Zoonotic Influenza A(H7N9) Evolution and Vaccine Development

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1 Influenza Zoonotic Influenza A(H7N9) Evolution and Vaccine Development David E. Wentworth Chief, Virology Surveillance and Diagnosis Influenza Division, NCIRD Centers for Disease Control and Prevention Atlanta, GA USA

2 Significant Increase in A(H7N9) Infections (W5) Influenza Division Wave 5 N=766 N=320 N=135 N=224 N=119 Epidemic Curve of Confirmed Avian Influenza A(H7N9) Virus Infections of Humans Reported by WHO or in Chinese Provincial or Hong Kong CHP Press Releases, 18 Feb Feb 2018 (N=1,567)

Geographic Distribution 1 st through 4 th waves Influenza 0 225 Heilongjiang Mongolia Inner Mongolia Jilin 2 Russia Nepal India Xinjiang 10 Tibet Bhutan India Bangladesh Qinghai Myanmar Thailand

3 Geographic Distribution 1 st through 4 th waves Influenza Heilongjiang Mongolia Inner Mongolia Jilin 2 Russia Nepal India Xinjiang 10 Tibet Bhutan India Bangladesh Qinghai Myanmar Thailand Sichuan Yunnan Gansu Ningxia Vietnam Laos Chongqing Guizhou 3 Shaanxi Guangxi 3 Shanxi Henan 4 Hubei 2 Hunan 34 Guangdong 195 Macao Hebei 4 Shandong 9 Anhui 38 Zhejiang Jiangxi Fujian 73 Hong Kong 16 Liaoning 1 Beijing 9 Tianjin 2 Taiwan 4 Jiangsu 103 North Korea Shanghai 50 South Korea Japan Geographic Distribution of 1 st 4 th Epidemics Confirmed Avian Influenza A(H7N9) Virus Human Infections*, March 2013-September 2016, (N=795) * Infections reported to WHO

Geographic Distribution 5 th wave Influenza Geographic Distribution of Fifth Epidemic Confirmed Avian Influenza A(H7N9) Virus Infections of Humans, Reported by WHO or in Chinese Provincial or Hong

4 Geographic Distribution 5 th wave Influenza Geographic Distribution of Fifth Epidemic Confirmed Avian Influenza A(H7N9) Virus Infections of Humans, Reported by WHO or in Chinese Provincial or Hong Kong CHP Press Releases, October 1, 2016-September 30, 2017 (N=766) Heilongjiang Mongolia Inner Mongolia 1 Jilin 1 Russia Nepal India Xinjiang 3 Tibet 3 Bhutan India Bangladesh Qinghai Myanmar Sichuan 38 Yunnan 7 Ningxia Gansu 5 Shaanxi 7 Chongqing 9 Guizhou 18 Vietnam Guangxi 28 Shanxi 3 Henan 24 Hubei 29 Hunan 61 Macao 2 Shandong 19 Anhui 63 Jiangxi 38 Fujian 34 Guangdong 63 Hong Kong 5 Liaoning 4 Beijing 27 Zhejiang 91 Taiwan 1 Thailand Laos Human Infections of A(H7N9) with HPAI mutation reported to WHO Human Infections of A(H7N9) with HPAI mutation identified by China CDC or Taiwan CDC LPAI human infections are by Province of Reporting; HPAI human infections are by Province of Exposure Hebei 25 Tianjin 3 Jiangsu 148 North Korea Shanghai 6 South Korea Japan

least one underlying disease in 53% Exposure - Poultry/live bird market exposure

5 Older Men and Bird Markets Common in All 5 waves Influenza Age - Median 57 yrs (4 93 yrs) In contrast, H5N1 is 19 yrs (5 32) Gender - Male 70% Chronic Illness - At least one underlying disease in 53% Exposure - Poultry/live bird market exposure in 90% MMWR CDC and China CDC. Sept 2017; H5 Epi Lai et al Lancet 2016; China Daily/AFP

6 Severity in Human A(H7N9) Cases Persists in Wave 5 Influenza Severe disease - death 39% - pneumonia 90% - ICU admission 70% No sustained humanto-human transmission MMWR CDC and China CDC, Sept 2017; Photo: CGTN.

