title: Functional aspects of intrahepatic hepatitis B virus-specific T cells induced by therapeutic DNA vaccination.
abstract: Current therapies for the hepatitis B virus (HBV), a major cause of severe liver disease, suppress viral replication but replication rebounds if therapy is withdrawn. It is widely accepted that immune activation is needed to control replication off-therapy. To specifically activate T cells crossreactive between the hepatitis B core and e antigens (HBcAg/HBeAg) in chronically infected patients, we developed a therapeutic vaccine candidate. The vaccine encompass codon-optimized HBcAg and IL-12 expressing plasmids delivered using targeted high-pressure injection combined with in vivo electroporation. One dose of the vaccine primed a B-cell-independent polyfunctional T-cell response, in wild-type, and in HBeAg-transgenic mice with an impaired ability to respond to HBc/eAg. The response peaked at 2 weeks and contracted at week 6 after vaccination. Coadministration of IL-12 improved antibody levels, and T-cell expansion and functionality. The vaccine primed T cells that, 2 weeks after a single dose, cleared hepatocytes transiently expressing HBcAg in vaccinated wild-type and HBeAg-transgenic mice. However, 4 weeks later, these functional responses were lost. Booster doses after 8-12 weeks effectively restored function and expansion of the rapidly contracting T cells. Thus, this vaccine strategy primes functional HBcAg-specific T cells in a host with dysfunctional response to HBV.
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Anette
authors.initials: A
authors.lastname: Brass
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Frelin
authors.affiliation: Vaccine Research Institute of San Diego, San Diego, California, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Milich
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Matti
authors.initials: M
authors.lastname: Sällberg
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Gustaf
authors.initials: G
authors.lastname: Ahlén
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D018274:Electroporation; D015870:Gene Expression; D006510:Hepatitis B Antibodies / Q000096:biosynthesis*; D006512:Hepatitis B Core Antigens / Q000235:genetics / Q000276:immunology; D017325:Hepatitis B Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D006513:Hepatitis B e Antigens / Q000235:genetics / Q000276:immunology; D006515:Hepatitis B virus / Q000235:genetics / Q000276:immunology*; D019694:Hepatitis B, Chronic / Q000235:genetics / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D022781:Hepatocytes / Q000276:immunology / Q000821:virology; D006801:Humans; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology; D008099:Liver / Q000276:immunology / Q000821:virology; D051379:Mice; D008822:Mice, Transgenic; D010957:Plasmids / Q000737:chemistry / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000821:virology; D014611:Vaccination; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*
chemical_list: D006510:Hepatitis B Antibodies; D006512:Hepatitis B Core Antigens; D017325:Hepatitis B Vaccines; D006513:Hepatitis B e Antigens; D019444:Vaccines, DNA; D018664:Interleukin-12