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Transmission of 2009 H1N1 Influenza Viruses in Ferrets Terrence Tumpey Immunology and Pathogenesis Branch Influenza Division, CDC EM of CA/04/2009 – CDC/C.S.

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Presentation on theme: "Transmission of 2009 H1N1 Influenza Viruses in Ferrets Terrence Tumpey Immunology and Pathogenesis Branch Influenza Division, CDC EM of CA/04/2009 – CDC/C.S."— Presentation transcript:

1 Transmission of 2009 H1N1 Influenza Viruses in Ferrets Terrence Tumpey Immunology and Pathogenesis Branch Influenza Division, CDC EM of CA/04/2009 – CDC/C.S. Goldsmith

2 Animal Models: Influenza Transmission Mice – Poor model Guinea Pigs – Good transmission model, but poor model for influenza pathogenesis Ferrets – Best model for transmission and pathogenesis (Lowen AC, S. Mubareka, J. Steel, P. Palese, PLoS Pathog. 2007 3:1470)

3 Inoculated Animals Transmission Study: Experimental Design Respiratory Droplet transmission

4 Inoculated Animals Naive Transmission Study: Experimental Design Respiratory Droplet transmission 10 6 PFU i.n.

5 Inoculated Animals Transmission Study: Experimental Design Respiratory Droplet transmission

6 Inoculated Animals Contact Animals Transmission Study: Experimental Design Contact Transmission X2 Respiratory Droplet Transmission

7 Avian H1N1 (Duck/NY/96) Log 10 EID 50 /ml Days post inoculation/contact Ferret Model of Respiratory Droplet Transmission Human H1N1 vs. avian H1N1 viruses 135135779119 2 4 6 8 1918 (H1N1) (SC18 HA) Log 10 EID 50 /ml Inoculated No transmission † † 2 4 6 8 135135779119 † Contact ferrets (3/3)

8 Human H2N2 (Albany/6/58) Log 10 EID 50 /ml InoculatedContact ferrets Avian H2N2 (Mallard/NY/6750/78) Log 10 EID 50 /ml 2 4 6 8 135135779119 Days post inoculation/contact Ferret Model of Respiratory Droplet Transmission Human vs. avian H2N2 viruses 2 4 6 8 135135779119 No transmission

9 What influenza virus genes confer efficient transmission? 1918 H1N1 (transmissible phenotype) Avian H1N1 (non-transmissible ) = Virus genes ? + Efficient Transmission

10 Two 1918 virus genes, HA and PB2, were sufficient to confer virus transmissibility in ferrets when rescued on the genetic background of an avian H1N1 virus. Summary of Findings HA PB2

11 Days post-inoculationDays Post-contact Two amino acid substitutions (D190E, D225G) in HA abolishes transmissibility of the 1918 virus Contact ferrets* 1 2 3 4 5 6 7 8 Virus titer (log 10 EID 50 /mL) 135791573911 Nasal Wash Titers: AV18 virus * Influenza sero-neg at day 0 and 18 p.c. †† Inoculated

12 1918 HAPB2:Dk/NY/96 Log 10 EID 50 /ml Inoculated Contact ferrets Log 10 EID 50 /ml Days Post-InoculationDays Post-Contact 135135779119 2 4 6 8 2 4 6 8 135135779 9 1918 HA:Duck/NY/96 1918 HA and PB2 virus genes confer efficient respiratory droplet transmission

13 PB2 Ten amino acid differences in PB2 of the avian Dk/NY/96 virus and 1918 virus These changes (positions 108, 114,199, 473, 475, 477, 539, 576, 627, and 702) occur in domains that are suggested to have a variety of functions including mRNA cap-binding and PB1 binding Of particular interest is the presence of a lysine (k) residue at 627 of the 1918 PB2 protein PB2 627K has been suggested to allow more efficient growth at the lower temperatures encountered in the upper airway of mammals (M. Hatta et al., 2007 PLoS Pathog 3)

14 Days post-inoculationDays post-contact A single amino acid substitution (PB2-K627E) in PB2 abolishes transmissibility of the 1918 virus Contact ferrets Virus titer (log 10 EID 50 /mL) Inoculated 2 3 4 5 6 7 8 135135779119 Nasal Wash Titers: 1918 (PB2-K627E)

15 Plaque morphology of H1N1 reassortant viruses

16 Plaque morphology of H1N1 reassortant viruses

17 Do similar molecular changes influence transmission of 2009 H1N1 virus? Transmission of 2009 H1N1 Influenza Viruses

18 Household Secondary Attack Rates (% ILI) Odaira et al. (Eurosurveillance 2009 14:35) North Carolina Study location U.S. Japan Transmission of 2009 H1N1 in humans Cauchemez et al. (NEJM 2009 361:29) Doyle & Hopkins (Epidemiol Infect. 2010 21:1) Lessler & Reich (NEJM 2009 361:2628) New York Leung et al. (Epidemiol Infect. 2010 21:7) Hong Kong Study 14.3 10.1 7.6 17.7 5.9 SAR of seasonal influenza range is 10 to 40% Transmissibility in households from previous pandemics (20-40%)

19 Three 2009 H1N1 viruses selected: 1.A/California/04/2009 (uncomplicated respiratory illness) 2.A/Mexico/4482/2009 (severe respiratory illness) 3.A/Texas/15/2009 (fatal respiratory illness) vs. Seasonal H1N1 Transmission of 2009 H1N1 Viruses in Ferrets

