A virus-like particle vaccine candidate for influenza A virus based on multiple conserved antigens presented on hepatitis B tandem core particles |
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| Institution: | 1. iQur Ltd, 2 Royal College Street, NW10NH London, UK;2. Luxembourg Institute of Health, 29 rue Henri Koch, L-4354, Luxembourg;1. Center for Vaccines and Immunology, University of Georgia, Athens, GA, USA;2. Department of Infectious Diseases, University of Georgia, Athens, GA, USA;3. University of Pittsburgh, Pittsburgh, PA, USA;4. Infectious Disease Research Institute, Seattle, WA, USA;5. Department of Global Health, University of Washington, Seattle, WA, USA;1. Research Institute of Influenza, Russian Federation Ministry of Health, St. Petersburg, Russia;2. Centre “Bioengineering”, Russian Academy of Science, Moscow, Russia;1. Centre for Medical Parasitology at the Department of Immunology and Microbiology, University of Copenhagen, Denmark;2. Department of Infectious Diseases, Copenhagen University Hospital, Denmark;3. Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark;1. Departments of Physiology and Microbiology & Immunology, Goodman Cancer Research Center, 3655 Promenade Sir William Osler, Montréal, Québec H3G 1Y6, Canada;2. Medicago Inc., 1020 route de l’Église, suite 600, Québec, Québec G1V 3V9, Canada;3. Research Institute of the McGill University Health Centre, 1001 Décarie Street, Montréal, Québec H4A 3J1, Canada;1. Centre ‘Bioengineering’, Russian Academy of Sciences, 117312 Prosp. 60-letya Oktyabrya 7-1, Moscow, Russia;2. Research Institute of Influenza, Russian Federation Ministry of Health, St. Petersburg, Russia |
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| Abstract: | Existing Influenza A virus (IAV) vaccines target variable parts of the virus that may change between seasons. Vaccine design relies on predicting the predominant circulating influenza strains but when there is a mismatch between vaccine and circulating strains, efficacy is sub-optimal. Furthermore, current approaches provide limited protection against emerging influenza strains that may cause pandemics. One solution is to design vaccines that target conserved protein domains of influenza, which remain largely unchanged over time and are likely to be found in emergent variants. We present a virus-like particle (VLP), built using the hepatitis B virus tandem core platform, as an IAV vaccine candidate containing multiple conserved antigens. Hepatitis B core protein spontaneously assembles into a VLP that is immunogenic and confers immunogenicity to proteins incorporated into the major insertion region (MIR) of core monomers. However, insertion of antigen sequences may disrupt particle assembly preventing VLP formation or result in unstable particles. We have overcome these problems by genetically manipulating the hepatitis B core to express core monomers in tandem, ligated with a flexible linker, incorporating different antigens at each of the MIRs. Immunisation with this VLP, named Tandiflu1, containing 4 conserved antigens from matrix protein 2 ectodomain and hemagglutinin stalk, leads to production of cross-reactive and protective antibodies. The polyclonal antibodies induced by Tandiflu1 can bind IAV Group 1 hemagglutinin types H1, H5, H11, H9, H16 and a conserved epitope on matrix protein 2 expressed by most strains of IAV. Vaccination with Tandiflu1 results in 100% protection from a lethal influenza challenge with H1N1 IAV. Serum transfer from vaccinated animals is sufficient to confer protection from influenza-associated illness in naïve mice. These data suggest that a Tandem Core based IAV vaccine might provide broad protection against common and emergent H1 IAV strains responsible for seasonal and pandemic influenza in man. |
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| Keywords: | Influenza vaccine Virus-like particle Tandem core Universal vaccine |
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