title: A heterologous prime/boost vaccination strategy enhances the immunogenicity of therapeutic vaccines for hepatitis C virus.
abstract: BACKGROUND
  We explored the concept of heterologous prime/boost vaccination using 2 therapeutic vaccines currently in clinical development aimed at treating chronically infected hepatitis C virus (HCV) patients: prime with a DNA-based vaccine expressing HCV genotype 1a NS3/4A proteins (ChronVac-C) and boost with a modified vaccinia virus Ankara vaccine expressing genotype 1b NS3/4/5B proteins (MVATG16643).
  
  
  METHODS
  Two ChronVac-C immunizations 4 weeks apart were delivered intramuscularly in combination with in vivo electroporation and subsequently 5 or 12 weeks later boosted by 3 weekly subcutaneous injections of MVATG16643. Two mouse strains were used, and we evaluated quality, magnitude, and functionality of the T cells induced.
  
  
  RESULTS
  DNA prime/MVA boost regimen induced significantly higher levels of interferon γ (IFN-γ) or interleukin 2 (IL-2) ELISpot responses compared with each vaccine alone, independent of the time of analysis and the time interval between vaccinations. Both CD8⁺ and CD4⁺ T-cell responses as well as the spectrum of epitopes recognized was improved. A significant increase in polyfunctional IFN-γ/tumor necrosis factor α (TNF-α)/CD107a⁺ CD8⁺ T cells was detected following ChronVac-C/MVATG16643 vaccination (from 3% to 25%), and prime/boost was the only regimen that activated quadrifunctional T cells (IFN-γ/TNF-α/CD107a/IL-2). In vivo functional protective capacity of DNA prime/MVA boost was demonstrated in a Listeria-NS3-1a challenge model.
  
  
  CONCLUSIONS
  We provide a proof-of-concept that immunogenicity of 2 HCV therapeutic vaccines can be improved using their combination, which merits further clinical development.
authors.affiliation: Département des Maladies Infectieuses, Transgene SA, Centre d'Infectiologie, Lyon, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Fournillier
authors.forename: Lars
authors.initials: L
authors.lastname: Frelin
authors.forename: Emilie
authors.initials: E
authors.lastname: Jacquier
authors.forename: Gustaf
authors.initials: G
authors.lastname: Ahlén
authors.forename: Anette
authors.initials: A
authors.lastname: Brass
authors.forename: Estelle
authors.initials: E
authors.lastname: Gerossier
authors.forename: Fredrik
authors.initials: F
authors.lastname: Holmström
authors.forename: Kate E
authors.initials: KE
authors.lastname: Broderick
authors.forename: Niranjan Y
authors.initials: NY
authors.lastname: Sardesai
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Bonnefoy
authors.forename: Geneviève
authors.initials: G
authors.lastname: Inchauspé
authors.forename: Matti
authors.initials: M
authors.lastname: Sällberg
mesh_terms: D000818:Animals; D000917:Antibody Formation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005838:Genotype; D016174:Hepacivirus; D006526:Hepatitis C / Q000276:immunology / Q000517:prevention & control*; D007117:Immunization, Secondary; D007371:Interferon-gamma / Q000097:blood; D007376:Interleukin-2 / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D014611:Vaccination / Q000379:methods*; D019444:Vaccines, DNA / Q000276:immunology; D014761:Viral Hepatitis Vaccines / Q000235:genetics / Q000276:immunology*
chemical_list: D007376:Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D019444:Vaccines, DNA; D014761:Viral Hepatitis Vaccines; D007371:Interferon-gamma
keywords: HCV; electroporation; prime/boost; therapeutic vaccine