A multi-genotype therapeutic human papillomavirus vaccine elicits potent T cell responses to conserved regions of early proteins.

Despite an efficacious prophylactic human papillomavirus (HPV) vaccine there is still a considerable global burden of HPV-related disease. Therapeutic vaccines that could prevent cancers in at-risk women are urgently needed. Most candidate therapeutic vaccines have focused on two high-risk (hr) HPV genotypes, 16 and 18, and two viral targets, E6 and E7, which may limit global coverage and efficacy. We designed the synthetic gene '5GHPV3' by selecting conserved regions from each of the six early proteins and generating consensus sequences to represent five hrHPV genotypes. 5GHPV3 was delivered by plasmid DNA, chimpanzee adenovirus (ChAdOx1) and modified vaccinia Ankara (MVA) vectors in prime-boost regimens to mice. ChAdOx1-5GHPV3 / MVA-5GHPV3 induced higher magnitude and more durable HPV-specific T cell responses than other regimens. Vaccine-induced T cells were polyfunctional and persisted at high frequencies for at least six weeks. Importantly, HPV-specific effector CD8 + T cells were detected in the cervix following systemic administration of ChAdOx1-5GHPV3 / MVA-5GHPV3 and increased in frequency over time, indicating continued trafficking of T cells to the cervix. Finally, T cells specific for 5GHPV3 encoded antigens were detected by IFN-γ Elispot in women with current or past hrHPV infections, confirming the presence of epitopes relevant to natural immune control.