Generation and characterization of a novel candidate gene therapy and vaccination vector based on human species D adenovirus type 56

• Published in: Journal of general virology 2018-01, Vol.99 (1), p.135-147
• Main Authors: Duffy, Margaret R, Alonso-Padilla, Julio, John, Lijo, Chandra, Naresh, Khan, Selina, Ballmann, Monika Z, Lipiec, Agnieszka, Heemskerk, Evert, Custers, Jerome, Arnberg, Niklas, Havenga, Menzo, Baker, Andrew H, Lemckert, Angelique
• Format: Article
• Language: English
• Subjects: adenovirus; Adenoviruses, Human - genetics; Adenoviruses, Human - immunology; Animals; Antibodies, Viral - biosynthesis; Antibodies, Viral - blood; Chemokine CCL2 - genetics; Chemokine CCL2 - immunology; Chemokine CXCL10 - genetics; Chemokine CXCL10 - immunology; Chemokine CXCL9 - genetics; Chemokine CXCL9 - immunology; Female; Gene Expression - drug effects; gene therapy; Genetic Therapy - methods; Genetic Vectors - chemistry; Genetic Vectors - immunology; Genetic Vectors - metabolism; HAdV-56; Humans; Injections, Intravenous; Interferon-gamma - genetics; Interferon-gamma - immunology; Interleukin-5 - genetics; Interleukin-5 - immunology; Interleukin-6 - genetics; Interleukin-6 - immunology; Lung - drug effects; Lung - immunology; Mice; Mice, Inbred BALB C; Spleen - drug effects; Spleen - immunology; Transgenes; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - immunology; Vaccination; vaccine vector; Viral Vaccines - administration & dosage; Viral Vaccines - biosynthesis
• ISSN: 0022-1317; 1465-2099; 1465-2099
• DOI: 10.1099/jgv.0.000978

The vectorization of rare human adenovirus (HAdV) types will widen our knowledge of this family and their interaction with cells, tissues and organs. In this study we focus on HAdV-56, a member of human Ad species D, and create ease-of-use cloning systems to generate recombinant HAdV-56 vectors carrying foreign genes. We present in vitro transduction profiles for HAdV-56 in direct comparison to the most commonly used HAdV-5-based vector. In vivo characterizations demonstrate that when it is delivered intravenously (i.v.) HAdV-56 mainly targets the spleen and, to a lesser extent, the lungs, whilst largely bypassing liver transduction in mice. HAdV-56 triggered robust inflammatory and cellular immune responses, with higher induction of IFNγ, TNFα, IL5, IL6, IP10, MCP1 and MIG1 compared to HAdV-5 following i.v. administration. We also investigated its potential as a vaccine vector candidate by performing prime immunizations in mice with HAdV-56 encoding luciferase (HAdV-56-Luc). Direct comparisons were made to HAdV-26, a highly potent human vaccine vector currently in phase II clinical trials. HAdV-56-Luc induced luciferase 'antigen'-specific IFNγ-producing cells and anti-HAdV-56 neutralizing antibodies in Balb/c mice, demonstrating a near identical profile to that of HAdV-26. Taken together, the data presented provides further insight into human Ad receptor/co-receptor usage, and the first report on HAdV-56 vectors and their potential for gene therapy and vaccine applications.