Abstract
There is an urgent need for a vaccine to prevent chronic infection by hepatitis C virus (HCV) and its many genetic variants. The first human vaccine trial, using recombinant viral vectors that stimulate pan-genotypic T cell responses against HCV non-structural proteins, failed to demonstrate efficacy despite significant preclinical promise. Understanding the factors that govern HCV T cell vaccine success is necessary for design of improved immunization strategies. Using a rat model of chronic rodent hepacivirus (RHV) infection, we assessed the impact of antigenic variation and immune escape upon success of a conceptually analogous RHV T cell vaccine. Naïve Lewis rats were vaccinated with a recombinant human adenovirus expressing RHV non-structural proteins (NS)3-5B and later challenged with a viral variant containing immune escape mutations within major histocompatibility complex (MHC) class I-restricted epitopes (escape virus). Whereas 7 of 11 (64%) rats cleared infection caused by wild-type RHV, only 3 of 12 (25%) were protected against heterologous challenge with escape virus. Uncontrolled replication of escape virus was associated with durable CD8 T cell responses targeting escaped epitopes alone. In contrast, clearance of escape virus correlated with CD4 T cell helper immunity and maintenance of CD8 T cell responses against intact viral epitopes. Interestingly, clearance of wild-type RHV infection after vaccination conferred enhanced protection against secondary challenge with escape virus. These results demonstrate that the efficacy of an RHV T cell vaccine is reduced when challenge virus contains escape mutations within MHC class I-restricted epitopes and that failure to sustain CD8 T cell responses against intact epitopes likely underlies immune failure in this setting. Further investigation of the immune responses that yield protection against diverse RHV challenges in this model may facilitate design of broadly effective HCV vaccines.
Highlights
Hepatitis C virus (HCV) chronically infects 71 million people worldwide and contributes to 399,000 deaths annually[1]
In this study we evaluated how immune escape mutations at major histocompatibility complex (MHC) class I-restricted viral epitopes influence the effectiveness of an adenoviral-vectored T cell vaccine in a rat model of chronic HCV-related rodent hepacivirus infection, currently the only animal model available for evaluation of HCV vaccine strategies
We show that vaccine efficacy is markedly diminished when challenge virus contains naturally-acquired escape mutations at dominant MHC class I-restricted viral epitopes that render a subset of vaccine-generated CD8 T cell responses ineffective
Summary
Hepatitis C virus (HCV) chronically infects 71 million people worldwide and contributes to 399,000 deaths annually[1]. Despite encouraging preclinical data[5,6] and a large body of evidence suggesting a critical role for T cells in immunity to HCV[7,8], no reduction in the overall incidence of chronic infection was observed[9]. Failure of this highly anticipated trial highlights a concerning gap in our understanding of protective immune responses to HCV and a need to identify factors that influence HCV vaccine efficacy
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