Identification of promiscuous HPV16‐derived T helper cell epitopes for therapeutic HPV vaccine design

Cervical carcinoma and several other human papillomavirus (HPV)‐induced malignancies are a global public health problem, thus novel treatment modalities are urgently needed. Immunotherapy is an attractive option for treatment of HPV infection and HPV‐mediated premalignant and malignant lesions. However, previous approaches—focusing on the induction of cytotoxic CD8+ T cells (CTLs)—have as yet not yielded clinical successes. Since CD4+ T cells have been shown to be crucial for the induction and maintenance of CTL responses, and more recently to be also important for direct anti‐tumor immunity, human leukocyte antigen (HLA) class II‐restricted epitopes are intensively investigated to improve the efficacy of peptide‐based HPV immunotherapy. We here present an approach to identify promiscuous HPV16‐derived CD4+ T helper epitopes, which are capable of inducing T cell immunity in a large proportion of the population. To this end, we combined HLA class II epitope prediction servers with in vitro immunological evaluation to identify HPV16 E2‐, E5‐, E6‐, and E7‐derived CD4+ T cell epitopes. Candidate selected HPV16‐derived epitopes were found to be restricted by up to nine HLA‐DR molecules. Furthermore, they were found to induce frequent and robust HPV16 peptide‐specific Th1 responses in healthy donors, as monitored by interferon (IFN)‐γ ELISPOT and cytokine secretion assays. Moreover, these selected peptides also induced specific IFN‐γ T cell responses in blood from HPV16+ CIN2/3 and cervical carcinoma patients. We thus conclude that the identified T helper epitopes are valuable candidates for the development of a comprehensive therapeutic HPV vaccine. What's new? The success of therapeutic vaccines for the treatment of cancers depends largely on the ability to activate both T helper cells and cytotoxic CD8+ T cells. Ideally, CTL and T helper epitopes are derived from the same tumor antigen. In this respect, the paucity of known HPV‐derived T helper epitopes presents a challenge for peptide‐based therapeutic HPV vaccine design. In this study, multiple HPV16‐derived T helper epitopes capable of inducing T‐cell immunity in individuals of diverse genetic backgrounds were identified. The epitopes were found to bind promiscuously to several HLA class II molecules and thus could be included in therapeutic vaccines that would be effective for a large percentage of the population.