Human papillomaviruses (HPVs) are DNA viruses responsible for causing premalignant lesions and epithelial malignancies of the upper digestive tract, including cancers of the mouth and throat and cancers of the lower anogenital tract such as cervix, anus, vagina, vulva and penis. Globally, HPV infection accounts for 7.5% (1,505,394 cases) of the cancer burden worldwide. Human papillomavirus (HPV)-driven malignancies, particularly cervical and head and neck cancers (HNC), continue to pose significant clinical challenges today despite standard interventions. Current treatment options remain inadequate, with high mortality rates persisting among patients with advanced disease. To address this gap, we have designed a novel therapeutic vaccine to elicit robust, antigen-specific CD8+ T cells responses against HPV-associated solid tumours, offering a promising avenue for improved clinical outcomes.
Previous studies from our group and others demonstrated that HPV-specific T-cell responses in HNC patients recognize a broad range of CD8+ T cell epitopes from multiple HPV antigens. Based on these findings, we have developed a therapeutic “off-the-shelf” immunotherapy to counter HPV-associated solid cancers. Five engineered adenoviral HPV polyepitope DNA constructs were successfully cloned using the adenoviral expression system. In parallel, two mRNA-based polyepitope vaccine candidates were developed and formulated with lipid nanoparticles (LNPs) for efficient delivery. These recombinant HPV polyepitope vaccines were engineered to encode multiple CD8⁺ T-cell epitopes derived from multiple HPV antigens and their immunogenicity was evaluated using in vitro assays and in vivo models. In vitro assays demonstrated robust antigen-specific CD8⁺ T-cell activation in human PBMC cultures. Notably in vivo immunogenicity was confirmed in HLA-transgenic mice, where both vaccine platforms elicited strong, multi-epitope CD8⁺ T-cell responses, indicating their potential for broad and effective HPV-targeted immunotherapy. To optimise the immunogenicity of HPV vaccines further and to overcome the inherent limitations of individual platforms, we have evaluated combination strategies to enhance the quality and magnitude of immune responses and characterised protective immune signatures using advanced approaches, including bulk RNA sequencing. These preclinical findings will offer valuable insights into the design of HPV vaccines capable of eliciting robust cellular immune responses. The data supports the rationale for advancing these vaccine candidates into human clinical trials to induce therapeutic immunity in HPV-infected individuals, paving the way for potential curative strategies against HPV-driven HNC and cervical cancer.