7 eb-2013 ar-2013 pr-2013 ay-2013 Jul-2013 ug-2013 ct-2013 ov-2013 ec-2013 an-2014 eb-2014 ar-2014 pr-2014 ay-2014 un-2014 ov-2014 ec-2014 an-2015 eb-2015 pr-2015 ec-2015 an-2016 eb-2016 ar-2016 pr-2016 ay-2016 un-2016 Jul-2016 ct-2016 ov-2016 ec-2016 an-2017 Evolution of Influenza A(H7) HA, H7N9 in the first 5 waves 5th epidemic H7N9 viruses Amino acid differences shown are relative to A/Shanghai/2/ A/Taiwan/3/2013 H7N9 A/Shanghai/5190T/2013 H7N9 A/Taiwan/1/2013 H7N9 A/pigeon/Zhejiang/P2/2013 H7N9 A/Taiwan/T02081/2013 H7N9 A/Zhenjiang/1/2013 H7N9 R47M A/Zhejiang/HZ1/2013 H7N9 A/Zhejiang/DTID-ZJU02/2013 H7N9 N190S A/chicken/Jiangsu/S002/2013 H7N9 A/Xuzhou/1/2013 H7N9 A/Suzhou/5/2013 H7N9 A/Nanjing/6/2013 H7N9 A/Huzhou/10/2013 H7N9 A/Nanjing/7/2013 H7N9 A/Wuxi/3/2013 H7N9 A/Huzhou/1/2013 H7N9 V24G A/Zhejiang/DTID-ZJU05/2013 H7N9 A/Zhejiang/DTID-ZJU08/2013 H7N9 A/Shanghai/07/2013 H7N9 A/Changsha/1/2013 H7N9 A/Beijing/1/2013 H7N9 A/chicken/Guangdong/SD641/20 13 H7N9 A/Shanghai/2/2013 H7N9 A/Wuxi/1/2013 H7N9 A/Anhui/1/2013 H7N9 Q213P A/Zhejiang/DTID-ZJU10/2013 H7N9 A/Zhejiang/22/2013 H7N9 A/Jiangsu/98342/2014 H7N9 A/chicken/Jilin/SD020/2014 H7N2 L168I S290N zzz A/silkie chicken/jiangxi/9469/2014 R47K R303K A/Zhejiang/LS01/2014 H7N9 A125V A125T V49I I280T A/Zhejiang/1/2016 H7N9 * T36K D109E z A/duck/Wenzhou/RAQL10/2 015 H7N9 * A/chicken/Zhangzhou/8585/ 2014 E104G V177A S237N D246V A/chicken/Shanghai/PD-CN -02/2 014 A/Huai'an/083/2014 H7N9 K2R R130K Q154H A/silkie chicken/huzhou/4213/2 013 N267D A/Hong Kong/214/2017 H7N9 E104K M227I A/Hong Kong/61/2016 H7N9 * N190S E104K N282K A/Guangdong/60923/2016 H7N9 * A/Hong Kong/VB /2016 H7N9 * E104R T156N T179I E104K A/chicken/Shantou/1550/2014 L168I A/Hong Kong/ /2014 H7N9 A/chicken/Guangdong/G1381/ 2014 H7N9 R47K N267D A/Hong Kong/5581/2014 H7N9 A74T S275N A9S A/chicken/Dongguan/1100/2014 mixed A/Hong Kong/4495/2014 H7N9 V177A A/Hong Kong/ /2014 H7N9 R47K I78V V262A N282K E104K A/Duck/Guangdong/DG103/2015 H7N9 * N267D A/Environment/Guangdong/DG127/ 2015 H7N9 * M256I N37S A/Guangdong/02496/2014 H7N9 G276R A/Hong Kong/2550/2015 H7N9 * A210E A/Hong Kong/ /2015 H7N9 * A/Chicken/Guangdong/DG592/2 014 H7N9 E25V T194I S207I R47K A/Duck/Guangdong/DG527/2014 H7N9 A/Guangdong/15SF010/2015 H7N9 * I280M I108L S134P Q213P G216A M227I S237N M256I N267D A/Hong Kong/5731/2014 H7N9 V264I N267G A/Hong Kong/3263/2014 H7N9 A/Hong Kong/ /2014 H7N9 A/silkie chicken/dongguan/1264/2014 D246E A/chicken/Shenzhen/138/2 014 V49I R47K A/silkie chicken/shantou/1406/2014 A/environment/Guangzhou/XN1291 7/2014 H7N9 A/environment/Guangzhou/XN0739 0/2014 H7N9 A/Hong Kong/ /2014 H7N9 A/Guangzhou/1/2014 H7N9 R47K T122A A/Shenzhen/SP-W1/2014 A/Guangdong/1/2013 H7N9 N282S N267D A/Hong Kong/470129/2013 H7N9 A/Hong Kong/5942/2013 H7N9 A/Hong Kong/734/2014 H7N9 T122A A/chicken/Shenzhen/712/2 013 mixed V86I R130K N282S R47K A/Guangdong/03/2013 H7N9 T116K R47K L217Q A/wild pigeon/jiangsu/sd001/2013 H7N9 A/chicken/Guangzhou/1/2 013 H7N9 A/chicken/Zhejiang/C481/2013 H7N9 A/chicken/Shanghai/S1410/2013 H7N9 A/pigeon/Wuxi/ G/2013 H7N9 L217Q A/Shanghai/JS01/2013 H7N9 G119E L217Q R130K R130K A/Environment/Guangdong/43966/ 2016 H7N9 * S118N A/Hong Kong/125/2017 H7N9 R130K A/Hong Kong/4553/2016 H7N9 * A/Hubei/39269/2016 H7N9 * R130K G261E A/Beijing/39450/2016 H7N9 * R130K A/Beijing/44066/2016 H7N9 * R130K A/Hebei/38604/2016 H7N9 * R130K N282S A/Environment/Hebei/40053/2016 H7N9 * A266D R130M N267Y R130K T122I M256I A/Jiangsu/15026/2016 A/Environment/Hebei/40052/2016 A/Environment/Hebei/40049/2016 H7N9 * H7N9 * H7N9 * R130M R130K T59A A/Hong Kong/793/2016 H7N9 * A/Anhui/45322/2016 H7N9 * A/Fujian/30766/2016 H7N9 * A/Hunan/02650/2016 H7N9 * A128V/A A/Fujian/4/2016 H7N9 * R130K A/Fujian/17527/2016 H7N9 * A/Fujian/54840/2016 H7N9 * K184N A/Fujian/45970/2016 H7N9 * A/Fujian/5/2016 H7N9 * K184N/K A/Jiangsu/15027/2016 H7N9 * A/Liaoning/44068/2016 K184N/K H7N9 * A/Jiangsu/05155/2016 H7N9 * A112T M227I S127G A/Tianjin/43917/2016 H7N9 A/Hunan/04137/2016 H7N9 * A/Hunan/04135/2016 H7N9 * A/Guangdong/16SF007/2016 H7N9 * I120T A/Fujian/3/2016 H7N9 * A/Hunan/06196/2016 H7N9 R130N * A/Anhui/26835/2016 H7N9 * R130K A/Guangdong/15SF871/2015 H7N9 * A/Environment/Guangdong/15125/ 2016 H7N9 * A/Fujian/30767/2016 H7N9 * S118N R130K V264I I317V A/Fujian/8/2016 H7N9 * A/Jiangsu/60454/2016 H7N9 * S118N R130K R303K A/Jiangsu/60460/2016 H7N9 * A/Jiangsu/60456/2016 H7N9 * S118N R130K M227L A292T A/Hunan/02286/2017 H7N9 A/Zhejiang/12/2016 H7N9 * A/Hebei/46587/2016 H7N9 * I38V A112T A/duck/Jiangsu/J3619/2014 H7N9 A/Jiangsu/03753/2016 H7N9 * T59I S118N R130K A/Jiangsu/06307/2014 H7N9 P212Q/P N17D A266V A/Environment/Jiangsu/03758/2015 H7N9 * A/Jiangsu/03756/2016 H7N9 * M256I I280V S218F M227I S118N A/Zhejiang/15/2016 H7N9 * A/Jiangsu/15028/2016 H7N9 * D367Y/D V86F I258V A/Anhui/26837/2016 H7N9 * A/Anhui/26836/2016 H7N9 * A/Anhui/40094/2015 H7N9 A125V A/Beijing/40610/2015 H7N9 * A/duck/Wenzhou/YJYF24/2015 H7N9 * A/Quzhou/1/2015 H7N9 * A/Guangdong/MZ828/2015 H7N9 * A/Environment/Guangdong/15120/ 2016 H7N9 * A/Environment/Guangdong/15123/ 2016 H7N9 * A112S S118N A/Guizhou/03240/2015 H7N9 * A/Fujian/09273/2015 H7N9 * G23E K319R A/Chicken/Guangdong/SW154/20 15 H7N9 * A/Shantou/2004/2015 H7N9 A/Fujian/10/2015 H7N9 * G133E D109E P206L A/Fujian/06198/2016 H7N9 * A/Fujian/1/2016 H7N9 * A/chicken/Wenzhou/HATS I101V R130K N282S LG01/2 015 H7N9 * A/Hunan/06197/2016 H7N9 * A/Environment/Hunan/10125/2015 H7N9 * V49I A/Environment/Hunan/10086/2016 H7N9 * A/Jiangsu/19758/2015 H7N9 * A/chicken/Anhui/A1065/2014 H7N9 A/Xinjiang/98692/2014 H7N9 R103K M256I D271I S118N E269V R130K S134P A/Xinjiang/05845/2015 H7N9 * A/duck/Anhui/A1618/2014 H7N9 L168I A/Huai'an/001/2015 H7N9 * S118N I288V A/chicken/China/028/2014 H7N9 I108L S218F I258V D289N A/Fujian/27/2015 H7N9 N37S S290R S118N A/British Columbia/1/2015 H7N9 * A/Fujian/18/2015 H7N9 * K184N G216D A/Fujian/5/2015 H7N9 A/goose/Jiangsu/J1111/2014 H7N9 A/Taiwan/2/2014 H7N9 A/Taiwan/1/2014 H7N9 R346K/R A/duck/Jiangxi/15044/2014 A/Huzhou/5/2013 H7N9 S304G A/Shanghai/PD-01/2014 P206S E269K A/Shanghai/Mix1/2014 H7N9 A/Shanghai/01/2014 H7N9 L217Q S127G R211G R47K L217P S281N L57R I38F L57R R252K S118N A/Jiangsu/60466/2016 H7N9 * A/Zhejiang/6/2016 H7N9 * A/Jiangsu/60451/2016 H7N9 * A/Fujian/02152/2017 H7N9 L217I A/Anhui/60936/2016 H7N9 * I120T A/Zhejiang/13/2016 H7N9 * A/Hunan/02285/2017 H7N9 A/Jiangsu/60459/2016 H7N9 * A/Jiangsu/60457/2016 H7N9 * V214F A/Jiangsu/60458/2016 H7N9 * A/Zhejiang/11/2016 H7N9 * A/Zhejiang/14/2016 H7N9 A/Jiangsu/60447/2016 H7N9 * A/Zhejiang/16/2016 H7N9 * S127N/S A/Zhejiang/10/2016 H7N9 * A/Jiangsu/60450/2016 H7N9 * P208T A/Zhejiang/9/2016 H7N9 * A/Hong Kong/VB /2016 H7N9 * A/Anhui/60931/2016 H7N9 * A/Anhui/60932/2016 H7N9 * A/Anhui/60933/2016 H7N9 * A/Anhui/60935/2016 H7N9 * A/Anhui/60934/2016 H7N9 * A/Anhui/60926/2016 H7N9 * V170I T126A/T V262A D271N R298K S281N/S G261R/G D271G Yangtze River Delta lineage Pearl River Delta lineage

