U N I V E R S I T Y O F B E R G E N En fremtidig universell influensavaksine Rebecca Jane Cox uib.no Influensa 2 uib.no Impact of influenza Deaths Requiring hospitalisation Deaths Requiring hospitalisation Clinical symptoms Asymptomatic Seasonal influenza 3 Proportion of cases (source ECDC) Clinical symptoms Asymptomatic Pandemic influenza uib.no Impact of influenza Deaths Requiring hospitalisation Deaths Requiring hospitalisation Clinical symptoms Asymptomatic Seasonal influenza 4 Proportion of cases (source ECDC) Clinical symptoms Asymptomatic Pandemic influenza uib.no Intervention delays and flattens epidemic peak Daily cases No intervention With intervention Days since first case 5 uib.no Inactivated virusvaccine Influenza vaccines 6 uib.no Seasonal influenza 7 uib.no Children are the main transmitters of influenza Photo from reallifesurvivalguide.com 8 CDC.photos uib.no UK recommends influenza vaccination for all children 9 uib.no Live Attenuated Influenza Vaccine- LAIV In 2-8 year olds, LAIV provides better protection than intramuscular vaccination. LAIV is therefore preferable in this age group unless contraindicated 10 uib.no High protective efficacy observed after LAIV low serum HI response measured Study Belshe, year 1 Belshe, year 2 A/H1N1 responses 30 100 Did not circulate 26 32 28 62 86 100 47 79 73 60 92 100 50 38 25 90 82 90 56 69 80 73 Did not circulate 28 81 10 14 49 -102 94 0 57 44 90 81 Bracco, year 2 Did not circulate 61 60 Vesikari, year 2 91 5 41 Vesikari, year 1 11 68 96 Did not circulate Tam, year 2 B strain responses 53 48 Tam, year 1 Bracco, year 1 A/H3N2 responses 25 50 75 100 Seroresponse, % Efficacy, matched strains, % 0 25 50 75 100 -100 -75 -50 -25 0 25 50 75 100 Bandell et al., Exp Rev Vaccine 2011 uib.no Recruitment 12 Hans Jørgen Aarstad, ENT uib.no Conflicts of interest Photo: K Mohn 13 uib.no Study design • • • • 20 boys & 18 girls 3-17 years old, median 4 years old Median weight 19 kg Median height 107cm Days n= 14 0 28 56 180 360 38 38 34 24 14 uib.no The immune response to influenza McKee, A.S., M.K.L. Macleod, et al. (2010). 15 BMC Biol 8: 37-‐46. uib.no Longevity serum antibody responses H3N2 H1N1 n = 38 n = 38 38 38 37 21 14 1280 24 1280 14 P<0.0001 320 80 40 20 HI titer HI titer 32 **** 320 80 40 20 5 Day 37 5 0 28 56 180 365 0 28 56 180 360 Days post vaccination Time postvaccination Days post vaccination 16 uib.no The immune response to influenza McKee, A.S., M.K.L. Macleod, et al. (2010). 17 BMC Biol 8: 37-‐46. uib.no % of total IgG+ MBC Longevity of memory B cell response *** * ** ** 2.5 2.0 1.5 1.0 0.5 0.0 0 28 56 180 360 0 28 % of total IgM+ MBC H1N1 50 56 180 360 H3N2 *** ** *** ** ** ** 0 28 56 180 360 B * ** *** 40 30 20 10 0 0 28 56 360 Days post vaccination 18 0 28 56 360 Days post vaccination 0 28 56 360 Days post vaccination uib.no The immune response to influenza McKee, A.S., M.K.L. Macleod, et al. (2010). 19 BMC Biol 8: 37-‐46. uib.no Cell mediated immunity Influenza Centre, Department of Clinical Science “The estimated protection curve indicated that the majority of infants and young children with ≥100 SFU/106 PBMC were protected against clinical influenza, establishing a possible target level of CMI for future influenza vaccine development” Majority of subjects with ≥ 100 SFU/106 PBMC protected against influenza infection after LAIV immunisation Probability of protection 1,0 95% CI 0,8 0,6 0,4 0,2 0,0 0.1 1 10 100 1,000 10,000 Interferon-γ ELISPOT (SFU/106 PBMC) Forrest Clin Vaccine Immunol 2008 20 uib.no Longevity of T cell response in blood * *** 800 H1N1 600 400 IFN-γ SFU/1*106 PBMC 200 0 * ** 800 600 400 H3N2 200 0 **** **** *** * 800 600 400 B 200 0 0 