HPAI. Update of H7N9 in china:the epidemiological and virological features LPAI. H7N9 avian influenza viruses (before 2013)

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1 Update of H7N9 in china:the epidemiological and virological features Yuelong Shu WHO Collaborating Center for Reference and Research on Influenza Chinese National Influenza Center National Institute for Viral Diseases Control and Prevention China CDC HPAI 1/USA 1959 LPAI 1/USA 4/USA /England / USA H7N2 89/ Netherlands 1/ Canada 1 died 7/ Italy / USA H7N2 H7 human cases(>100 cases) USA, UK, Italy, Netherland, Cananda (H7N2,, ) / Canada / Norfolk 4/ Wales H7N2 2/ Mexico 2012 H7 avian influenza viruses in China (before ) H7N9 avian influenza viruses (before ) A/Baer's pochard/hunan/414/2010(h7n1) A/chicken/Hebei/1/2002(H7N2) A/duck/Guangdong/1/1996() A/duck/Hubei/126/1985(H7N8) A/duck/Jiangxi/1742/03() A/duck/Jiangxi/1760/03() A/duck/Jiangxi/1786/03() A/duck/Jiangxi/1814/03() A/duck/Nanchang/1904/1992(H7N1) A/duck/Nanchang/1944/92(H7N1) A/duck/Zhejiang/10/2011() A/duck/Zhejiang/12/2011() A/duck/Zhejiang/2/2011() A/magpie-robin/China/28710/93(H7) subtypes:h7n1, H7N2,,, H7N8 LPAI No human H7cases Totally 25 isolates all LPAI All from wild birds No human infection 1

2 Timely identification of first three H7N9 cases 3.24 Sample from Shanghai 3.25 A/H7 positive 3.26 Sample from Anhui 3.28 H7N9 Virus isolated 3.29 Full genome Sequence Chinese National Influenza center A novel avian influenza H7N9 virus was firstly identified HA: A/duck/Zhejiang/12/2011()-like NA: A/wild bird/korea/a14/2011(h7n9)-like Six internal genes: A/brambling/Beijing/16/2012(H9N2)- like Gao R et al NEJM J Human H7N9 Confirmed Cases in China (as of April,28,2014, Beijing time) Epidemic Curve of Confirmed Cases in Mainland China (n=417) Provinces* 2014 Total cases deaths cases deaths Guangdong Zhejiang Hunan Fujian Jiangsu Shanghai Anhui Guangxi Beijing Shandong Jilin Guizhou Jiangxi Henan Hebei Hongkong SAR Taiwan Total *This table CHINESE is counted CENTER by FOR the provinces DISEASE CONTROL where cases AND were PREVENTION reported. 2

3 Geographic Distribution of A(H7N9) Cases in Mainland China As of April,28, 2014 Case Fatality Rate by Age and Sex (as of April, 28, 2014) Total First wave* Second wave# Age(year) cases death CFR(%) cases death CFR(%) cases death CFR(%) 0~ ~ ~ ~ ~ total Male Female *First wave:before Oct 1, ; Second wave:after 0ct 1, #CFR% in the second wave may be under estimated as some cases are still in hospital. Exposure History & Family Clusters Human infection cases with A(H7N9) avian influenza mainly come from exposure to infected poultry or contaminated live bird markets. There is no difference regarding exposure to infected poultry or contaminated live bird markets between the first wave(82%) and the second wave (85%). To date, there are 13 family clusters. 12clusters are with 2 cases per cluster 1 cluster is with 3 cases (father/mother/daughter) No sustainable human to human Characterization of molecular markers of avian influenza H7N9 viruses HA NA PB2 PB1 PB1-F2 M2 RBS del Increased path in mice Enhance Increased in Ferret Increased path Amantidine resistant G(2)/V(38) Q(2)/L(36) /I(2) Yes(39) /No E(12)/K(28) D(36)/N(4) I(7)/V(33) 90aa(30)/76aa(2) /25aa(8) HA NA PB2* PB1* PB1-F2* M2 Increased path Enhance Increased RBS Amantidine resistant in mice del in Ferret Increased path V(69) L(69) Yes(69) E(13)/K(51)/mi x(3) D(64)/N(3) V(60)/A Q(11)/L(48) 90aa(45)/36aa/2 Yes(61) E(58)/K(2) D(60) V(60) N(60) /mix(2) 5aa(14) V(68) 90aa(64)/57aa(3)/25a a HA# NA PB2 PB1 PB1-F2 M2 RBS del Increased path in mice Enhance Increased in Ferret Increased path N(69) N(40) Amantidine resistant First wave Second wave Non-human 3

4 Transient genotypes Genotypes isolated on more than one sampling occasion November December January February 2014 HA NA November December January February 2014 PB2 PB1 PA HA NA NP MP NS A Collection Feb.25 Mar.04 Mar.11 Mar.18 Mar.25 Apr.01 Apr.08 Apr.15 Apr.22 Apr.29 May.06 May.27 Jul.15 Aug.05 Oct.14 Nov.04 Nov.25 Dec.16 Jan.27 Feb.03 Date AnH1 (3) (2) (6) (11) (18) (7) (9) (5) (2) SH7 November December January February 2014 JS1 SH1 (2) (7) (8) (5) (3) (10) (3) (2) HB1 (2) ZJ2 SD1 (2) GD1 (2) GD2 GX8970 (2) SH5 SH13 JS537 ZJ007 HK1 SH1080 HZ48 ZJ410 SH1436 HZ109 ZJHZ1 SH1437 SH1438 SH1439 ZJ4 RZ871 Clade A Clade B Clade C Clade D Clade E Clade F Clade G Clade H HA NA NA(del) 4

5 The geographic distribution of Genotypes B China Novel H7N9 Six internal genes: domestic-poultry derived H9N2, chicken or wild-bird AnH1 SH7 JS Morens DM et al, NEJM, D liu et al., Lancet, Genetic tuning mediated the interspecies Taijiao Jiang et al, Cell Host Microbes, 5

6 Receptor Binding Profile α2,3 α2,3 α2,3 α2,6 α2,6 α2,6 Growth Properties of H7N9 virus in mammalian cell lines Human Canine HA G186V, Q226L α2,6 α2,3 Zhou JF, et al. Nature, α2,3 & α2,6 Porcine CA04:A/California/04/2009 (2009pdmH1N1) SH1: A/Shanghai/1/ (H7N9) AH1: A/Anhui/1/ (H7N9) Zhou JF, et al. Nature, Growth Properties of H7N9 virus in different temperature Ex vivo infection of H7N9 virus in trachea or lung tissue Watanabe T. et al, Nature, Belser JA. et al., Nature, Zhou JF, et al. Nature, 6

7 Animal model studies Why severe case? host infectivity Transmissibility pathogenicity chicken duck Pigeon quail pig mild mice NA mild ferret mild monkey NA mild Guinea pig mild Fatality risk for all age: 36% Yu, H et al Lancet Retrospective serological study Demographic Characteristics Study subjects N(%) N=1544 Shanghai Zhejiang Jiangsu Anhui Age group, years (0.2%) 1(0.2%) 1(0.3%) (8.5%) 12(2.7%) 2(0.5%) 2(0.7%) (74.2%) 343(78.1%) 272(65.5%) 195(67.0% 60 69(17.3%) 83(18.9%) 140(33.7%) 93(32.0%) Gender F 200(50.1%) 240(54.7%) 194(46.7%) 115(39.5%) M 199(49.9%) 199(45.3%) 221(53.3%) 176(60.5%) Occupational places Live poultry market 192(48.1%) 106(24.1%) 39(9.4%) 0 Farms 129(32.3%) 182(41.5%) 193(46.5%) 241(82.8%) Poultry backyard 8(2.0%) 131(29.8%) 128(30.8%) 50(17.2%) Slaughter house 70(17.5%) 20(4.6%) 22(5.3%) 0 Wild-birds habitat (8.0%) 0 Collection date Jan-May, Oct-Nov, Total Bian T. et al., NEJM, No Positive Elevated cytokine levels in acute infected patients P= P= A B C D P= P< P= Infected Healthy Infected Healthy H5N1 IP10 P= H7N9 P= E F G H P= P= P= P= P< Infected Healthy Infected Healthy H5N1 H7N9 Infected Healthy Infected Healthy H5N1 H7N9 P= MIG MIP-1ß MCP-1 IL-6 IL-8 IFN-α P= P= Infected Healthy Infected Healthy H5N1 P= H7N9 Zhou JF, et al. Nature, 7