L168I L168I N267D E378A D340N N282K 180 rotation 180 rotation Not visible V425I S485R Site A -

8 A(H7N9) 5 th wave hemagglutinin changes compared to A/Shanghai/2/2013 (candidate vaccine virus) Pearl River Delta lineage Yangtze River Delta lineage S118N A125V M227I A112T R130K M227I E104K L168I L168I N267D E378A D340N N282K 180 rotation 180 rotation Not visible V425I S485R Site A - green Site B - brownish Site C - dark blue Site D - cyan Site E - yellow CHO orange HA2 changes in red

treated with antivirals Antiviral Treatment China CDC had recommended early treatment with oseltamivir

9 H7N9: Treatment Implications Influenza Division Antiviral Susceptibility Observing genetic markers of reduced susceptibility ~ 9-10% available NA gene segments Viruses typically recovered from patients treated with antivirals Antiviral Treatment China CDC had recommended early treatment with oseltamivir based on clinical presentation An H7N9 bird flu patient being treated in a hospital in Hubei province Photo: STAT News

10 Status of influenza A(H7N9) candidate vaccine viruses (CVV): March 2017 Vaccine Viruses CDC and other WHO CCs developed GLP candidate vaccine virus (CVV) using reverse genetics in 2013 A/Shanghai/2/2013 RG32A used for vaccine stockpile and clinical trials Candidate vaccine virus Type Institution Available A/Anhui/1/2013 (H7N9) IDCDC-RG33A Reverse Genetics CDC Yes A/Anhui/1/2013 (H7N9) NIBRG-268 Reverse Genetics NIBSC Yes A/Anhui/1/2013 (H7N9) NIIDRG-10.1 Reverse Genetics NIID Yes A/Anhui/1/2013 (H7N9) SJ005 Reverse Genetics SJCRH Yes A/Shanghai/2/2013 (H7N9) NIBRG-267 Reverse Genetics NIBSC Yes A/Shanghai/2/2013 (H7N9) CBER-RG4A Reverse Genetics FDA Yes A/Shanghai/2/2013 (H7N9) IDCDC-RG32A Reverse Genetics CDC Yes A/Shanghai/2/2013 (H7N9) IDCDC-RG32A.3 Reverse Genetics CDC Yes

11 Analysis of Human Viruses Available March 2017 Phylogenetics of HA vrna Genetic diversity Pearl RD antigenically similar Well-inhibited by antisera to existing CVVs Yangtze RD antigenically distinct Reduced cross-reactivity with sera to existing CVV fold reduced Emergence of HPAI viruses - genetically and antigenically distinct WHO VCM Meeting Confirmed significant antigenic changes in Yangtze RD viruses - China CDC - Hong Kong University CVVs Available A/Fujian/02152/ A/Jiangsu/06463/ A/Jiangsu/06454/2017 A/Anhui/60936/2016 A/Jiangsu/60466/2016 A/Jiangsu/15027/2016 A/Hunan/04137/2016 A/Jiangsu/15026/2016 A/chicken/Fujian/11089/2016 A/Hunan/02650/2016 A/silkie chicken/shantou/9473/2016 A/Anhui/60933/2016 A/Liaoning/44068/2016 A/Tianjin/43917/2016 A/Hubei/39269/2016 A/chicken/Fujian/11766/2016 A/Hong Kong/4553/2016 A/Hong Kong/125/2017 A/Fujian/30767/2016 A/Fujian/45970/2016 A/Fujian/54840/ A/Beijing/44066/2016 A/Hebei/38604/2016 A/Anhui/45322/2016 A/Jiangsu/60460/2016 A/Hunan/06196/2016 A/Jiangsu/18828/2014 A/Jiangsu/03753/ A/Hunan/06948/2017 A/Hebei/46586/2016 A/Jiangsu/15028/2016 A/chicken/Wenzhou/WZTSLG02/2015 A/Taiwan/1/2017 A/Guangdong/17SF003/ A/Guangdong/17SF006/2017 A/Environment/Guangdong/C / A/chicken/Jiangxi/14879/2015 A/Hunan/02287/2017 A/chicken/Guangzhou/4954/2016 A/Fujian/1/ A/Xinjiang/05916/ A/Fujian/18/ A/British_Columbia/1/2015 A/Taiwan/2/2014 A/Environment/Jiangsu/03137/2013 A/chicken/Jiangxi/18482/2014 A/Taiwan/1/2014 A/chicken/Wuxi/SC4315/2015 A/chicken/Guangzhou/1083/2016 A/Guangdong/60923/ A/Hong Kong/VB /2016 A/Guangdong/60061/ A/Hong Kong/VB / A/Hong Kong/214/ A/Guangdong/60060/ A/Guangdong/17SF004/2017 A/Hong Kong/ /2015 A/Shenzhen/SP195/2015 A/Guangdong/0012/2014 A/chicken/GD/874/2014 A/Guangdong-Guangzhou/XN08763/2014 A/Guangzhou/1/2014 A/Guangdong/SP38/2014 A/Hong Kong/5942/2013 A/Anhui/02/2013 A/chicken/Wenzhou/201/2014 A/Shandong/01/2014 A/Zhejiang/1/ A/Zhejiang/17/2014_W A/chicken/Shaoxing/5201/2013 A/Huaian/065/2014 A/ZJ/22/ A/Fujian/15/2014 A/Jiangsu/09387/2014 A/Shanghai/14/2013 A/Anhui/1/2013 A/Beijing/01-A/2013 A/Shanghai/2/2013 A/ZJ/DTID-ZJU05/2013 A/shanghai/05/2013 A/Shanghai/1/2013 HPAI Pearl River Delta Yangtze River Delta CDC and WHO, Feb 2017 VCM. Human viruses are in bold font. The available CVVs are in red. The proposed CVVs are indicated by a red dot.

12 IRAT Impact & Emergence Average Risk Scores Influenza Division Impact Risk H5N6 [A/Yunnan/../2015] H7N9 [A/Hong Kong/125/2017] H7N9 [A/Shanghai/../2013] H5N1 clade 1 [A/VN/../2004] 5 H5N8 [gyrfalcon/../2014] 4 H5N1 [Am. g-w teal/../2014] H5N2 [N. pintail/../2014] 3 2 H1N1 [A/duck/NY/96] 1 = no human cases = human cases Feb 2017 Emergence Risk

13 New A(H7N9) CVVs Recommended, WHO VCM March 2017 Influenza Division From WHO s Antigenic and genetic characteristics of zoonotic influenza viruses and candidate vaccine viruses developed for potential use in humans vaccines report, dated March 2, 2017.

