title: A poxvirus vaccine is safe, induces T-cell responses, and decreases viral load in patients with chronic hepatitis C.
abstract: OBJECTIVE
  Therapy for chronic hepatitis C (CHC) has limited efficacy, adverse effects, and high costs. Cohort and vaccine-based preclinical studies have indicated the importance of T-cell-based immunity in controlling viral infection. TG4040 is a recombinant poxvirus vaccine that expresses the hepatitis C virus (HCV) proteins NS3, NS4, and NS5B. We performed a phase I clinical trial to assess the safety, immunogenicity, and early antiviral efficacy of TG4040 in patients with CHC.
  
  
  METHODS
  In an open-label, dose-escalating study, patients with mild CHC (genotype 1) were assigned to 3 groups of 3 patients each; they received subcutaneous injections of 10⁶, 10⁷, or 10⁸ plaque-forming units of TG4040 on study days 1, 8, and 15. Six additional patients were given the highest dose of vaccine (10⁸ plaque-forming units). Patients were followed for 6 months after the last injection. T-cell-based and antibody responses and levels of HCV RNA were measured.
  
  
  RESULTS
  All 3 doses of TG4040 were well tolerated, without serious adverse events. Vaccine-induced HCV-specific cellular immune responses were observed in 5 of the 15 patients (33%). A transient decrease in circulating levels of HCV RNA, from -0.52 log₁₀ to -1.24 log₁₀, was observed in 8 patients; in 5 patients, the lowest level of HCV RNA was observed on day 37, after the first injection. The most pronounced decrease in viral load occurred in 2 patients, who also had marked vaccine-induced T-cell responses.
  
  
  CONCLUSIONS
  In patients with CHC, the viral-vector-based vaccine TG4040 had a good safety profile, induced HCV-specific cellular immune responses, and reduced viral load. This vaccine should be investigated in further clinical studies, in combination with standard of care.
authors.affiliation: INSERM, Strasbourg, France; Université de Strasbourg, Strasbourg, France. francois.habersetzer@chru-strasbourg.fr
authors.forename: François
authors.initials: F
authors.lastname: Habersetzer
authors.forename: Géraldine
authors.initials: G
authors.lastname: Honnet
authors.forename: Christine
authors.initials: C
authors.lastname: Bain
authors.forename: Marianne
authors.initials: M
authors.lastname: Maynard-Muet
authors.forename: Vincent
authors.initials: V
authors.lastname: Leroy
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Zarski
authors.forename: Cyrille
authors.initials: C
authors.lastname: Feray
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Baumert
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Bronowicki
authors.forename: Michel
authors.initials: M
authors.lastname: Doffoël
authors.forename: Christian
authors.initials: C
authors.lastname: Trépo
authors.forename: Delphine
authors.initials: D
authors.lastname: Agathon
authors.forename: Myew-Ling
authors.initials: ML
authors.lastname: Toh
authors.forename: Martine
authors.initials: M
authors.lastname: Baudin
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Bonnefoy
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Limacher
authors.forename: Geneviève
authors.initials: G
authors.lastname: Inchauspé
mesh_terms: D000328:Adult; D000914:Antibodies, Viral / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000473:pathology* / Q000821:virology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011212:Poxviridae / Q000276:immunology*; D012367:RNA, Viral / Q000097:blood; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D019562:Viral Load / Q000187:drug effects*; D017361:Viral Nonstructural Proteins / Q000276:immunology; D014765:Viral Vaccines / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000914:Antibodies, Viral; D007371:Interferon-gamma; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins; D014765:Viral Vaccines; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C093542:NS4 protein, hepatitis C virus; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase