title: Heterologous prime-boost immunizations with a virosomal and an alphavirus replicon vaccine.
abstract: Heterologous prime-boost immunization strategies in general establish higher frequencies of antigen-specific T lymphocytes than homologous prime-boost protocols or single immunizations. We developed virosomes and recombinant Semliki Forest virus (rSFV) as antigen delivery systems, each capable of inducing strong CTL responses in homologous prime-boost protocols. Here, we demonstrate that a heterologous prime-boost with recombinant Semliki Forest virus (rSFV) encoding a fusion protein of E6 and E7 of human papillomavirus (HPV) type 16 and virosomes containing the HPV16 E7 protein resulted in higher numbers of antigen-specific CTL in mice than homologous protocols. Evasion of vector-specific immunity appeared to play a role in establishing these high frequencies, as coinduction of vector-specific responses during the prime immunization reduced the frequency of antigen-specific CTL after a heterologous booster. However, the high numbers of CTL initially primed by the heterologous protocols did not correlate with enhanced responsiveness to in vitro antigenic stimulation, nor in improved cytolytic activity or antitumor responses in vivo compared to a homologous protocol with rSFV. This lack of correlation could not be explained by changes in numbers of regulatory T cells. However, we observed differences in the frequencies of T cell subsets within the E7-specific CD8(+) T cell population, e.g. higher frequencies of central memory T cells upon homologous immunizations compared to heterologous immunizations. The induction of central memory T cells is crucial for a cancer vaccine as these cells are known to rapidly expand upon recall stimulation. This study demonstrates that the strongly increased number of antigen-specific CTL as induced by heterologous prime-boost immunizations, often used as a proof for the enhanced efficacy of such regimes, does not necessarily equal superior functional antitumor responses.
authors.affiliation: Department of Medical Microbiology, Molecular Virology Section, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Mateusz
authors.initials: M
authors.lastname: Walczak
authors.forename: Arjan
authors.initials: A
authors.lastname: de Mare
authors.forename: Annelies
authors.initials: A
authors.lastname: Riezebos-Brilman
authors.forename: Joke
authors.initials: J
authors.lastname: Regts
authors.forename: Baukje-Nynke
authors.initials: BN
authors.lastname: Hoogeboom
authors.forename: Jeroen T
authors.initials: JT
authors.lastname: Visser
authors.forename: Marc
authors.initials: M
authors.lastname: Fiedler
authors.forename: Pidder
authors.initials: P
authors.lastname: Jansen-Dürr
authors.forename: Ate G J
authors.initials: AG
authors.lastname: van der Zee
authors.forename: Hans W
authors.initials: HW
authors.lastname: Nijman
authors.forename: Jan
authors.initials: J
authors.lastname: Wilschut
authors.forename: Toos
authors.initials: T
authors.lastname: Daemen
mesh_terms: D000524:Alphavirus / Q000276:immunology*; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D005260:Female; D005434:Flow Cytometry; D051379:Mice; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D050725:Papillomavirus E7 Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012093:Replicon / Q000235:genetics / Q000276:immunology*; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012672:Semliki forest virus / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D002583:Uterine Cervical Neoplasms / Q000276:immunology / Q000517:prevention & control; D022701:Virosomes / Q000276:immunology*
chemical_list: C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; D022701:Virosomes; C059731:oncogene protein E7, Human papillomavirus type 16