14 CVV Development and Safety Testing Influenza Division Genetic Engineering Illustration by Jennifer Oosthuizen

15 H7N9 CVV Generation Influenza Division A/HK/125/2017 (H7N9) LPAI - Selected at February, 2017 WHO VCM Rescue and analysis - Good Laboratory Practice rescue and amplification - Sequence analysis of the HA gene low pathogenic influenza cleavage site - Genetic stability of the HA gene upon multiple passaging (10 passages) - Chicken embryo lethality - Pathogenicity analysis in ferrets

16 IDCDC-RG56B CVV Passed 2-way Antigenic Test IDCDC-RG56B HI reactivity patterns consistent with wild-type virus A/Hong Kong/125/2017 Antisera REFERENCE ANTIGENS Clade ML/NL HK/ 125 RG56B IDCDC-RG1 (Mallard/Netherlands/12/2000-like) A/Hong Kong/125/2017 YRD IDCDC-RG56B YRD TEST ANTIGENS A/Hong Kong/4553/2016 (LP) YRD A/Hong Kong/61/2016 (LP) PRD A/Hong Kong/214/2017 (LP) PRD A/Guangdong/17SF003/2016 (HP) YRD A/Taiwan/1/2017 (HP) YRD

17 A(H7N9) CVVs May, 2017

AS-A L217Q K130R T112P 180-helix 140-loop AS-C V/G177 H174 Y186 W142

18 Engineering Additional Constructs and CVVs Influenza Division A/Hong Kong/125/2017 A/HK/125/2017 CVVs Receptor Binding Pocket C AS-B AS-D AS-A L217Q K130R T112P 180-helix 140-loop AS-C V/G177 H174 Y186 W142 K164E AS-E P/T212 Q/L217 Y loop 210-loop S/A128 CHO 1. L217Q->Yield and HPAI

19 Influenza Division Engineering Additional Constructs and CVVs A/Hong Kong/125/2017 A/HK/125/2017 CVVs A/Guangdong/16SF003/2016 AS-B AS-A K130R K130R AS-D L217Q T112P L217Q T112P R163K AS-C K164E G261R K164E AS-E I38T CHO Fusion peptide has polybasic insertion (RKRTA) Not visible E389K I317V V425I 1. L217Q->Yield and HPAI 2. HPAI-like 4 substitutions

20 mg HA/100 eggs Influenza Division HA Yield of A(H7N9) CVVs and Antigenic Testing 7 6 IDMS SDS-PAGE Low Pathogenic YRD HPAI YRD

21 mg HA/100 eggs Influenza Division HA Yield of A(H7N9) CVVs and Antigenic Testing IDMS Low Pathogenic YRD HPAI YRD SDS-PAGE Pass Fail Fail Fail Pass

