title: Comparative analysis of immunization schedules using a novel adenovirus-based immunotherapeutic targeting hepatitis B in naïve and tolerant mouse models.
abstract: Development of active targeted immunotherapeutics is a rapid developing field in the arena of chronic infectious diseases. The question of repeated, closely spaced administration of immunotherapeutics to achieve a rapid impact on the replicating agent is an important one. We analyzed here, using a prototype adenovirus-based immunotherapeutic encoding Core and Polymerase from the hepatitis B virus (Ad-HBV), the influence of closely spaced repeated immunizations on the level and quality of induced HBV-specific and vector-specific immune responses in various mouse models. Ad-HBV, whether injected once or multiple times, was able to induce HBV- and adeno-specific T cells both in HBV-free mice and in a HBV tolerant mouse model. Adenovirus-specific T cell responses and titers of neutralizing anti-Ad5 antibodies increased from time of the 3rd injection. Interestingly, single or multiple Ad-HBV injections resulted in detection of Polymerase-specific functional T cells in HBV tolerant mice. Overall no modulation of the levels of HBV-specific cytokine-producing (IFNγ/TNFα) and cytolytic T cells was observed following repeated administrations (3 or 6 weekly injections) when compared with levels detected after a single injection with the exception of two markers: 1. the proportion of HBV-specific IFNγ-producing cells bearing the CD27+/CD43+ phenotype appeared to be sustained in C57BL/6J mice following 6 weekly injections; 2. the percentage of IFNγ/TNFα Core-specific producing cells observed in spleens of HLA-A2 mice as well as of that specific of Polymerase observed in livers of HBV tolerant mice was maintained. In addition, percentage of HBV-specific T cells expressing PD-1 was not increased by multiple injections. Overall these data show that, under experimental conditions used, rapid, closely spaced administrations of an adenovirus-based HBV immunotherapeutics does not inhibit induced T-cell responses including in a HBV-tolerant environment.
authors.affiliation: TRANSGENE SA, 321 Avenue Jean Jaures, 69364 Lyon cedex 07, France.
authors.forename: Houda
authors.initials: H
authors.lastname: Boukhebza
authors.affiliation: TRANSGENE SA, 321 Avenue Jean Jaures, 69364 Lyon cedex 07, France.
authors.forename: Clarisse
authors.initials: C
authors.lastname: Dubois
authors.affiliation: TRANSGENE SA, Boulevard Gonthier d'Andernach, 67405 Illkirch Graffenstaden, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Koerper
authors.affiliation: TRANSGENE SA, 321 Avenue Jean Jaures, 69364 Lyon cedex 07, France.
authors.forename: Alexei
authors.initials: A
authors.lastname: Evlachev
authors.affiliation: TRANSGENE SA, Boulevard Gonthier d'Andernach, 67405 Illkirch Graffenstaden, France.
authors.forename: Yasmine
authors.initials: Y
authors.lastname: Schlesinger
authors.affiliation: TRANSGENE SA, Boulevard Gonthier d'Andernach, 67405 Illkirch Graffenstaden, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Menguy
authors.affiliation: TRANSGENE SA, Boulevard Gonthier d'Andernach, 67405 Illkirch Graffenstaden, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Silvestre
authors.affiliation: ULM University, Klinik für Innere Medizin I, Albert Einstein Allee 23, 89081 Ulm, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Riedl
authors.affiliation: TRANSGENE SA, 321 Avenue Jean Jaures, 69364 Lyon cedex 07, France.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Inchauspé
authors.affiliation: TRANSGENE SA, 321 Avenue Jean Jaures, 69364 Lyon cedex 07, France. Electronic address: perrine.martin@transgene.fr.
authors.forename: Perrine
authors.initials: P
authors.lastname: Martin
mesh_terms: D000256:Adenoviridae; D000818:Animals; D015684:Gene Products, pol / Q000276:immunology; D015789:HLA-A2 Antigen; D006509:Hepatitis B / Q000517:prevention & control*; D006512:Hepatitis B Core Antigens / Q000276:immunology; D017325:Hepatitis B Vaccines / Q000276:immunology*; D007111:Immunity, Cellular; D007115:Immunization Schedule; D007167:Immunotherapy; D007371:Interferon-gamma / Q000276:immunology; D008099:Liver / Q000276:immunology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D015684:Gene Products, pol; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D006512:Hepatitis B Core Antigens; D017325:Hepatitis B Vaccines; C066027:P protein, Hepatitis B virus; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma
keywords: Adenovirus; Hepatitis B virus; Immunotherapy; Multiple injections; T cells