Although the influenza vaccine has been used for over 60 years, the current vaccination strategy against influenza A and B viruses is vulnerable to the unanticipated emergence of epidemic strains that are poorly matched by the vaccine. Epidemics of seasonal influenza and increased circulation of avian influenza virus subtypes constitute a significant healthcare problem in all regions of the world, including the U.S. The annually recommended vaccination is the principal means of controlling influenza epidemics. However, the current licensed vaccines (trivalent inactivated or live, attenuated trivalent virus vaccines) provide protection only against the strains that are matched with the vaccine composition. There is no influenza pandemic vaccine available to the general public. In addition, the current vaccine production is based on egg substrates and would not meet the surge demand in vaccination during a pandemic outbreak. Therefore, development of influenza vaccines with improved protective efficacy against influenza virus is an imperative. Zetra's uniquely engineered adjuvant-containing viral nanoparticles (cVLPs) provided proof-of-concept that a broadly cross-protective, non-replicating vaccine with the possibility of cross reactivity with other influenza subtypes A and B, can be developed by the company's proprietary technology. The protective immune responses induced by these cVLPs have been maintained at high levels in mice for over 14-months. This desirable quality of our vaccines provides a potential to avoid the need to change the seasonal vaccine formulation every year. Importantly, a single immunization induced protective immunity against a high dose of challenge virus. A major goal of this project is to develop and evaluate novel adjuvant-containing influenza cVLPs vaccines against influenza virus in order to enhance broadly cross protective and long-lasting immunity. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is known to increase the immunogenicity of various co-administered antigens and is considered as an adjuvant appropriate for human use. We propose the novel approach to use GM-CSF in a membrane-anchored form in VLPs with influenza antigens. We have already developed chimeric influenza VLPs incorporating GM-CSF which show desirable vaccine qualities. Cross-protection as well as heterosubtypic protection models have been well established in our laboratory for seasonal influenza. In Phase I of this project, we will determine the cross-protective efficacy including heterosubtypic immunity induced by chimeric influenza VLPs containing the immunostimulatory molecule, GM-CSF, in well-established mouse and ferret models. The physical co-localization of the cytokine adjuvant and antigen in the same VLP is important to increase the efficacy of our novel vaccines. Our approach to development of a safe and effective vaccine that induces broadly cross protective immunity against influenza viruses will have a significant impact on public health in general.
Public Health Relevance: Epidemics of seasonal influenza and increased circulation of avian influenza virus subtypes constitute a significant healthcare problem in all regions of the world, including the U.S. The annually recommended vaccination is the principal means of controlling influenza epidemics. However, the current licensed vaccines (trivalent inactivated or live, attenuated trivalent virus vaccines) provide protection only against the strains that are matched with the vaccine composition. The goal of this project is the development of an engineered adjuvant-containing and improved influenza vaccine that will induce broadly cross-protective and long-lasting immunity.
Public Health Relevance Statement: NARRATIVE Epidemics of seasonal influenza and increased circulation of avian influenza virus subtypes constitute a significant healthcare problem in all regions of the world, including the U.S. The annually recommended vaccination is the principal means of controlling influenza epidemics. However, the current licensed vaccines (trivalent inactivated or live, attenuated trivalent virus vaccines) provide protection only against the strains that are matched with the vaccine composition. The goal of this project is the development of an engineered adjuvant-containing and improved influenza vaccine that will induce broadly cross-protective and long-lasting immunity.
NIH Spending Category: Biodefense; Biotechnology; Emerging Infectious Diseases; Immunization; Infectious Diseases; Influenza; Pneumonia & Influenza; Prevention; Vaccine Related
Project Terms: APC; ATGN; Adjuvant; Animal Model; Animal Models and Related Studies; Antigen-Presenting Cells; Antigens; Attenuated; Avian Influenza A Virus; B Virus; Blood Circulation; Bloodstream; Care, Health; Cercopithecid herpesvirus 1; Cercopithecine Herpesvirus 1; Circulation; Clinical Research; Clinical Study; Colony-Stimulating Factors; Development; Disease Outbreaks; Dose; Drug Formulations; Engineering; Engineerings; Epidemic; Ferrets; Flu epidemic; Flu vaccine; Formulation; Formulations, Drug; Fowl Plague Virus; GM-CSF; GMCSF; General Population; General Public; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Grippe; H1N1 Virus; H3N2 Virus; Healthcare; Hemagglutination; Herpes Virus B; Herpes simiae; Herpesvirus 1 (alpha), Cercopithecine; Herpesvirus 1, Cercopithecine; Herpesvirus B; Herpesvirus simiae; Histamine-Producing Cell-Stimulating Factor; Human; Human, General; Immune response; Immunity; Immunization; Immunologic Accessory Cells; Immunologic Stimulation; Immunological Stimulation; Immunostimulation; Influenza; Influenza A Virus, Avian; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza A virus; Influenza Vaccines; Influenza Virus; Influenza Virus, Avian; Influenza Viruses Type A; Influenza virus vaccine; Laboratories; Length of Life; Licensing; Life; Longevity; MGI-1 Protein; Mammals, Mice; Man (Taxonomy); Man, Modern; Measures; Membrane; Mice; Modeling; Molgramostin; Monkey B Virus; Monocytes / Macrophages / APC; Murine; Mus; Myeloid Cell-Growth Inducer; Myxovirus pestis galli; Orthomyxovirus Type A; Orthomyxovirus Type A, Avian; Outbreaks; Particulate; Phase; Philipines; Philippines; Phillipines; Phillippines; Public Health; Sensitization, Immunologic; Sensitization, Immunological; Simian Herpesvirus; Structure; TC-GM-CSF; Technology; Testing; Tumor-Cell Human GM Colony-Stimulating Factor; Vaccination; Vaccine Production; Vaccines; Virus; Virus-like particle; Viruses, General; accessory cell; avian flu virus; base; bird flu virus; cross reactivity; cytokine; egg; flu infection; granulocyte macrophage colony stimulating factor; host response; immunogen; immunogenicity; immunoresponse; improved; influenza epidemic; influenza infection; influenzavirus; influenzavirus (unspecified); life span; lifespan; meetings; membrane structure; model organism; mouse model; new approaches; new vaccines; next generation vaccines; novel; novel approaches; novel strategies; novel strategy; novel vaccines; pandemic; pandemic disease; pandemic flu; pandemic influenza; protective efficacy; public health medicine (field); public health relevance; response; scale up; seasonal influenza; vaccination strategy; vaccine candidate; viral nanoparticle; viruslike particle