22 A(H7N9) HPAI CVV November, 2017

23 Antigenic characterization of RG viruses (RG56B-derived) containing HA1 mutations identified in 5th wave viruses Influenza Division YRD lineage T112A I227M T112A V125A S134P I227M V49I I101V T112A N282S I227M T112A A292T S127G A/duck/Jiangsu/J3619/2014 H7N9 A/Jiangsu/03753/2016 H7N9 * A/Jiangsu/06307/2014 H7N9 A/Hong Kong/VB /2016 H7N9 * A/Jiangsu/15027/2016 H7N9 * D109E V262A A/Tianjin/43917/2016 H7N9 * A/Jiangsu/05155/2016 H7N9 * S165N A/Liaoning/44068/2016 H7N9 * A/Suzhou/78/2016 H7N9 * A/Suzhou/73/2016 H7N9 * A/Suzhou/92/2017 H7N9 * R303K I120T A/Jiangsu/60460/2016 H7N9 * A/Suzhou/60/2016 H7N9 * A/Suzhou/84/2016 H7N9 * A/Jiangsu/60454/2016 H7N9 * A/Suzhou/54/2016 H7N9 * A/Suzhou/56/2016 H7N9 * A/Jiangsu/60456/2016 H7N9 * A/Suzhou/80/2016 H7N9 A/Suzhou/67/2016 H7N9 * A/Environment/Guangdong/43966/2016 H7N9 * V264I A/Fujian/30767/2016 H7N9 * A/Fujian/8/2016 H7N9 * A/Fujian/4/2016 H7N9 * A/Fujian/02151/2017 H7N9 * A/Fujian/11/2017 H7N9 * A/Fujian/14/2017 H7N9 * A/Fujian/56600/2016 H7N9 * A/Fujian/54840/2016 H7N9 * A/Fujian/17527/2016 H7N9 * A/Fujian/45970/2016 H7N9 * A/Fujian/5/2016 H7N9 * H274Y A/Anhui/13425/2017 H7N9 * D85E A/Anhui/13424/2017 H7N9 * A/Anhui/13444/2017 H7N9 * A/Anhui/13428/2017 H7N9 * A/Anhui/13427/2017 H7N9 A/Anhui/13426/2017 H7N9 * A/Anhui/13434/2017 H7N9 * A/Anhui/60925/2016 H7N9 * A/Anhui/60926/2016 H7N9 A/Anhui/13436/2016 H7N9 * A/Anhui/60932/2016 H7N9 * A/Henan/11159/2017 H7N9 * R47L A/Henan/13705/2017 H7N9 * V262A A/Henan/13706/2017 H7N9 A/Henan/11157/2017 H7N9 * A/Anhui/60935/2016 H7N9 * A/Anhui/60934/2016 H7N9 * A/Anhui/60929/2016 H7N9 A/Anhui/13442/2017 H7N9 * A/Anhui/60933/2016 H7N9 * A/Anhui/60927/2016 H7N9 * A/Anhui/13431/2017 H7N9 * A/Anhui/13441/2017 H7N9 * A/Anhui/60928/2016 H7N9 A/Anhui/13421/2017 H7N9 * A/Anhui/60931/2016 H7N9 D271N A/Anhui/13439/2017 H7N9 * A/Anhui/13433/2017 H7N9 * A/Anhui/13432/2017 H7N9 A/Guangdong/16SF007/2016 H7N9 * A/Hunan/04137/2016 H7N9 * A/Fujian/30766/2016 H7N9 * A/Hunan/02650/2016 H7N9 * A/Hubei/39269/2016 H7N9 T122I M256I A/Jiangsu/15026/2016 H7N9 * A/Hong Kong/793/2016 H7N9 * A266D A/Environment/Hebei/40053/2016 H7N9 * G261E A/Hebei/38604/2016 H7N9 * A/Beijing/39450/2016 H7N9 * A/Fujian/3/2016 A/Anhui/45322/2016 H7N9 * H7N9 * A/Hong Kong/4553/2016 H7N9 * A/Hong Kong/125/2017 H7N9 * A/Guangdong/15SF871/2015 H7N9 * A/Environment/Guangdong/15125/2016 H7N9 * A/Guangxi/6/2017 H7N9 * A/Hebei/46587/2016 H7N9 * A/Hong Kong/VB /2017 H7N9 * A/Fujian/17/2017 H7N9 * I227L K184N A/Fujian/13558/2017 H7N9 * A/Zhejiang/5/2017 A/Zhejiang/18/2016 H7N9 H7N9 * VPT17-V12.4 * A/Xinjiang/98692/2014 H7N9 A/Xinjiang/05845/2015 H7N9 * A/Henan/11158/2017 H7N9 * A/Environment/Hunan/10125/2015 H7N9 * A/Hunan/02287/2017 H7N9 * A/Hunan/06197/2016 H7N9 * P208T A/Zhejiang/9/2016 H7N9 * A/Suzhou/88/2016 H7N9 * A/Jiangsu/60450/2016 H7N9 * A/Jiangsu/60461/2016 H7N9 * A151T Q202K A/Jiangsu/60465/2016 H7N9 * A/Suzhou/65/2016 H7N9 * A/Jiangsu/60462/2016 H7N9 * A/Zhejiang/4/2017 H7N9 * A/Hunan/00001/2016 H7N9 * V214F A/Jiangsu/60457/2016 H7N9 * A/Suzhou/57/2016 H7N9 * A/Changsha/41/2017 H7N9 * A/Chongqing/1/2017 H7N9 VPT17-V9.4 T156N A/Chongqing/2/2017 H7N9 * A/environment/ChongqingHC/2-20/2017 H7N9 * A/Guangxi/12219/2017 H7N9 * A/Guangxi/12218/2017 H7N9 * A/Suzhou/95/2017 H7N9 * A/Suzhou/96/2017 H7N9 * A/Jiangsu/60447/2016 H7N9 * A/Fujian/02152/2017 H7N9 * A/Zhejiang/14/2016 H7N9 * I120T A/Anhui/60936/2016 H7N9 * A/Zhejiang/8/2016 H7N9 * A/Zhejiang/11/2016 H7N9 * A/Zhejiang/13/2016 H7N9 * A/Jiangsu/60458/2016 H7N9 * A/Suzhou/58/2016 H7N9 * A/Suzhou/87/2016 H7N9 * A/Hubei/11951/2017 H7N9 * A/Hubei/11944/2017 H7N9 * A/Henan/11156/2017 H7N9 * A/Jiangsu/60459/2016 H7N9 * A/Suzhou/59/2016 A/Jiangsu/11581/2017 H7N9 * H7N9 * A/Zhejiang/17/2016 H7N9 * A/Anhui/60924/2016 H7N9 * A/Zhejiang/2/2017 H7N9 * A/Hunan/02285/2017 H7N9 * A/Jiangsu/11554/2017 H7N9 * A/Jiangsu/11553/2017 H7N9 * A/Zhejiang/1/2017 H7N9 * A/Hubei/11950/2017 H7N9 * A/Suzhou/74/2016 H7N9 * A/Jiangsu/11556/2017 H7N9 * A/Jiangsu/11557/2017 H7N9 * A/Jiangsu/11555/2017 H7N9 * A/Suzhou/91/2017 H7N9 * A/Jiangsu/11589/2017 H7N9 * A/Suzhou/86/2016 H7N9 * A/Zhejiang/16/2016 H7N9 * A/Jiangsu/11587/2017 H7N9 * A/Jiangsu/11586/2017 H7N9 A/Jiangsu/11590/2017 H7N9 * A/Jiangsu/11588/2017 H7N9 * A/Liaoning/13454/2017 H7N9 * A/Suzhou/90/2017 H7N9 * A/Suzhou/93/2017 H7N9 A/Jiangsu/11583/2017 H7N9 * A/Jiangsu/11585/2017 H7N9 A/Zhejiang/7/2016 A/Zhejiang/10/2016 H7N9 H7N9 * * A/Jiangsu/60452/2016 H7N9 * A/Suzhou/51/2016 H7N9 * A/Jiangsu/60451/2016 H7N9 * A/Zhejiang/6/2016 H7N9 * A/Jiangsu/60466/2016 H7N9 * A/Suzhou/79/2016 H7N9 * A/Jiangsu/60467/2016 H7N9 * A/Jiangsu/60463/2016 H7N9 A/Suzhou/63/2016 H7N9 * V93M A/Suzhou/467/2016 H7N9 * A/Zhejiang/3/2017 H7N9 