8 Reference antigens Antigenicity analysis of avian influenza A(H7N9 ) viruses Passage history subtype Ferret anti sera AH1* SH2 # PC0360 MN12 1 A/Anhui/1/ E2 H7N A/Shanghai/2/ E1 H7N A/wild gs/dongting/pc0360/2012 E A/mallard/Netherlands/12/2000 EX+E1/E Test antigens 5 A/Shanghai/02619/2014 E1 H7N A/Guangdong/02620/2014 E1 H7N A/Guizhou/01502/2014 E1 H7N A/Guangdong/02125/2014 E1 H7N A/Fujian/1/2014(H7N9) E1 H7N A/Zhejiang/07807/2014 E1 H7N A/ Zhejiang /07802/2014 E1 H7N A/Hunan/07833/2014 E1 H7N A/Hunan/08963/2014 E1 H7N A/Guangxi/08970/2014 E1 H7N A/Guangxi/08971/2014 E1 H7N A/Environment/Guangdong/25003/ E1 H7N A/Environment/Zhejiang/07818/2014 E1 H7N A/Environment/Hunan/07836/2014 E1 H7N remain antigenically similar to the candidate vaccine viruses derived from A/Anhui/1/-like viruses Virus susceptibility of human H7N9 viruses to Neuraminidase Inhibitors Viruses IC50( Mean± SD a ) Oseltamivir Zanamivir A/Shanghai/1/ (H7N9) 0.7± ±0.016 A/Shanghai/2/ (H7N9) 1.08± ±0.016 A/Shanghai/3/ (H7N9) 0.69± ±0.05 A/Shanghai/4/ (H7N9) 1.03± ±0.03 A/Shanghai/5/ (H7N9) 1.27± ±0.06 A/Anhui1/ (H7N9) 2± ±0.01 A/Jiangsu/1/ (H7N9) 1.15± ±0.07 A/Zhejiang/1/ (H7N9) 1.05± ±0.11 A/Pigeon/Shanghai/S1069/ (H7N9) 1.47± ±0.03 A/Chicken/Shanghai/S1053/ (H7N9) 1.47± ±0.05 A/Environment/Shanghai/S1088/ (H7N9) 0.67± ±0.04 A/Environment/jiangxi/2009 (H11N9) 1.62± ±0.13 A/Washington/1/2007(H3N2, WT) <10e ±0.04 A/Texas/12/2007(H3N2, E119V) ± ±0.04 A/California/7/2009 (2009pdmH1N1, WT) 0.979± ±0.01 A/NorthCarolina/39/2009 ( 2009pdmH1N1, H275Y) 239.7± ±0.02 Sensitive to Oseltamivir and Zanamivir Zhou JF, et al. Nature, Emergence of the NA R292K mutation that confers resistance to NA inhibitors summarize A novel reassorment virus containing genes derived from at least 3 subtypes Genetic tuning mediated the interspecies The high diversity of internal genes caused the different genotypes Dual receptor binding profile cytokine storm may contribute to the clinical severity of human infection Hu Y. et al., Lancet, 8

9 summarize All viruses were highly homologous No change about infectivity and pathogenicity No change about drug resistance Resistance to amantadine Sensitive to oseltamivir and Zanamivir Surveillance, always surveillance 411 network labs 556 sentinel hospitals 63 network labs 197 sentinel hospitals Thank you! 9