Use of an Outbred Rat Hepacivirus Challenge Model for Design and Evaluation of Efficacy of Different Immunization Strategies for Hepatitis C Virus.

Hepatology (Baltimore, Md.) 2020 Mar

filter terms:

The lack of immunocompetent small animal models for hepatitis C virus (HCV) has greatly hindered the development of effective vaccines. Using rodent hepacivirus (RHV), a homolog of HCV that shares many characteristics of HCV infection, we report the development and application of an RHV outbred rat model for HCV vaccine development. Simian adenovirus (ChAdOx1) encoding a genetic immune enhancer (truncated shark class II invariant chain) fused to the nonstructural (NS) proteins NS3-NS5B from RHV (ChAd-NS) was used to vaccinate Sprague-Dawley rats, resulting in high levels of cluster of differentiation 8-positive (CD8+ ) T-cell responses. Following RHV challenge (using 10 or 100 times the minimum infectious dose), 42% of vaccinated rats cleared infection within 6-8 weeks, while all mock vaccinated controls became infected with high-level viremia postchallenge. A single, 7-fold higher dose of ChAd-NS increased efficacy to 67%. Boosting with ChAd-NS or with a plasmid encoding the same NS3-NS5B antigens increased efficacy to 100% and 83%, respectively. A ChAdOx1 vector encoding structural antigens (ChAd-S) was also constructed. ChAd-S alone showed no efficacy. Strikingly, when combined with ChAd-NS, ChAD-S produced 83% efficacy. Protection was associated with a strong CD8+ interferon gamma-positive recall response against NS4. Next-generation sequencing of a putative RHV escape mutant in a vaccinated rat identified mutations in both identified immunodominant CD8+ T-cell epitopes. A simian adenovirus vector vaccine strategy is effective at inducing complete protective immunity in the rat RHV model. The RHV Sprague-Dawley rat challenge model enables comparative testing of vaccine platforms and antigens and identification of correlates of protection and thereby provides a small animal experimental framework to guide the development of an effective vaccine for HCV in humans. © 2019 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of American Association for the Study of Liver Diseases.

Citation

Erwan Atcheson, Wenqin Li, Carly M Bliss, Senthil Chinnakannan, Kathrin Heim, Hannah Sharpe, Claire Hutchings, Isabelle Dietrich, Dung Nguyen, Amit Kapoor, Michael A Jarvis, Paul Klenerman, Eleanor Barnes, Peter Simmonds. Use of an Outbred Rat Hepacivirus Challenge Model for Design and Evaluation of Efficacy of Different Immunization Strategies for Hepatitis C Virus. Hepatology (Baltimore, Md.). 2020 Mar;71(3):794-807