Viral Vaccine Vectors for the Treatment of Chronic Hepatitis B Virus Infection

Despite an effective prophylactic vaccine, over 240 million people worldwide are chronically infected with hepatitis B virus (HBV). Furthermore, over 500,000 people will die per year from the chronic liver diseases that result from this infection. Vesicular stomatitis virus (VSV)-based vaccine vectors have shown promising results in animal models as both improved prophylactic vaccines and as therapeutics for HBV. However, the translational use of these viral vectors in humans may still be limited by the ability to attenuate VSV. In this dissertation, I present two novel viral vaccine platforms that take advantage of some of VSV's properties as a vector, yet have improved safety profiles with potential for use as therapeutics for HBV.;The first vaccine platform expresses interferon (IFN)-lambda from a recombinant VSV vector as a method of vector attenuation. The type III IFN (IFN-lambda) family of cytokines shares common signaling pathways with the IFN-alpha/beta family, and thus evokes similar antiviral activities. However, IFN-lambda signals through a distinct receptor complex that is expressed in a cell type-specific manner, restricting its activity to epithelial barriers, particularly the respiratory and gastrointestinal tracts. In the data presented, it was determined how IFN-lambda expression from recombinant VSV influences vector replication, spread, and immunogenicity. I demonstrate that IFN-lambda expression severely attenuates VSV in cell culture. In vivo, IFN-lambda limits VSV replication in the mouse lung and reduces virus spread to other organs. Despite this attenuation however, the vector retains its capacity to induce protective CD8 T cell and antibody responses after a single immunization.;In the second system, I use Semliki Forest virus (SFV) RNA replicons that express the VSV glycoprotein (VSV-G) and which generate infectious particles that bud from the cell surface. These "virus-like vesicles" (VLVs) contain VSV-G but no other viral structural proteins, spread from cell-to-cell, and can be further engineered to express additional foreign antigens. Furthermore, they are highly immunogenic and seemingly non-pathogenic in multiple animal models. I found that a VLV vector expressing the HBV middle surface envelope glycoprotein (MHBs) induces strong CD8 T cell responses in mice. These responses are directed towards multiple epitopes and are greater in magnitude and more consistent than other immunization strategies, including recombinant protein and DNA. Additionally, immunization with VLV-MHBs protects mice from HBV challenge, and this protection correlated with the elicitation of a CD8 T cell recall response. In contrast to MHBs, a VLV expressing HBcAg neither induced a CD8 T cell response in mice, nor protected against subsequent challenge, providing further evidence for a critical role of CD8 T cells in controlling HBV replication in the liver. The ability of VLV-MHBs to induce a strong, multispecific T cell response capable of controlling HBV replication combined with the safety profile of the VLV system indicates that VLV vaccine platforms offer a unique strategy for HBV therapeutic vaccination.