Nasal vaccination using novel mucosal adjuvants - with main focus on influenza A virus
نویسنده
چکیده
........................................................................................................................... 2 Populärvetenskaplig sammanfattning ............................................................................... 3 Abbreviations ................................................................................................................... 5 Introduction ..................................................................................................................... 7 History ................................................................................................................................................. 7 Classification and structure ................................................................................................................. 7 Influenza A virus .............................................................................................................................. 8 Replication ......................................................................................................................................... 10 Immune response towards influenza A virus ................................................................... 11 Innate immune response .................................................................................................................. 11 Professional antigen presenting cell the dendritic cell ............................................................... 12 Adaptive immune response .............................................................................................................. 12 Cell-mediated immune response .................................................................................................. 13 Humoral immune response ........................................................................................................... 13 Mucosal immunity ............................................................................................................................. 14 Mucosal IgA/Secretory IgA ............................................................................................................ 15 Immune escape mechanisms of the influenza virus ......................................................................... 15 Transmission and symptoms ............................................................................................................. 16 Treatment ...................................................................................................................................... 17 Influenza vaccines ........................................................................................................... 18 Parenteral vaccination ....................................................................................................................... 19 Immune response after inactivated influenza vaccination ........................................................... 19 Advantages and disadvantages with inactivated vaccines ............................................................ 19 Mucosal vaccination .......................................................................................................................... 20 Immune response stimulated after mucosal vaccination ............................................................. 20 Advantages and disadvantages with live attenuated vaccines administered intra nasally .......... 21 Influenza vaccination of risk groups .................................................................................................. 21 Children ......................................................................................................................................... 21 Elderly ............................................................................................................................................ 22 Correlation of protection .................................................................................................................. 22 DNA-vaccination ............................................................................................................. 24 Adjuvants ....................................................................................................................... 26 Adjuvants used in influenza vaccines ................................................................................................ 26 Aluminum salt, the first adjuvant .................................................................................................. 26 MF59 .............................................................................................................................................. 27 Virosomes ...................................................................................................................................... 27 ASO3 .............................................................................................................................................. 27 Very potent but toxic mucosal adjuvantsCT and LT ........................................................................ 28 Adjuvants studied in this thesis ......................................................................................................... 28 EndocineTM ..................................................................................................................................... 28 N3, N3OA and N3OASq.................................................................................................................. 31 Flagellin (FliC) ................................................................................................................................ 31 Severe adverse events observed after influenza vaccination............................................ 32 Guillain-Barré syndrome ................................................................................................................... 32 Bell ́s palsy ......................................................................................................................................... 32 Narcolepsy ......................................................................................................................................... 32 Aim of the thesis ............................................................................................................. 34 Methods ......................................................................................................................... 35 Enzyme-linked immunosorbent assay (ELISA)................................................................................... 35 Cell culturing and virus propagation ................................................................................................. 36 Hemagglutination assay and Hemagglutination inhibition assay (HAI) ............................................ 36 Tissue culture infectious dose 50 (TCID50) and Neutralization assay/Virus neutralizing assay ......... 36 ELISpot ............................................................................................................................................... 37 Flow cytometry of stimulated DCs .................................................................................................... 37 Results and discussion .................................................................................................... 38 Paper I. EndocineTM, N3OA and N3OASq; Three Mucosal Adjuvants That Enhance the Immune Response to Nasal Influenza Vaccination .......................................................................................... 38 Paper II. DNA-Encoded Flagellin Activates Toll-Like Receptor 5 (TLR5), Nod-like Receptor Family CARD Domain-Containing Protein 4 (NLRC4), and Acts as an Epidermal, Systemic, and MucosalAdjuvant ............................................................................................................................................ 38 Paper III. Comparison of the mucosal adjuvant EndocineTM with two well-known adjuvants: cholera toxin and alum ................................................................................................................................... 39 Paper IV. The mucosal adjuvant EndocineTM increases immune responses to influenza antigen in aged mice .......................................................................................................................................... 40 Concluding remarks ........................................................................................................ 42 Acknowledgements ........................................................................................................ 44 References ...................................................................................................................... 46
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