Despite the availability of a safe and effective prophylactic vaccine for hepatitis B virus (HBV), each year a significant number of new infections are reported to the CDC in the United States. Worldwide more than 2 billion people have been infected with HBV, and more than 350 million have developed chronic infections, which frequently lead to liver cirrhosis and liver cancer. None of the currently available antiviral therapies result in clearance of HBV infection which complicates the goal of eradicating HBV in the US. Clearly, new treatments of chronic HBV infections are needed. Notably, studies in chronically infected chimpanzees and liver transplant patients demonstrated a causal role for T cells during HBV viral clearance. This suggests that active immunotherapies which induce potent T cell immunity may be effective for the treatment of chronic hepatitis B. Recent advances in the field of bacterial-based vaccine vectors have shown promising results for infectious disease-targeted immunotherapy. One such example is the use of live-attenuated and killed strains of the intracellular bacterium Listeria monocytogenes (Lm). Lm represents an attractive platform for therapeutic HBV vaccines due to its ability to induce robust innate immunity as well as acquired CD4+ and CD8+ T-cell immunity. T cells represent the immune system's most potent weapon against chronic viral infections such as HBV. However, Lm is a pathogenic infectious agent in man, and in order to provide an appropriate therapeutic window, we have developed two highly attenuated vaccine platforms. The first is live- attenuated Lm in which two virulence genes have been completely deleted from the bacterial chromosome (Lm actA inlB). The second platform is based on Lm that is inactivated in such a way to prevent its replication while retaining its metabolic activity. These ""killed but metabolically active"" (KBMA) Lm are still able to induce robust cellular immunity and therefore provide a promising approach for therapeutic vaccine development. The live-attenuated Lm platform has already been tested clinically under three separate U.S. Investigational New Drug Applications (INDs), and is therefore the more advanced of the two approaches. Our proposal will help to define an Lm-based clinical vaccine candidate in the setting of chronic hepatitis B virus infection. The overall goal of this NIH SBIR Phase 1 proposal is to establish proof-of-concept (POC) to support the initiation of a development program for a KBMA Lm-based hepatitis B therapeutic vaccine expressing several HBV antigens (HBsAg, HBcAg, and HBV Pol), that ultimately results in safety and efficacy testing in human clinical trials. To this end, we propose the following aims: (1) Construct a panel of recombinant HBV antigen-expressing Lm strains;(2) Select the best monovalent configuration for each HBV Ag based ability to stimulate a reporter T cell line, expression of HBV antigens in cell culture, and immunogenicity in mice;and (3) Select a polyvalent KBMA Lm HBV clinical vaccine strain candidate for further development.
Public Health Relevance: An effective treatment for hepatitis B virus infection remains a significant unmet medical need in the United States and worldwide, despite the availability of a safe and effective prophylactic vaccine. Current small molecule-based treatments suppress viral gene expression, but fail to induce viral clearance. Recent findings in chronically infected chimpanzees and liver transplant patients suggest that therapeutic vaccines which induce multifunctional T cell immunity may be effective for the treatment of chronic hepatitis B.
Thesaurus Terms: 2',3'-Dideoxy-3'-Thiacytidine;2(1h)-Pyrimidinone, 4-Amino-1-(2-(Hydroxymethyl)-1,3-Oxathiolan-5-Yl)-, (2r-Cis)-;3tc;Aids Virus;Atgn;Acquired Immune Deficiency Syndrome Virus;Acquired Immunodeficiency Syndrome Virus;Active Immunotherapy;Acute;Address;Advanced Cancer;Advanced Malignant Neoplasm;Animal Model;Animal Models And Related Studies;Antigens;Antiviral Therapy;Attenuated;Attenuated Vaccines;Bacteria;Bacterial Chromosomes;Benchmarking;Best Practice Analysis;Blood Group Antigen S;Cd8;Cd8b;Cd8b1;Cd8b1 Gene;Cdc;Cancer Treatment;Cell Culture Techniques;Cell Line;Cell Mediated Immunology;Cell-Mediated Immunity;Cellline;Cells;Cellular Immunity;Centers For Disease Control;Centers For Disease Control And Prevention;Centers For Disease Control And Prevention (U.S.);Chimp;Chimpanzee;Chronic;Chronic Hepatitis B;Chronic Hepatitis C;Chronic Type C Viral Hepatitis;Chronic Viral Hepatitis C;Clinical;Clinical Evaluation;Clinical Testing;Clinical Trials;Communicable Diseases;Cultured Cells;Development;Dose;Early-Stage Clinical Trials;Employee Strikes;Evaluation;Fermentation;Foundations;Gene Expression;Genes;Goals;Hbv;Hbv Vaccine;Hbv Polymerase;Hbv-P Protein;Hbcag;Hcv;Hiv;Htlv-Iii;Hepatic Cancer;Hepatic Cells;Hepatic Cirrhosis;Hepatic Parenchymal Cell;Hepatic Transplantation;Hepatitis B;Hepatitis B Core Antigen;Hepatitis B Infection;Hepatitis B Therapeutic;Hepatitis B Vaccines;Hepatitis B Virus;Hepatitis B Virus Vaccine;Hepatitis C Virus;Hepatitus C;Hepatocyte;Homologous Serum Hepatitis Virus;Human;Human Immunodeficiency Viruses;Human T-Cell Leukemia Virus Type Iii;Human T-Cell Lymphotropic Virus Type Iii;Human T-Lymphotropic Virus Type Iii;Immune Response;Immune System;Immunity;Immunologically Directed Therapy;Immunotherapy;Infection;Infection Prevention;Infectious Agent;Infectious Disease Pathway;Infectious Diseases;Infectious Diseases And Manifestations;Infectious Disorder;Innate Immunity;Investigational New Drug Application;Killings;L. Monocytogenes;Lav-Htlv-Iii;Lyt3;Lamivudine;Lead;Life;Listeria Monocytogenes;Liver;Liver Cells;Liver Cirrhosis;Liver Grafting;Liver Transplant;Lymphadenopathy-Associated Virus;M. Tuberculosis Infection;M.Tuberculosis Infection;Mtb Infection;Malaria;Malignant Neoplasm Therapy;Malignant Neoplasm Treatment;Malignant Neoplasm Of Liver;Man (Taxonomy);Medical;Metabolic;Methods;Mice;Mice Mammals;Modern Man;Mtb Infection [{C0041296}];Murine;Mus;Mycobacterium Tuberculosis (Mtb) Infection;Mycobacterium Tuberculosis Infection;Nih;National Institutes Of Health;Native Immunity;Natural Immunity;Non-Specific Immunity;Paludism;Pan Genus;Pan Species;Patients;Pb Element;Phase;Phase 1 Clinical Trials;Phase I Clinical Trials;Plasmodium Infections;Polyvalent Vaccine;Prevent Infection;Prevention;Program Development;Proteins;Publications;Recombinant Vaccines;Recombinants;Reporter;Reporting;Role;S Antigen;Sbir;Sbirs (R43/44);Scientific Publication;Small Business Innovation Research;Small Business Innovation Research Grant;Strains Cell Lines;Strikes;T-Cells;T-Lymphocyte;Testing;Therapeutic;Thymus-Dependent Lymphocytes;Transplant Recipients;Tuberculosis;United States;United States Centers For Disease Control;United States Centers For Disease Control And Prevention;United States National Institutes Of Health;Vaccines;Viral;Viral Antigens;Viral Diseases;Viral Gene Products;Viral Gene Proteins;Viral Genes;Viral Hepatitis B;Viral Proteins;Virulence;Virus Diseases;Virus-Hiv;Allergic/Immunologic Body System;Allergic/Immunologic Organ System;Anticancer Therapy;Base;Cancer Therapy;Cell Culture;Chronic Hbv Infection;Chronic Hcv Infection;Chronic Hepatitis B Virus Infection;Chronic Hepatitis C Virus Infection;Clinical Investigation;Clinical Test;Cultured Cell Line;Develop A Vaccine;Development Of A Vaccine;Developmental;Disseminated Tb;Disseminated Tuberculosis;Effective Therapy;Effective Treatment;Efficacy Testing;Gene Product;Heavy Metal Pb;Heavy Metal Lead;Hepatic Body System;Hepatic Organ System;Hepatitis B Virus P Protein;Hepatitis B Virus Polymerase;Host Response;Immune Therapy;Immunogen;Immunogenicity;Immunoresponse;Infection Due To Mycobacterium Tuberculosis;Infection With Hbv;Infection With Hepatitis B Virus;Infectious Organism;Live Vaccine;Liver Cancer;Liver Transplantation;Malignant Liver Tumor;Man;Man's;Model Organism;Phase 1 Trial;Phase I Protocol;Phase I Trial;Prevent;Preventing;Prophylactic;Research Clinical Testing;Safety Testing;Serum Hepatitis;Small Molecule;Social Role;Therapeutic Vaccine;Thymus Derived Lymphocyte;Transplant Patient;Treatment Strategy;Tuberculous Spondyloarthropathy;Vaccine Candidate;Vaccine Development;Vector-Based Vaccine;Viral Infection;Viral Infectious Disease Treatment;Virus Antigen;Virus Infection;Virus Protein;Virus-Induced Disease;Weapons
