The objective of this NIAID Advanced STTR Phase I proposal is to combine the strengths of academic investigators from the fields of immunology and animal disease modeling with the resources of ApoImmune Inc. to develop a novel vaccine, ApoVax104-TB"" targeting both active and latent Tuberculosis (TB) infections. ApoVax104-TB"" uses a novel proprietary vaccine based on ApoImmune's chimeric protein consisting of streptavidin and the costimulatory ligand, 4-1BBL, conjugated with known Mycobacterium tuberculosis T-cell antigens. This vaccine concept bears significant potential as a preventive and therapeutic vaccine against TB since the 4-1BBL component of the vaccine has been shown to induce adaptive (CD4+ and CD8+ T cell responses) and innate (dendritic cells, macrophages, and NK cells) immunity and overcome various immune evasion mechanisms (CD4+CD25+FoxP3+ Treg cells and clonal anergy). This application proposes to develop a subunit vaccine against TB based on a triple antigen strategy consisting of recombinant Ag85B, ESAT-6, and Mpt83 TB proteins. Ag85B and ESAT-6 are expressed by actively growing bacteria, and Mpt83 is expressed in non-dividing bacteria, thereby targeting both subpopulations in the lung. These antigens will be biotinylated and conjugated to chimeric 4-1BBL via biotin- streptavidin interaction and delivered in vivo specifically to dendritic cells constitutively expressing the 4-1BB receptor. The underlying hypothesis is that 4-1BBL interaction with 4-1BB on dendritic cells will activate these cells for antigen uptake, processing, and presentation to T cells, thereby generating potent adaptive immunity. At a second stage, 4-1BBL may directly work on activated CD4+ and CD8+ T cells with upregulated 4-1BB receptor to expand these cells and augment the memory response. At a third stage, 4-1BBL may overcome various immune evasion mechanisms, such as clonal anergy and CD4+CD25+FoxP3+ Treg cells, implicated in persistent TB. These combined effects are expected to result in protective as well as therapeutic effects against TB. This hypothesis is supported by our strong preliminary data demonstrating better efficacy of ApoVax104 than two bench-mark adjuvants, Monophosphoryl Lipid A and CpG, as components of a therapeutic vaccine against cervical cancer. The efficacy of ApoVax104-TBTM will be tested in preventive and therapeutic settings of TB in an animal model. If proven effective, these studies will be followed by a Phase II STTR application to further develop the vaccine for testing in a Phase I clinical trail. The development of a vaccine against TB will have tremendous societal benefits as well as target a global market in the billions of dollars.
Public Health Relevance: This project will establish the necessary fundamental parameters to develop a novel vaccine against tuberculosis (TB). Using ApoImmune's lead vaccine, ApoVax104"", we will develop a vaccine that will suppress the spread of TB by acting as a preventative as well as a therapeutic vaccine. ApoImmune's novel immunotherapy, ApoVax104 TM vaccine, is a new innovative approach to treating infectious diseases.
