Removal of the C6 vaccinia virus interferon-β inhibitor in the hepatitis C vaccine candidate MVA-HCV elicited in mice high immunogenicity in spite of reduced host gene expression

Abstract

Hepatitis C virus (HCV) represents a major global health problem for which a vaccine is not available. MVA-HCV is a unique HCV vaccine candidate based in the modified vaccinia virus Ankara (MVA) vector expressing the nearly full-length genome of HCV genotype 1a that elicits broad and polyfunctional CD8+ T-cell responses in mice. With the aim to improve the immune response of MVA-HCV and due to the importance of interferon (IFN) in HCV infection, we deleted in MVA-HCV the vaccinia virus (VACV) C6L gene, encoding an inhibitor of IFN-{beta} that prevents activation of the transcription factors IRF3 and IRF7. The resulting vaccine candidate (MVA-HCV {Delta}C6L) expresses all HCV antigens and deletion of C6L had no effect on viral growth in permissive chicken cells. In human monocyte-derived dendritic cells, infection with MVA-HCV {Delta}C6L triggered severe down-regulation of IFN-{beta}, IFN-{beta}-induced genes and cytokines similarly to MVA-HCV, as defined by real-time PCR and microarray analysis. In infected mice both vectors had a similar profile of recruited immune cells and induced comparable levels of adaptive and memory HCV-specific CD8+ T-cells, mainly against p7+NS2 and NS3 HCV proteins, with a T cell effector memory (TEM) phenotype. Furthermore, antibodies against E2 were also induced. Overall, our findings showed that while these vectors had a profound inhibitory effect on gene expression of the host, they strongly elicited CD8+ T cell and humoral responses against HCV antigens. These observations add support to the consideration of these vectors as potential vaccine candidates against HCV.\n\nIMPORTANCEHepatitis C virus represents a global health problem with 71 million of people infected worldwide. While direct-acting antivirals agents can cure hepatitis C virus infection in most of patients, their high cost and the emergence of drug resistant variants make them not a feasible and affordable strategy to eradicate the virus. Therefore, a vaccine is an urgent goal that requires efforts in understanding the correlates of protection for hepatitis C virus clearance. Poxvirus vectors, in particular the attenuated modified vaccinia virus Ankara, are ideal as vaccine candidates due to their ability to induce both T and B cell immune responses against heterologous antigens and protection against a wide spectrum of pathogens. Here we describe the generation, genetics and immunogenicity elicited by MVA-HCV {Delta}C6L, a novel vaccine candidate for hepatitis C virus that expresses nearly all of hepatitis C proteins but lacks an IFN-{beta} inhibitor, the C6 vaccinia virus protein.