20 2009 H1N1 Viruses Spread Efficiently by Direct Contact InoculatedContact ferrets (1/3) Log 10 PFU/ml Days Post-Inoculation Days Post-Contact InoculatedContact ferrets (3/3) Mex/4482/2009 Avian H1N1 (Duck/NY/96) 13513577911 135135779 2 4 6 8 2 4 6 8

21 Seasonal H1N1 vs. 2009 H1N1 RD Transmission Brisbane/2007 (seasonal) InoculatedContact ferrets (3/3) 13513577911 2 4 6 8 Log 10 PFU/ml InoculatedContact ferrets (2/3) Mex/4482/2009 13513577911 2 4 6 8 Log 10 PFU/ml Days Post-InoculationDays Post-Contact

22 Seasonal vs. Texas/15/009 H1N1 Virus Transmission Solomon Is/3/06 (seasonal H1N1) InoculatedContact ferrets (3/3) 2 4 6 8 Log 10 PFU/ml InoculatedContact ferrets (2/3) Days Post-InoculationDays Post-Contact Tx/15/2009 13513577911 2 4 6 8 Log 10 PFU/ml 13513577911

23 H1N1 Viruses of Swine Origin Failed to Form Significant Plaques at 33 o C

24 What is the transmission phenotype of a 2009 H1N1 PB2 (E627K) mutant virus? PB2PAHANPNAMNSPB1 CA/04/09 PB2 627K CA/04/2009 Glutamic acid → Lysine at position 627 PB2PAHANPNAMNSPB1 627K 627E PB2

25 E627K in PB2 Enhances RD Transmission in Ferrets InoculatedContact ferrets (3/3) CA/04/09 PB2 E627K 13513577911 2 4 6 8 Log 10 PFU/ml InoculatedContact ferrets (2/3) Log 10 EID 50 /ml 13513577911 2 4 6 8 CA/04/2009 Days Post-InoculationDays Post-Contact

26 InoculatedContact ferrets (3/3) 13513577911 NL/1132/2009 PB2 E627K RD Transmission of a natural 2009 H1N1 E627K isolate Log 10 PFU/ml Days Post-InoculationDays Post-Contact

27 Novel HA mutation (D222G) associated with increased disease severity? HA Amino acid position 222 resides in the RBS of the HA protein and may possibly influence the binding specificity and thus the cellular tropism of the virus. HA (D222G) mutation was found with increased frequency in fatal and severe cases in Norway (Kilander et al. 2010 Eurosurveillance Vol. 15 (9). D222G mutants were detected more frequently in viruses isolated from patients with fatal outcomes and in lung samples (Glinsky Cell Cycle 9 (5) 958-970)

28 CA/04/09 HA D222G CA/04/2009 PB2PAHANPNAMNSPB1 PB2PAHANPNAMNSPB1 222D What is the transmission phenotype of a 2009 H1N1 HA (D222G) mutant virus? Aspartic acid → Glycine at 222 HA (H1 numbering) 222G HA

29 13513577911 2 4 6 8 CA/04/2009 The effect of HA (D222G) mutation on RD transmission Log 10 PFU/ml InoculatedContact ferrets (2/3) InoculatedContact ferrets (2/3), 4/6 total Days Post-InoculationDays Post-Contact CA/04/09 HA D222G 13513577911 2 4 6 8 Log 10 PFU/ml

30 HA mutation at position 219 (I219K) improves the human-receptor binding affinity of CA/04 HA CA/04 HA I219K 1918 HA CA/04 wt HA Direct glycan array binding assay of HA’s to alpha 2,6 SA human receptor

31 CA/04/09 HA 219K CA/04/2009 PB2PAHANPNAMNSPB1 PB2PAHANPNAMNSPB1 219I What is the transmission phenotype of a 2009 H1N1 HA (I219K) mutant virus? Isoleucine → Lysine at 219 HA 219K HA

32 13513577911 2 4 6 8 CA/04/2009 A single amino acid substitution (I219K) in HA slightly enhances RD transmission of CA/04/2009 virus Log 10 PFU/ml InoculatedContact ferrets (2/3) InoculatedContact ferrets (3/3) Days Post-InoculationDays Post-Contact CA/04/09 HA I219K 13513577911 2 4 6 8 Log 10 PFU/ml

33 Weight Loss (%) % RD Transmission Lung Titers (log 10 ) Brisbane/59 (seasonal)100<1.2 (PFU/gm) Comparative H1N1 Results in Ferrets CA/4/2009 - D222G 66 6.3 Virus 4.9 11.4 CA/4/2009 – Wild-type66 5.8 10.3 Lethality 0/6 CA/4/2009 - E219K 1005.410.10/6 CA/4/2009 - E627K 100 5.9 11.3 0/6

34 CDC Atlanta Acknowledgements Pathogenesis team

35 Acknowledgements Mount Sinai School of Medicine USDA/Southeast Poultry Research Laboratory Centers for Disease Control and Prevention NIH Grants; 5R01 AI0506919-02 and AI058113-01 University of Washington School of Medicine The Scripps Research Institute Influenza Division/IVPB David Swayne Neal van Hoeven Debra Wadford Jacqueline Katz Nancy Cox

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