A/Zhejiang/19/2016 H7N9 * A/Changsha/58/2017 H7N9 * A/Changsha/44/2017 H7N9 A/Fujian/12/2017 H7N9 * A/Fujian/8/2017 H7N9 * A/Yunnan/13501/2017 H7N9 * A/Hunan/02286/2017 H7N9 * A/Jiangxi/10683/2017 H7N9 * A/Zhejiang/12/2016 H7N9 * A/Yunnan/13500/2017 H7N9 * A/Zhejiang/6/2017 H7N9 * A/Zhejiang/20/2016 H7N9 * A/Anhui/13446/2017 H7N9 * A/Anhui/13447/2017 H7N9 * A/Anhui/13449/2017 H7N9 * A/Anhui/13423/2017 VPT17-V8.4 A/Henan/14905/2017 H7N9 * A/Henan/15337/2017 H7N9 * A/Changsha/26/2017 H7N9 * H A/Guangdong/17SF064/2017 H7N9 * HPAI and PRD lineage T112A V125A S134P I227M A/Guangzhou/1/2014 H7N9 A/Hong Kong/5942/2013 H7N9 V125A I168L I227M A/Hong Kong/734/2014 H7N9 A/Guangdong/03/2013 H7N9 R47K A/Shenzhen/SP-W1/2014 T112A N118S V125A T122A R47K K130R A/Guangdong/1/2013 H7N9 K130R I168L I227M A/Shanghai/5190T/2013 H7N9 A/Taiwan/1/2013 H7N9 A/pigeon/Zhejiang/P2/2013 H7N9 A/Taiwan/T02081/2013 H7N9 V125A I168L Q213P A/Zhejiang/DTID-ZJU10/2013 H7N9 A/Zhejiang/22/2013 H7N9 T112A N118S K130R I227M V49I I280T V125A I168L A/chicken/Zhangzhou/8585/2014 A/chicken/Shanghai/PD-CN-02/2014 R47K R303K A/Jiangsu/98342/2014 H7N9 A/silkie chicken/jiangxi/9469/2014 A/Zhejiang/LS01/2014 H7N9 T112A N118S V125A I168L A/chicken/Jilin/SD020/2014 H7N2 K130R I168L I227M A/Shanghai/Mix1/2014 H7N9 A/Shanghai/01/2014 H7N9 T112A N118S V125A A/Taiwan/3/2013 H7N9 A/Shanghai/07/2013 H7N9 K130R I168L I227M A/Changsha/1/2013 H7N9 A/Beijing/1/2013 H7N9 T112A N118S V125A A/Anhui/1/2013 H7N9 K130R I168L I227M R47M A/Zhenjiang/1/2013 H7N9 A/chicken/Jiangsu/S002/2013 H7N9 N190S A/Xuzhou/1/2013 H7N9 A/Suzhou/5/2013 H7N9 T112A N118S V125A A/Nanjing/6/2013 H7N9 K130R I168L I227M A/chicken/Guangdong/SD641/2013 H7N9 A/Shanghai/2/2013 H7N9 A/Wuxi/1/2013 H7N9 A/pigeon/Wuxi/ G/2013 H7N9 A/Shanghai/JS01/2013 H7N9 V177G A/Shanghai/1/2013 H7N9 V177G Yangtze River delta A/Xinjiang/98692/2014 H7N9 A/Xinjiang/05845/2015 H7N9 * V49I I101V T112A N282S A/Henan/11158/2017 H7N9 * A/Environment/Hunan/10125/2015 H7N9 * A/Hunan/02287/2017 H7N9 * I227M A/Hunan/06197/2016 H7N9 * H A/Guangdong/17SF064/2017 H7N9 * H A/Environment/Guangzhou/K4072/2016 H7 * H A/Environment/Guangdong/KGZ4048/2016 H7 * P112S F115L HPAI H A/Environment/Guangdong/KGZ4068/2016 VPT17-V15.4 H A/Environment/Guangdong/KGZ4075/2016 H7 * H A/Environment/Guangdong/C /2016 H7 * H A/Environment/Guangdong/C /2016 H7 * K163R R261G R320G H A/Environment/Guangdong/C /2016 H7 * H A/Environment/Guangdong/C /2016 H7N9 * R22K K163R I169V R261G H A/Guangdong/17SF037/2017 H7N9 * A/Guangdong/17SF059/2017 H7N9 H A/Guangdong/17SF033/2017 H7N9 * H A/Guangxi/7/2017 H7N9 * H A/Guangxi/1/2017 H7N9 * D148N A150T S203F H A/Guangxi/4/2017 H7N9 * Q217L H A/Taiwan/1/2017 H7N9 * H A/Guangdong/8H324/2017 H7N9 * H A/Guangdong/17SF003/2016 VPT17-V13.4 H A/Guangdong/17SF032/2017 H7N9 * K130R H A/Guangdong/17SF006/2017 H7N9 * VPT17-V14.4 H A/Guangdong/17SF039/2017 H7N9 * K163R R261G H A/Guangdong/17SF062/2017 H7N9 * V205I A/Environment/Guangdong/15120/2016 H7N9 * T112A A/Fujian/1/2016 H7N9 * A/Jiangsu/19758/2015 H7N9 * A/chicken/Wenzhou/HATSLG01/2015 H7N9 * A/Shantou/2004/2015 H7N9 I227M A/Guizhou/03240/2015 H7N9 * A/Guangdong/MZ828/2015 H7N9 * A/Chicken/Guangdong/SW154/2015 H7N9 * T112A A/Fujian/10/2015 H7N9 * N17D A266V A/Jiangsu/03756/2016 H7N9 * A/Zhejiang/15/2016 H7N9 * I227M V86F A/Jiangsu/11550/2017 VPT17-V11.4 A/Jiangsu/15028/2016 H7N9 * A/Anhui/26836/2016 H7N9 * T112A K130R I258V I227M A/Anhui/40094/2015 H7N9 A/Beijing/40610/2015 H7N9 * T112A V125A K130R I227M I288V A/duck/Wenzhou/YJYF24/2015 H7N9 * A/Quzhou/1/2015 H7N9 * A/Huai'an/001/2015 H7N9 * A/chicken/China/028/2014 H7N9 V125A N37S K130R S290R A/British Columbia/1/2015 H7N9 * A/Fujian/5/2015 H7N9 A/Taiwan/2/2014 H7N9 A/Taiwan/1/2014 H7N9 T112A N118S I227M A/duck/Jiangxi/15044/2014 K130R A/Guangxi/2/2017 H7N9 * E104K I227M V125A A/Changsha/70/2017 H7N9 * A/Hong Kong/214/2017 H7N9 * N267D A/Guangdong/60060/2016 H7N9 * A/Hong Kong/61/2016 H7N9 * A/Guangdong/60061/2016 H7N9 * V125A A/Guangdong/60923/2016 H7N9 * VPT17-V10.7 K130R N190S A/Hong Kong/VB /2016 H7N9 * A/Guangdong/15SF010/2015 H7N9 * A/Hong Kong/ /2014 H7N9 V177A N267D A/Duck/Guangdong/DG103/2015 H7N9 * M256I A/Environment/Guangdong/DG127/2015 H7N9 * E104K V125A A/Hong Kong/ /2015 H7N9 * G276R A/Hong Kong/2550/2015 H7N9 * A/Guangdong/02496/2014 H7N9 I227M A/chicken/Shantou/1550/2014 A/Hong Kong/ /2014 H7N9 A/Hong Kong/5731/2014 H7N9 T112A A/chicken/Guangdong/G1381/2014 H7N9 N118S R47K A/Hong Kong/5581/2014 H7N9 N267D A/Hong Kong/4495/2014 H7N9 A/Hong Kong/3263/2014 H7N9 A/Hong Kong/ /2014 H7N9 R47K K130R A/Hong Kong/ /2014 H7N9 A/Zhejiang/1/2016 H7N9 * A/duck/Wenzhou/RAQL10/2015 H7N9 * H A/Guangxi/5/2017 H7N9 * A/Guangxi/3/2017 H7N9 H A/chicken/Heinan/ZZ01/2017 H7N9 * Pearl River delta 0.005

