Enhancing Immunogenicity of VLV-Based Vaccines for Treatment of Chronic HBV

PROJECT SUMMARY ABSTRACT The host T cell response to HBV is vigorous and multi specific in acutely infected patients who clear the virusbut it is weak and more narrowly focused in those who become chronically infectedThereforealthough the human immune response is capable of eliminating the infectionit often fails to do soTherapeutic immunization to induce an immune response sufficient to control the virus is a possible new approach for treating chronic hepatitis BUnfortunately however the current HBV vaccine is not effective for therapeutic vaccinationAlthough it elicits a strong neutralizing antibody response that prevents infectionthe current vaccine does not induce the potent CDT cell response needed to eliminate the virus after infectionAn important step forward would be to develop immune therapy approaches that induce both CDcellular immunity and effective antibodies in vaccinated individualsThe VLV technological innovation under development is capable of inducing both a robust antibody responses as well as multi specific CDT cell responses addressing the need for HBV immunotherapyWe have previously found that an improved version of the reverse engineered platform that generatesvirus like vesiclesVLVscontaining VSV G but no other viral structural proteins are safeare genetically stable and lack neurovirulence in miceEmploying this evolved VLV vector engineered to express the HBV middle surface envelope glycoproteinMHBswe have found that it induces CDT cell responses in mice that were greater in magnitude and broader in specificity than those obtained with other immunization strategiesincluding recombinant protein and DNAA prime boost immunization enhanced CDT cell responses in na ve mice and that regimen induced HBV specific CDT cells in a transgenic mouse model of CHB infectionWe have rationally designed and engineered a VLV vaccine that encompasses multiple antigens of the HBV genome and show that this multimeric vaccine induces CDspecific T cells in a single immunizationWe have further engineered these polyproteins to be secretedWe will now test the hypothesis that the secreted versions of the non secreted VLV Multi Antigen constructs will not only drive both a superior cell mediated and antibody immunity but would also increase the breadth and magnitude of these responses when compared to a single antigen MHBs antigen constructTo evaluate our hypothesiswe will carry out three specific aimsFirstwe will characterize the immune response to the VLV Multi Antigen vectors in normal miceSecondwe will develop and optimize a primeboost strategy in order to enhance the immune responses to these vectorsFinallywe will establish milestones for phase II developmentThe propose research is significant because an effective therapeutic vaccine that cures chronic HBV would have a substantial impact on the prevention of HBV associated chronic liver diseases PROJECT NARRATIVE Chronic hepatitis B virusHBVinfection affects more thanmillion people worldwideand is a significant health problem because it substantially increases the risk for developing liver diseases such as cirrhosis and hepatocellular carcinomaBecause current therapies for chronic HBV typically do not eliminate the virus from the livernew approaches to cure HBV infection are neededThe research proposed in this application is directed at developing novel vaccine vectors for the prevention and treatment of this disease