This document contains proprietary information that Profectus BioSciences requests not be released to persons outside the Government, except for purposes of review and evaluation. Abstract DNA vaccination is an appealing approach for developing prophylactic and therapeutic vaccines for mucosa tropic pathogens such as HIV. Unfortunately, DNA immunization in the muscle or skin does not induce mucosal immunity. DNA vaccination does, however, offer a unique opportunity to co-express adjuvants that could induce mucosal immunity. Retinoic acid (RA) instructs naove lymphocytes to home to mucosal tissues and Retinaldehyde dehydrogenases (RALDHs) are the key enzymes that convert retinal to RA. The RA receptor (RAR) binds RA and instructs cells to up-regulate mucosal homing molecules and to become RA producers themselves. We propose to use a dominant-positive mutant of the RAR (DP-RAR) 1 RALDH isoform 2 (RALDH2) as a mucosal homing adjuvant(s) for an HIV DNA vaccine. We postulate that intramuscular administration of plasmids expressing the antigens and the RA-producing adjuvants will trigger mucosal immune responses. We will demonstrate the potential of the RA adjuvant(s) with the following specific aims: (1) demonstrate that coadministration of plasmids expressing HIV antigens and DP-RAR 1 RALDH2 will induce mucosal antigen-specific immune responses in mice; and (2) demonstrate that adjuvanting a HIV pDNA vaccine with a RA inducing construct will improve protection against a mucosal challenge in the Vaccinia-HIV virus mouse model. If the DP-RAR 1 RALDH2 adjuvant significantly enhances mucosal immune responses and/or significantly enhances protection from virus challenge, it will be further evaluated in primate studies as components of an advanced HIV DNA vaccine/adjuvant combination in a Phase II SBIR application. 2
Public Health Relevance: The objective of this project is to develop novel mucosal adjuvants that will improve the efficacy of HIV DNA vaccines. These adjuvants will be based on a constructs such as a dominant-positive retinoic acid receptor and the enzyme RALDH2 that initiate retinoic acid production.
Thesaurus Terms: (All-E)-3,7-Dimethyl-9-(2,6,6-Trimethyl-1-Cyclohexen-1-Yl)-2,4,6,8-Nonatetraenoic Acid; Aids Antigens; Aids Virus; Atgn; Atra; Acquired Immune Deficiency Syndrome Virus; Acquired Immunodeficiency Syndrome Virus; Active Follow-Up; Adjuvant; All-Trans Retinoic Acid; Animal Model; Animal Models And Related Studies; Antibodies; Antigens; Cells; Dna; Dna Vaccines; Dendritic Cells; Deoxyribonucleic Acid; Drug Formulations; Enzymes; Evaluation; Formulation; Formulations, Drug; Government; Hiv; Hiv Antigens; Hiv Vaccine; Hiv-Associated Antigens; Hiv/Aids Vaccines; Htlv-Iii; Htlv-Iii Antigens; Htlv-Iii-Lav Antigens; Home; Home Environment; Homing; Human; Human Immunodeficiency Viruses; Human T-Cell Leukemia Virus Type Iii; Human T-Cell Lymphotropic Virus Type Iii; Human T-Lymphotropic Virus Type Iii; Human, General; Immune Response; Immunity; Immunization; Immunologic Stimulation; Immunological Stimulation; Immunostimulation; Infection; Intramuscular; Isoforms; Lav Antigens; Lav-Htlv-Iii; Lymph Node Proper; Lymphadenopathy-Associated Antigens; Lymphadenopathy-Associated Virus; Lymphocyte; Lymphocytic; Mammals, Mice; Mammals, Primates; Man (Taxonomy); Man, Modern; Measurable; Measures; Mice; Modeling; Mucosa; Mucosal Immune Responses; Mucosal Immunity; Mucosal Tissue; Mucous Membrane; Murine; Mus; Muscle; Muscle Cells; Muscle Cells, Mature; Muscle Tissue; Myocytes; Naked Dna Vaccines; Persons; Phase; Phenotype; Plasmids; Poxvirus Officinale; Primates; Production; Protein Isoforms; Receptor Protein; Recombinants; Reticuloendothelial System, Lymph Node; Retinal; Retinoic Acid; Retinoic Acid Receptor; Sbir; Sbirs (R43/44); Safety; Sensitization, Immunologic; Sensitization, Immunological; Site; Skin; Small Business Innovation Research; Small Business Innovation Research Grant; Staging; T-Lymphotropic Virus Type Iii Antigens, Human; Trans Vitamin A Acid; Tretinoin; Tretinoinum; Vsv; Vaccination; Vaccine Adjuvant; Vaccine Antigen; Vaccines; Vaccines, Dna; Vaccines, Recombinant Dna; Vaccinia; Vaccinia Virus; Variant; Variation; Veiled Cells; Vesicular Stomatitis Virus; Vesicular Stomatitis Indiana Virus; Virus; Virus-Hiv; Viruses, General; Vitamin A Acid; Abstracting; All-Trans-Retinoic Acid; All-Trans-Vitamin A Acid; Base; Follow-Up; Host Response; Human Immunodeficiency Virus Vaccine; Immunogen; Immunoresponse; Imprint; Improved; Lymph Cell; Lymph Gland; Lymph Nodes; Model Organism; Mouse Model; Mucosal Site; Mutant; Novel; Pathogen; Plasmid Vaccine; Product Development; Prophylactic; Public Health Relevance; Receptor; Receptor Binding; Recombinant Vaccinia Virus; Response; Retinaldehyde Dehydrogenase; Therapeutic Vaccine; Trafficking; Trans-Retinoic Acid; Vector Vaccine