24 Antigenic Diversity of A(H7N9) viruses produced by reverse genetics and derived from the RG56B (YRD) virus Boosted Boosted REFERENCE ANTIGENS Mutations ML/NL/12 RG 1 RG 56B RG56N 1 A/mld/Neth/12/ IDCDC-RG56B A/Hong Kong/125/2017 x PR IDCDC-RG56N^ T112P, K130R, K164E, L217Q VPT17-V13.4 * I38T, T112P, K130R, R163K, K164E, L217Q, G261R TEST ANTIGENS 5 VPT17-V10.7* E104R, T112A, N118S, V125A, K130R, T156N, T179I, N190S, N267D VPT17-V8.4* D109E, S127G, N146S, V262A VPT17-V9.4* T156N, V214I, G216D VPT17-V11.4* N17D, T59I, V86F, T112A, K130R, I227M, I258V, A266V VPT17-V12.4* T112A, K184N, I227L, A292T VPT17-V14.4* I38T, T112P, K130R, K164E, L217Q VPT17-V15.4* I38T, T112S, F115L, K130R, K164E, L217Q GD/ 17SF003 ^RG56N is a reverse genetics generated virus derived from RG56B with HA1 mutations that are conserved in HPAI A(H7N9) viruses *VPT17 antigens are reverse genetics generated viruses derived from RG56B with HA1 mutations identified in wt 5th wave viruses.

