title: Design of a highly effective therapeutic HPV16 E6/E7-specific DNA vaccine: optimization by different ways of sequence rearrangements (shuffling).
abstract: Persistent infection with the high-risk Human Papillomavirus type 16 (HPV 16) is the causative event for the development of cervical cancer and other malignant tumors of the anogenital tract and of the head and neck. Despite many attempts to develop therapeutic vaccines no candidate has entered late clinical trials. An interesting approach is a DNA based vaccine encompassing the nucleotide sequence of the E6 and E7 viral oncoproteins. Because both proteins are consistently expressed in HPV infected cells they represent excellent targets for immune therapy. Here we report the development of 8 DNA vaccine candidates consisting of differently rearranged HPV-16 E6 and E7 sequences within one molecule providing all naturally occurring epitopes but supposedly lacking transforming activity. The HPV sequences were fused to the J-domain and the SV40 enhancer in order to increase immune responses. We demonstrate that one out of the 8 vaccine candidates induces very strong cellular E6- and E7- specific cellular immune responses in mice and, as shown in regression experiments, efficiently controls growth of HPV 16 positive syngeneic tumors. This data demonstrates the potential of this vaccine candidate to control persistent HPV 16 infection that may lead to malignant disease. It also suggests that different sequence rearrangements influence the immunogenecity by an as yet unknown mechanism.
authors.affiliation: Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Fahad N
authors.initials: FN
authors.lastname: Almajhdi
authors.affiliation: German Cancer Research Center, Heidelberg, Germany.
authors.forename: Tilo
authors.initials: T
authors.lastname: Senger
authors.affiliation: Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia; Virology Department, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt.
authors.forename: Haitham M
authors.initials: HM
authors.lastname: Amer
authors.affiliation: Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia; German Cancer Research Center, Heidelberg, Germany.
authors.forename: Lutz
authors.initials: L
authors.lastname: Gissmann
authors.affiliation: Department of Chemistry and Biotechnology, Aachen University of Applied Sciences, Jülich, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Öhlschläger
mesh_terms: D052685:Alphapapillomavirus / Q000276:immunology*; D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis; D045744:Cell Line, Tumor; D005260:Female; D000068857:Human Papillomavirus Recombinant Vaccine Quadrivalent, Types 6, 11, 16, 18; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000473:pathology; D009856:Oncogene Proteins, Viral / Q000276:immunology*; D050725:Papillomavirus E7 Proteins / Q000276:immunology*; D053918:Papillomavirus Vaccines / Q000235:genetics*; D012097:Repressor Proteins / Q000276:immunology*; D019444:Vaccines, DNA / Q000235:genetics*
chemical_list: D000914:Antibodies, Viral; C068651:E6 protein, Human papillomavirus type 16; D000068857:Human Papillomavirus Recombinant Vaccine Quadrivalent, Types 6, 11, 16, 18; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D053918:Papillomavirus Vaccines; D012097:Repressor Proteins; D019444:Vaccines, DNA; C059731:oncogene protein E7, Human papillomavirus type 16