsid protein, L2. Compared to L1 VLP, L2 is less immunogenic. However, with appropriate presentation to the immune system, L2 can elicit durable, broadly cross-neutralizing antibody responses and protection against skin and genital challenge with diverse HPV types. Such approaches to enhance the strength and breadth of the humoral response include the display of L2 peptides on VLPs or viral capsids, bacteria, thioredoxin and other platforms for multimerization. Neither L2 nor L1 vaccinations elicit a therapeutic response. However, fusion of L2 with early viral antigens has the potential to elicit both prophylactic and therapeutic immunity. This review of cross-protective HPV vaccines based on L2 is timely as several candidates have recently entered early-phase clinical trials.
Highlights
Therapeutic vaccines aimed at treating pre-existing infections and disease generally target early antigens, primarily E6 and E7, as they are obligately expressed in infected cells and cancer, and are being developed to help those suffering human papillomaviruses (HPVs)-related disease
The immunogenicity of peptide vaccines has been increased by chemical coupling of protective L2 epitopes to the surface amino acids of a protein carrier, typically keyhole limpet hemocyanogen (KLH) which provides a source of T helper epitopes and potentially irregular multimerization tethered at one end only [35,37,56,57]
The above vaccines are formulated by mixing with a conventional adjuvant prior to administration, but improved immunogenicity might be achieved by direct conjugation of L2 to a defined adjuvant, such as a toll-like receptor (TLR) agonist
Summary
Papillomaviruses are small DNA tumor viruses with a range of malignant potential; most infections are benign and self-limiting but a ‘high risk’ group of HPVs are the etiologic agents of 4.5% of cancers worldwide [1]. The ‘low risk’ types in this genus, e.g., HPV6 and HPV11, induce benign skin warts as well as laryngeal papillomas that very rarely progress to cancer, as in the slow growing Buschke Lowenstein tumors or lung cancers, respectively. Even these benign papillomas are associated with significant morbidity and healthcare costs. Beta HPVs typically produce only subclinical infections or flat warts They are the subject of considerable interest as mounting evidence suggests the role of a subset of types as a co-carcinogen with UV light in the development of cutaneous squamous cell carcinoma (CSCC) [17,18].
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