title: Development of a replication-deficient adenoviral vector-based vaccine candidate for the interception of HPV16- and HPV18-induced infections and disease.
abstract: High-risk Human papilloma virus (HPV) types are the causative agents of cervical cancer and several other anogenital malignancies. The viral proteins expressed in the (pre)malignant cells are considered ideal targets for immunological intervention. Many approaches have been evaluated for this purpose, mostly aiming at the induction of HPV16 E7- and/or E6-specific cellular immunogenicity. As clinical success has so far been limited, novel approaches are required. We describe the development and pre-clinical testing of a vaccine candidate consisting of replication-deficient adenovirus type 26 and 35 based vectors for the interception of HPV16- and HPV18-related disease. We developed HPV16- and HPV18-specific antigens consisting of fusion proteins of E2, E6 and E7. The vaccine will be suitable for every disease stage, from incident and persistent infections where E2 is predominantly expressed up to late stages where E6 and E7 expression are upregulated. Importantly E6 and E7 are present as reordered fragments to abrogate the transforming activity of these two proteins. Loss of transforming activity was demonstrated in different in vitro models. Robust T-cell immunogenicity was induced upon immunization of mice with the vaccine candidate. Finally, the developed vaccine vectors showed considerable therapeutic efficacy in the TC-1 mouse model. The absence of transforming activity of the antigens and the favorable immunogenicity profile of the adenovirus based vectors along with the fact that these vectors can be readily produced on a large scale makes this approach attractive for clinical evaluation.
authors.affiliation: Janssen Vaccines and Preventions BV, CA, Leiden, The Netherlands.
authors.forename: Selina
authors.initials: S
authors.lastname: Khan
authors.affiliation: Janssen Vaccines and Preventions BV, CA, Leiden, The Netherlands.
authors.forename: Koen
authors.initials: K
authors.lastname: Oosterhuis
authors.affiliation: Janssen Vaccines and Preventions BV, CA, Leiden, The Netherlands.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Wunderlich
authors.affiliation: Janssen Vaccines and Preventions BV, CA, Leiden, The Netherlands.
authors.forename: Evelien M
authors.initials: EM
authors.lastname: Bunnik
authors.affiliation: Janssen Vaccines and Preventions BV, CA, Leiden, The Netherlands.
authors.forename: Melissa
authors.initials: M
authors.lastname: Bhaggoe
authors.affiliation: Janssen Vaccines and Preventions BV, CA, Leiden, The Netherlands.
authors.forename: Satish
authors.initials: S
authors.lastname: Boedhoe
authors.affiliation: Janssen Vaccines and Preventions BV, CA, Leiden, The Netherlands.
authors.forename: Santusha
authors.initials: S
authors.lastname: Karia
authors.affiliation: Department of Pathology, VU University Medical Center Amsterdam, The Netherlands.
authors.forename: Renske D M
authors.initials: RDM
authors.lastname: Steenbergen
authors.affiliation: Department of Pathology, VU University Medical Center Amsterdam, The Netherlands.
authors.forename: Leontien
authors.initials: L
authors.lastname: Bosch
authors.affiliation: Janssen Vaccines and Preventions BV, CA, Leiden, The Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Serroyen
authors.affiliation: Janssen Vaccines and Preventions BV, CA, Leiden, The Netherlands.
authors.forename: Sarah
authors.initials: S
authors.lastname: Janssen
authors.affiliation: Janssen Vaccines and Preventions BV, CA, Leiden, The Netherlands.
authors.forename: Hanneke
authors.initials: H
authors.lastname: Schuitemaker
authors.affiliation: Janssen Vaccines and Preventions BV, CA, Leiden, The Netherlands.
authors.forename: Jort
authors.initials: J
authors.lastname: Vellinga
authors.affiliation: Janssen Vaccines and Preventions BV, CA, Leiden, The Netherlands.
authors.forename: Gert
authors.initials: G
authors.lastname: Scheper
authors.affiliation: Janssen Vaccines and Preventions BV, CA, Leiden, The Netherlands.
authors.forename: Roland
authors.initials: R
authors.lastname: Zahn
authors.affiliation: Janssen Vaccines and Preventions BV, CA, Leiden, The Netherlands.
authors.forename: Jerome
authors.identifier: 0000-0002-7151-8654
authors.initials: J
authors.lastname: Custers
mesh_terms: D000818:Animals; D000957:Antigens, Viral, Tumor / Q000276:immunology; D000229:Dependovirus / Q000502:physiology*; D005260:Female; D052162:Human papillomavirus 16 / Q000276:immunology*; D052161:Human papillomavirus 18 / Q000276:immunology*; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D030361:Papillomavirus Infections / Q000628:therapy*; D053918:Papillomavirus Vaccines / Q000276:immunology; D002583:Uterine Cervical Neoplasms / Q000628:therapy* / Q000821:virology; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
chemical_list: D000957:Antigens, Viral, Tumor; D053918:Papillomavirus Vaccines
keywords: HPV; adenovirus vector; therapeutic vaccine