title: Attenuated Recombinant Influenza A Virus Expressing HPV16 E6 and E7 as a Novel Therapeutic Vaccine Approach.
abstract: Persistent infection with high-risk human papillomavirus (HPV) types, most often HPV16 and HPV18, causes all cervical and most anal cancers, and a subset of vulvar, vaginal, penile and oropharyngeal carcinomas. Two prophylactic virus-like particle (VLPs)-based vaccines, are available that protect against vaccine type-associated persistent infection and associated disease, yet have no therapeutic effect on existing lesions or infections. We have generated recombinant live-attenuated influenza A viruses expressing the HPV16 oncogenes E6 and E7 as experimental immunotherapeutic vaccine candidates. The influenza A virus life cycle lacks DNA intermediates as important safety feature. Different serotypes were generated to ensure efficient prime and boost immunizations. The immune response to vaccination in C57BL/6 mice was characterized by peptide ELISA and IFN-γ ELISpot, demonstrating induction of cell-mediated immunity to HPV16 E6 and E7 oncoproteins. Prophylactic and therapeutic vaccine efficacy was analyzed in the murine HPV16-positive TC-1 tumor challenge model. Subcutaneous (s.c.) prime and boost vaccinations of mice with recombinant influenza A serotypes H1N1 and H3N2, followed by challenge with TC-1 cells resulted in complete protection or significantly reduced tumor growth as compared to control animals. In a therapeutic setting, s.c. vaccination of mice with established TC-1 tumors decelerated tumor growth and significantly prolonged survival. Importantly, intralesional vaccine administration induced complete tumor regression in 25% of animals, and significantly reduced tumor growth in 50% of mice. These results suggest recombinant E6E7 influenza viruses as a promising new approach for the development of a therapeutic vaccine against HPV-induced disease.
authors.affiliation: Laboratory of Viral Oncology (LVO), Division of Immunology, Allergy and Infectious Diseases (DIAID), Department of Dermatology, Medical University of Vienna, Vienna, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Jindra
authors.affiliation: Laboratory of Viral Oncology (LVO), Division of Immunology, Allergy and Infectious Diseases (DIAID), Department of Dermatology, Medical University of Vienna, Vienna, Austria.
authors.forename: Bettina
authors.initials: B
authors.lastname: Huber
authors.affiliation: Laboratory of Viral Oncology (LVO), Division of Immunology, Allergy and Infectious Diseases (DIAID), Department of Dermatology, Medical University of Vienna, Vienna, Austria.
authors.forename: Saeed
authors.initials: S
authors.lastname: Shafti-Keramat
authors.affiliation: Research Group Oncology (RGO), Equine Clinic, Veterinary University of Vienna, Vienna, Austria; Bluesky Vaccines, Vienna, Austria.
authors.forename: Markus
authors.initials: M
authors.lastname: Wolschek
authors.affiliation: Bluesky Vaccines, Vienna, Austria.
authors.forename: Boris
authors.initials: B
authors.lastname: Ferko
authors.affiliation: Bluesky Vaccines, Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Muster
authors.affiliation: Research Group Oncology (RGO), Equine Clinic, Veterinary University of Vienna, Vienna, Austria.
authors.forename: Sabine
authors.initials: S
authors.lastname: Brandt
authors.affiliation: Laboratory of Viral Oncology (LVO), Division of Immunology, Allergy and Infectious Diseases (DIAID), Department of Dermatology, Medical University of Vienna, Vienna, Austria.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Kirnbauer
mesh_terms: D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology*; D005260:Female; D052162:Human papillomavirus 16 / Q000276:immunology*; D007111:Immunity, Cellular / Q000276:immunology; D009980:Influenza A virus / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D030361:Papillomavirus Infections / Q000276:immunology / Q000517:prevention & control*; D053918:Papillomavirus Vaccines / Q000276:immunology*; D002583:Uterine Cervical Neoplasms / Q000517:prevention & control / Q000821:virology; D014611:Vaccination; D014613:Vaccines, Attenuated / Q000276:immunology
chemical_list: D019496:Cancer Vaccines; D053918:Papillomavirus Vaccines; D014613:Vaccines, Attenuated