Universal influenza vaccines should be possible if conserved antigens of influenza are effectively targeted and effective antiviral immune responses are generated against those antigens. DNA vaccination is an appealing approach for delivering universal influenza vaccines, however, natural immune responses to conserved influenza antigens are typically weak and most DNA vaccines tested in humans have not elicited robust humoral immunity. To overcome the obstacles to developing universal influenza DNA vaccines, we are using novel composite immunogens and delivering them with a next generation Gene Gun device that combines several engineering and formulation innovations that increase immunogenicity by increasing the number of skin cells and antigen presenting cells expressing vaccine antigen. We have already obtained encouraging results with a universal influenza A (UFluA) DNA vaccine. Under this SBIR proposal, we intend to test a companion universal influenza B (UFluB) DNA vaccine to create a more comprehensive universal A/B vaccine (UFluA/B) that will provide broad protective coverage from all influenza A and B types capable of infecting humans. If we are successful at demonstrating that a single UFluA/B DNA vaccine can induce broad responses and protection in mice in the phase I effort, we will advance this this product to preclinical testing under the phase II portion of this application where we will investigate immunogenicity and protective efficacy in naïve and pre-immune ferrets and safety and efficacy in a nonhuman primate model that closely resembles humans in their dosing, immune response to DNA vaccination and susceptibility to influenza. If successful, these data will provide Orlance with a strong preclinical IND data package to advance this strategy to phase I human clinical trials. 2
Public Health Relevance Statement: Project Narrative The objective of this project is to continue development of a "universal" influenza vaccine that targets all A and B strain viruses. Such a vaccine is needed provide protection against all influenza A and B viruses to a substantial portion of the world's population.
Project Terms: Antibodies; Antigen-Presenting Cells; accessory cell; Antigens; immunogen; Antiviral Agents; Antiviral Drugs; Antivirals; anti-viral agents; anti-viral drugs; anti-virals; Cells; Cell Body; Clinical Trials; DNA; Deoxyribonucleic Acid; Engineering; Exhibits; Ferrets; Gold; Human; Modern Man; Humoral Immunities; antibody-based immunity; Inflammation; Influenza; Grippe; flu infection; influenza infection; Lung; Lung Respiratory System; pulmonary; Macaca; Macaque; Macaca fascicularis; Crab-Eating Macaque; Crab-Eating Monkey; Cynomolgus Monkey; Cynomolgus macaque; M fascicularis; M. fascicularis; Macaca mulatta; M mulatta; M. mulatta; Rhesus Macaque; Rhesus Monkey; Mucous Membrane; Mucosa; Mucosal Tissue; Mus; Mice; Mice Mammals; Murine; United States National Institutes of Health; NIH; National Institutes of Health; Publishing; Reagent; Role; social role; Safety; Syringes; T-Lymphocyte; T-Cells; thymus derived lymphocyte; Testing; Vaccination; Vaccines; Viremia; viraemia; viral sepsis; virusemia; Virus Replication; viral multiplication; viral replication; virus multiplication; Virus; Body Weight decreased; Weight Loss; Weight Reduction; body weight loss; wt-loss; Site; Clinical; Phase; electroporative delivery; gene electrotransfer; Electroporation; Susceptibility; Predisposition; non-human primate; nonhuman primate; Mucosal Immune Responses; Immunological response; host response; immunoresponse; Immune response; fluid; liquid; Liquid substance; Companions; Naked DNA Vaccines; Recombinant DNA Vaccines; DNA Vaccines; Immunes; Immune; experience; Toxicities; Toxic effect; novel; Devices; Pathogenesis; Reporting; Modeling; response; Biolistics; Gene-Gun Technique; gene gun; Influenza A; Influenza Viruses Type A; Influenzavirus A; Orthomyxovirus Type A; Type A Influenza; Influenza A virus; Influenza B; Influenza Viruses Type B; Orthomyxoviruses Type B; Influenza B Virus; Skin; Inflammatory Response; vaccine screening; vaccine testing; vaccine evaluation; Influenza Virus; influenzavirus; Dose; Data; Preclinical Models; Pre-Clinical Model; pre-clinical testing; Preclinical Testing; Strategic Planning; SBIR; Small Business Innovation Research; Small Business Innovation Research Grant; Vaccinated; Vaccine Antigen; Immunochemical Immunologic; Immunologic; Immunological; Immunologically; Immunologics; developmental; Development; preclinical; pre-clinical; immunogenicity; designing; design; next generation; Population; innovate; innovative; innovation; deliver DNA; DNA delivery; protective efficacy; T cell response; Antibody Response; Formulation; universal flu vaccine; universal influenza vaccine
