TOMEGAVAX, INC. — Department of Health and Human Services SBIR Phase I: R

Description

Abstract Although an efficient prophylactic vaccine is available for hepatitis B virus HBV chronic hepatitis B CHB affects up to million people worldwide and despite advances remains mostly incurable In adults acute HBV infection is cleared in of cases by CD T cell mediated mechanisms but chronic lifelong infection ensues in the remaining individuals which can lead to liver cirrhosis and cancer The 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 tolerance one of the hallmarks of CHB To overcome these challenges we 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 problem CMV vectored HBV vaccines have several unique features They can be programmed to elicit conventional MHC I restricted and unconventional MHC II and MHC E restricted CD T cells that recognize a larger number of epitopes than traditional vaccines CMV vectors will elicit and maintain high frequencies of non exhausted effector memory T cells in the blood and liver CMV vectors overcome pre existing anti CMV immunity by evading vector specific immune responses Use of defined attenuations maintain the immunological induction profile Our epigraph algorithm based antigen design accounts for global genotype variations by integrating data from over worldwide HBV sequences We hypothesize that CMV based HBV immunotherapy will lead to control and immunologic cure of CHB due to the recruitment of novel HBV specific CD T cells Our goal is to test this hypothesis in chronically infected humans in which we expect that vaccination with either one or two injections will result in lifelong immune control of HBV In the Phase of this Fast Track Program we will first design construct and characterize a spread deficient HCMV vector expressing HBV antigens with global epitope coverage We will insert two complementary HBV episensus antigens into a safety enhanced HCMV vector through BAC recombineering to generate the final HCMV HBV construct that can be taken forward for clinical development In the Phase program we will generate a pre master virus seed stock ready for GMP production and optimize the manufacturing process of HCMV HBV vectors We will characterize the HCMV HBV vaccine with respect to stability upon multiple passages maintenance of antigen expression and genomic integrity We will then characterize the vaccine and the HBV specific T cell responses in non human primates NHP We will immunize NHP with HCMV HBV to determine the effective dose the timing and the magnitude of the antigen specific T cell response We will further determine the breadth and strain specificity of peripheral and liver T cells upon necropsy using peptides representative of different HBV genotypes Upon 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 affects million people worldwide and is a leading etiology for the development of cirrhosis hepatocellular carcinoma and resulting liver transplants While the approved vaccines provide a protective antibody response if administered prior to infection they offer no therapeutic benefit once chronic infection is established We propose the development of an HBV immunotherapeutic vaccine harnessing the unique CMV vector platform to cover the global genotype diversity circumvent T cell liver tolerance and provide immunologic control and clearance of detectable infection The vaccine will result in lifelong surveillance of the liver and provide protection from recurrence or reinfection