21 28 56 180 Days postvaccination 360 uib.no Conclusions 22 Dr. Karl Brokstad, UIB uib.no 23 uib.no Influenza pandemics 1918: 1957: 1968: “Spanish Flu” 50 million deaths “Asian Flu” “Hong Kong Flu” A(H1N1) 24 5 million deaths A(H2N2) 2 million deaths A(H3N2) 2009: “Swine flu” >16700deaths A(H1N1) 2009 uib.no 25 uib.no Avian influenza: the ever present threat Low pathogenic H7N9 26 High pathogenic H7N1/H5N1 uib.no H7 Influenza • Influenza H7 in Europe & North America (H7N2, H7N3, H7N7) – Conjunctivitis or mild influenza like illness – 1 death • H7N9 in China -656 cases 27 uib.no Making safe H7 influenza vaccine 28 uib.no Development of H7N1 vaccine virus Highly pathogenic chicken virus A/chicken/Italy/13474/99 (H7N1) Human vaccine virus A/Puerto Rico/8/8/34 (H1N1) NA HA Removal of multibasic cleavage site in HA Vaccine candidate RD3 virus (H7N1) 29 uib.no Generation of cell based H7 vaccine 30 uib.no Phase I Clinical trial H7 (Italian) vaccine Days 0 7 14 21 28 35 42 Serum samples 31 uib.no No protective antibodies after two H7 vaccinations 64 protec HI Titre 32 16 8 4 2 32 12 12+ 24 24+ 1st dose 12 12+ 24 24+ 2nd dose uib.no H7N9 Influenza in China 33 uib.no • 1st wave Spring 2013 136 cases -44 deaths • 2nd wave 2013-14 -318 cases -54 deaths • 3rd wave 2014-15 202 cases -40 deaths 34 uib.no 35 uib.no 36 uib.no H7 divided into Eurasian & North American lineages HA 37 uib.no Cross reactivity to H7 viruses Days 0 7 14 21 28 35 42 6M Serum samples Florian Krammer Mount Sinai 38 uib.no Increase in antibody to Chinese H7 after Italian H7 vaccination Vaccine strain Italian H7 39 Chinese H7 strain uib.no Can antibodies from our vaccinees protect mice against lethal H7N9 Chinese virus ? Days 0 7 14 21 28 35 42 Serum samples 40 uib.no Antibodies protect mice against lethal H7N9 Chinese virus 41 uib.no H7 haemagglutinin is highly conserved Site A Red amino acid changes between Chinese and Italian viruses 42 uib.no 43 uib.no HA stalk is highly conserved Globular Head Immunodominant HA Stalk 44 uib.no HA stalk is conserved among group 1 or group 2 H11 GROUP 1 H13 H16 H1 H2 H5 H6 H17 H8 H12 H9 Stalk H15 H10 H3 H4 H14 GROUP 2 H7 0.04 45 uib.no Are stalk antibodies induced after pandemic vaccination? 46 uib.no H7 vaccination increases H3 stalk antibody response * p=0.0326 Irrelevant H5 head domain H3 stalk domain 47 uib.no U NisI also V E R conserved S I T Y O F among B E R Ggroup E N HA stalk 1 H11 GROUP 1 H13 H16 H1 H2 H5 H6 H17 H8 H12 H9 H15 H10 H3 H4 H14 GROUP 2 H7 0.04 Shaw and Palese, 2011, Field’s Virology uib.no Phase I Clinical trial H5 vaccine H5N1 virosomal vaccine Days 0 7 14 3rd generation ISCOM™ 21 28 35 42 6M 12M Serum 49 uib.no Is an H1 stalk response induced after H5 vaccination? Irrelevant head H6 Raffael Nachbagauer Mount Sinai Stalk H1 50 Florian Krammer Mount SInai uib.no Significant Increase in H1 stalk antibodies after H5 vaccination H6/H1 51 uib.no Can these H1 stalk antibodies neutralise virus? 52 uib.no Do stalk antibodies protect against infection? Pre vaccination sera pooled (Day 0) Post vaccination sera pooled (Day 42) Infected cH6/1 virus 53 uib.no Stalk specific antibodies protect against weight loss and lower respiratory tract infection 54 uib.no Mechanisms of neutralisation Classical HI antibodies 55 Stalk-reactive antibodies uib.no Are chimeric vaccines a universal influenza vaccine? 56 uib.no Stalk Immunodominant head Therapeutic stalk antibodies in clinical trial 57 Ekiert et al., 2009, Science uib.no The future? Universal vaccines for specific groups 58 uib.no uib.no Acknowledgements K.G. Jebsen centre for Influenza vaccine research 60 uib.no
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