A Cytomegalovirus-based therapeutic vaccine for chronic hepatitis B

Abstract Although an efficient prophylactic vaccine is available for hepatitis B virusHBVchronic hepatitis BCHBaffects up tomillion people worldwideand despite advances remains mostly incurableIn adultsacute HBV infection is cleared inof cases by CDT cell mediated mechanismsbut chroniclifelong infection ensues in the remaining individualswhich can lead to liver cirrhosis and cancerThe induction and maintenance of HBV specific T cells in the liver of infected individuals by traditional vaccine methods has been a challenge due to immunological toleranceone of the hallmarks of CHBTo overcome these challengeswe will use a CMV vector platform to provide persistent antigen presentation capable of recruiting an expanded set of new HBV specific T cell populations that are expected to circumvent this problemCMV vectored HBV vaccines have several unique featuresThey can be programmed to elicit conventionalMHC I restrictedand unconventionalMHC II and MHC E restrictedCDT cells that recognize a larger number of epitopes than traditional vaccinesCMV vectors will elicit and maintain high frequencies of non exhausted effector memory T cells in the blood and liverCMV vectors overcome pre existing anti CMV immunity by evading vector specific immune responsesUse of defined attenuations maintain the immunological induction profileOurepigraphalgorithm based antigen design accounts for global genotype variations by integrating data from overworldwide HBV sequencesWe hypothesize that CMV based HBV immunotherapy will lead to control and immunologic cure of CHB due to the recruitment of novel HBV specific CDT cellsOur goal is to test this hypothesis in chronically infected humansin which we expect that vaccination with either one or two injections will result in lifelong immune control of HBVIn the Phaseof this Fast Track Program we will first designconstruct and characterize a spread deficient HCMV vector expressing HBV antigens with global epitope coverageWe will insert two complementary HBVepisensusantigens into a safety enhanced HCMVvector through BAC recombineering to generate the final HCMV HBV construct that can be taken forward for clinical developmentIn the Phaseprogram we will generate a pre master virus seed stock ready for GMP production and optimize the manufacturing process of HCMV HBV vectorsWe will characterize the HCMV HBV vaccine with respect to stability upon multiple passagesmaintenance of antigen expression and genomic integrityWe will then characterize the vaccine and the HBV specific T cell responses in non human primatesNHPWe will immunize NHP with HCMV HBV to determine the effective dosethe timingand the magnitude of the antigen specific T cell responseWe will further determine the breadth and strain specificity of peripheral and liver T cells upon necropsy using peptides representative of different HBV genotypesUpon completion of these Aims we will have generated and characterized a novel immunotherapy for HBV that is ready for GMP manufacture and for human safety and efficacy studies Chronic hepatitis B infection affectsmillion people worldwideand is a leading etiology for the development of cirrhosishepatocellular carcinomaand resulting liver transplantsWhile the approved vaccines provide a protective antibody response if administered prior to infectionthey offer no therapeutic benefit once chronic infection is establishedWe propose the development of an HBV immunotherapeutic vaccine harnessing the unique CMV vector platform to cover the global genotype diversitycircumvent T cell liver toleranceand provide immunologic control and clearance of detectable infectionThe vaccine will result in lifelong surveillance of the liverand provide protection from recurrence or reinfection