Viral vectored hepatitis C virus vaccines generate pan-genotypic T cell responses to conserved subdominant epitopes |
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| Affiliation: | 1. Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, OX1 3SY, United Kingdom;2. Jenner Institute, Nuffield Department of Medicine, University of Oxford, OX3 7DQ, United Kingdom;3. Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan;2. Molecular Diagnostic Laboratory, National Institute of Biologicals, Noida, India;3. Department of Biotechnology, Mangalmay Institute of Management and Technology, Greater Noida, India;4. School of Agricultural Biotechnology, Punjab Agricultural University, Ludhiana, Punjab, India;1. Department of Medical Microbiology, Faculty of Medicine, Tripoli University, CC 82668, Tripoli, Libya;2. Department of Laboratory Medicine, Faculty of Biotechnology, Tripoli University, CC 82668, Tripoli, Libya;3. Department of Microbiology and Parasitology, Faculty of Veterinary Medicine, Tripoli University, CC 82668, Tripoli, Libya;4. Department of Surgery, Tripoli Medical Centre, Faculty of Medicine, Tripoli University, CC 82668, Tripoli, Libya;5. Department of Pharmacology and Toxicology, Faculty of Medical Technology, Naluit Alga-bal Algarbi University, Libya;6. Clinical Microbiology & Microbial Epidemiology, Acting Physician of Internal Medicine, Scientific Coordinator of Libyan National Surveillance Studies of Viral Hepatitis & HIV, Tripoli, Libya;1. Center for Genetic Engineering and Biotechnology (CIGB), Ave 31, P.O. Box 6162, Havana, 10 600, Cuba;2. Institut de Biologie de Lille (UMR8161), CNRS, Universite de Lille I & II and Institut Pasteur de Lille, Lille, France;1. Center for Vaccinology, Dept. of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium;2. Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, USA;3. Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, USA;1. Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA;2. Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA;3. Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA |
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| Abstract: | BackgroundViral genetic variability presents a major challenge to the development of a prophylactic hepatitis C virus (HCV) vaccine. A promising HCV vaccine using chimpanzee adenoviral vectors (ChAd) encoding a genotype (gt) 1b non-structural protein (ChAd-Gt1b-NS) generated high magnitude T cell responses. However, these T cells showed reduced cross-recognition of dominant epitope variants and the vaccine has recently been shown to be ineffective at preventing chronic HCV. To address the challenge of viral diversity, we developed ChAd vaccines encoding HCV genomic sequences that are conserved between all major HCV genotypes and adjuvanted by truncated shark invariant chain (sIitr).MethodsAge-matched female mice were immunised intramuscularly with ChAd (108 infectious units) encoding gt-1 and -3 (ChAd-Gt1/3) or gt-1 to -6 (ChAd-Gt1-6) conserved segments spanning the HCV proteome, or gt-1b (ChAd-Gt1b-NS control), with immunogenicity assessed 14-days post-vaccination.ResultsConserved segment vaccines, ChAd-Gt1/3 and ChAd-Gt1-6, generated high-magnitude, broad, and functional CD4+ and CD8+ T cell responses. Compared to the ChAd-Gt1b-NS vaccine, these vaccines generated significantly greater responses against conserved non-gt-1 antigens, including conserved subdominant epitopes that were not targeted by ChAd-Gt1b-NS. Epitopes targeted by the conserved segment HCV vaccine induced T cells, displayed 96.6% mean sequence homology between all HCV subtypes (100% sequence homology for the majority of genotype-1, -2, -4 sequences and 94% sequence homology for gt-3, -6, -7, and -8) in contrast to 85.1% mean sequence homology for epitopes targeted by ChAd-Gt1b-NS induced T cells. The addition of truncated shark invariant chain (sIitr) increased the magnitude, breadth, and cross-reactivity of the T cell response.ConclusionsWe have demonstrated that genetically adjuvanted ChAd vectored HCV T cell vaccines encoding genetic sequences conserved between genotypes are immunogenic, activating T cells that target subdominant conserved HCV epitopes. These pre-clinical studies support the use of conserved segment HCV T cell vaccines in human clinical trials. |
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| Keywords: | Universal HCV vaccine Adenovirus Conserved sequence Cross-reactive Invariant chain |
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