Thesaurus Terms: 1h-Thieno(3,4-D)Imidazole-4-Pentanoic Acid, Hexahydro-2-Oxo-, (3as-(3aalpha,4beta,6aalpha))-; Apc; Atgn; Adjuvant; Animal Disease Models; Animal Model; Animal Models And Related Studies; Antigen Presentation; Antigen Targeting; Antigen-Presenting Cells; Antigens; Arm; Bacteria; Bears; Binding; Binding (Molecular Function); Biotin; C57bl/6 Mouse; Cd8; Cd8b; Cd8b1; Cd8b1 Gene; Cancer Of Cervix; Cancer Of The Uterine Cervix; Cell Communication And Signaling; Cell Signaling; Cells; Cervical Cancer; Cervix Cancer; Chimera Protein; Chimeric Proteins; Chronic; Clinical; Clonal Anergy; Comment; Comment (Pt); Comment [publication Type]; Commentary; Commentary (Pt); Communicable Diseases; Cytokines, Chemotactic; Cytotoxic Cell; Data; Dendritic Cells; Development; Dose; Down-Regulation; Down-Regulation (Physiology); Downregulation; Drug Formulations; Editorial Comment; Editorial Comment (Pt); Effector Cell; External Domain; Extracellular Domain; Figs; Figs - Dietary; Formulation; Formulations, Drug; Fusion Protein; Generations; Head; Histocompatibility Antigens; Homologous Chemotactic Cytokines; Itx; Immune; Immune Response; Immune System; Immunity; Immunologic Accessory Cells; Immunologically Directed Therapy; Immunology; Immunology (Including Brmp); Immunology (Nci Program); Immunotherapy; Infection; Infectious Disease Pathway; Infectious Diseases; Infectious Diseases And Manifestations; Infectious Disorder; Intercrines; Intracellular Communication And Signaling; Investigators; K Lymphocyte; Knockout Mice; Lps; Lyt3; Lead; Ligands; Lipopolysaccharides; Lung; Lytotoxicity; M. Tb; M. Tuberculosis; M.Tb; M.Tuberculosis; Malignant Cervical Neoplasm; Malignant Cervical Tumor; Malignant Neoplasm Of The Cervix; Malignant Tumor Of The Cervix; Malignant Tumor Of The Cervix Uteri; Malignant Uterine Cervix Neoplasm; Malignant Uterine Cervix Tumor; Malignant Neoplasm Of Cervix Uteri; Mammals, Mice; Marketing; Memory; Methods And Techniques; Methods, Other; Mice; Mice, Knock-Out; Mice, Knockout; Modeling; Molecular Interaction; Monocytes / Macrophages / Apc; Murine; Mus; Mycobacterium Tuberculosis; N-Terminal; Nh2-Terminal; Niaid; Nk Cells; National Institute Of Allergy And Infectious Disease; Natural Killer Cells; Null Mouse; Pb Element; Phase; Preventive; Process; Protein Biochemistry; Protein/Amino Acid Biochemistry; Proteins; Published Comment; Receptor Protein; Recombinants; Research Personnel; Research Resources; Researchers; Resources; Respiratory System, Lung; Sis Cytokines; Sttr; Signal Transduction; Signal Transduction Systems; Signaling; Small Business Technology Transfer Research; Staging; Strepavidin; Streptavidin; Structure; Subunit Vaccines; T-Cell Proliferation; T-Cells; T-Lymphocyte; Tb Vaccine; Techniques; Testing; Therapeutic; Therapeutic Effect; Thymus-Dependent Lymphocytes; Transplantation Antigens; Treatment Efficacy; Tuberculosis; Tuberculosis Vaccines; Up-Regulation; Up-Regulation (Physiology); Upper Arm; Upregulation; Ursidae; Ursidae Family; Vaccinated; Vaccination; Vaccines; Vaccines, Subunit; Veiled Cells; Viewpoint; Viewpoint (Pt); Vitamin H; Work; Accessory Cell; Anti-Tb Vaccine; Base; Biological Signal Transduction; Body System, Allergic/Immunologic; Chemoattractant Cytokine; Chemokine; Clinical Applicability; Clinical Application; Coenzyme R; Cross-Link; Crosslink; Cytokine; Cytotoxicity; Design; Designing; Disseminated Tb; Disseminated Tuberculosis; Gene Product; Heavy Metal Pb; Heavy Metal Lead; Host Response; Immune Therapy; Immunogen; Immunoresponse; In Vivo; Innovate; Innovation; Innovative; Interest; Lipid A Mp; Macrophage; Model Organism; Monophosphoryl Lipid A; Mouse Model; New Vaccines; Next Generation Vaccines; Novel; Novel Vaccines; Organ System, Allergic/Immunologic; Prevent; Preventing; Prophylactic; Public Health Relevance; Pulmonary; Receptor; Response; Therapeutic Efficacy; Therapeutic Vaccine; Therapeutically Effective; Thymus Derived Lymphocyte; Tuberculous Spondyloarthropathy; Tumor; Uptake; Vaccine Development; Vaccine Efficacy; Vaccine Evaluation; Vaccine Screening; Vaccine Testing
