Design and non-viral delivery of live attenuated virus vaccine to prevent chronic hepacivirus (HCV-like) infection 3916

Abstract Description The development of an effective prophylactic vaccine for hepatitis C virus (HCV) is an unmet medical need. We described that rat HCV-like virus (RHV) infection in laboratory rats recapitulates the life-long hepatotropic infection and dysfunctional immunity observed during HCV infection in humans. Here, we designed a live-attenuated vaccine (LAV) strain for RHV and determined its infection, immunogenicity, and efficacy in preventing chronic HCV-like infection. The LAV was generated by introducing hundreds of synonymous mutations to increase the frequencies of dinucleotides UpA or CpG in the genomic regions that contain fewer RNA-secondary structures. Rats were vaccinated using in vitro transcribed and lipid nanoparticle-encapsulated viral RNA (LNP-vRNA) for assaying immunogenicity and protection. The vaccine-induced T cells were characterized using MHC class I and II tetramers and intracellular cytokines assays. Rats were challenged with a wild-type RHV-rn1 that invariably produced HCV-like lifelong chronic infection in naïve rats. Notably, 76% of vaccinated rats (17 of 21 rats) cleared RHV-rn1 viremia within 2-5 weeks of the challenge. The clearance of infection correlated with a 10-100-fold expansion of vaccine-specific memory T cells in the liver. In conclusion, we showed that attenuated hepacivirus genomes administered as LNP vaccine induced immunity against wild-type virus, a strategy with an apparent translational path towards human HCV immunization. Funding Sources Funding: National Institute of Health awards R01AI185926, R01AI183877, R01AI151175. Topic Categories Vaccines and Immunotherapy (VAC)