title: Antigen design enhances the immunogenicity of Semliki Forest virus-based therapeutic human papillomavirus vaccines.
abstract: Cellular immunity against cancer can be achieved with viral vector- and DNA-based immunizations. In preclinical studies, cancer vaccines are very potent, but in clinical trials these potencies are not achieved yet. Thus, a rational approach to improve cancer vaccines is warranted. We previously demonstrated that the relatively low intrinsic immunogenicity of DNA vaccines could be enhanced by inclusion of endoplasmic reticulum (ER) targeting and universal helper epitopes within the vaccine. We now evaluated whether an optimal antigen format, as defined in DNA vaccines, can further enhance the effectiveness of recombinant Semliki Forest virus (rSFV) vaccines. To this purpose, we generated, characterized and evaluated the efficacy of rSFV replicon particles expressing human papillomavirus E6 and/or E7 proteins fused to several helper T-cell epitopes and an ER targeting signal. Here, we show that inclusion of a helper cassette and an ER targeting signal enhanced protein stability and markedly augmented the frequencies of human papillomavirus-specific T cells. Even at an immunization dose of as low as 10(5) replicon particles, this novel vaccine achieved tumor regression and protection. Thus, even highly effective viral vector vaccines can benefit from an improved antigen format, based on the inclusion of defined helper epitopes and ER targeting.
authors.affiliation: Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: P P
authors.initials: PP
authors.lastname: Ip
authors.affiliation: Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Boerma
authors.affiliation: Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Walczak
authors.affiliation: Division of Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: K
authors.initials: K
authors.lastname: Oosterhuis
authors.affiliation: Division of Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: J B
authors.initials: JB
authors.lastname: Haanen
authors.affiliation: Division of Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: T N
authors.initials: TN
authors.lastname: Schumacher
authors.affiliation: Department of Gynecological Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: H W
authors.initials: HW
authors.lastname: Nijman
authors.affiliation: Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: T
authors.initials: T
authors.lastname: Daemen
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D006224:Cricetinae; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry; D005260:Female; D006801:Humans; D007668:Kidney / Q000166:cytology; D008810:Mice, Inbred C57BL; D009856:Oncogene Proteins, Viral / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D050725:Papillomavirus E7 Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D053918:Papillomavirus Vaccines / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D012672:Semliki forest virus / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000517:prevention & control; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology
chemical_list: D000956:Antigens, Viral; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D053918:Papillomavirus Vaccines; D019444:Vaccines, DNA