25 Clinical Trials Using IDCDC-RG56B Started: February, 2018 Influenza

26 Status of A(H7N9) CVVs March, 2018 Influenza Candidate vaccine virus Reactivity Institute Status IDCDC-RG56B Cross-reactive with YRD and PRD; (A/Hong Kong/125/2017-like) Does not cross-react with HPAI viruses CDC Available CNIC-HN02650 Cross-reactive with YRD and PRD; (A/Hunan/02650/2016-like) Does not cross-react with HPAI viruses China CDC Available IDCDC-RG56N Cross-reactive with LPAI and HPAI 5 th and (A/Guangdong/17SF003/2016-like) 6 th wave viruses tested CDC Available CNIC-GD003 Cross-reactive with LPAI and HPAI 5 th and (A/Guangdong/17SF003/2016-like) 6 th wave viruses tested China CDC Pending NIBRG-375 Cross-reactive with LPAI and HPAI 5 th (A/Guangdong/17SF003/2016-like) wave viruses tested NIBSC Pending CBER-RG7C Cross-reactive with LPAI and HPAI 5 th (A/Guangdong/17SF003/2016-like) wave viruses tested FDA/CBER Pending

27 A(H7N9) Summary of A(H7N9) 5th Wave 2016/2017 wave 5 epidemic -> dramatic increase in zoonosis ~ half of total cases (i.e., 766 of 1,567) Geographic dissemination Severe disease (38-40% CFR) Genetic drift of the HA viral RNA segment Pearl river delta viruses Well-inhibited by antisera to existing CVVs Yangtze River Delta HA group Predominant viruses in W5 Emergence of HPAI viruses Antigenically distinct Reduced cross-reactivity with sera to existing CVVs WHO VCM MAR, > New CVVs for low pathogenic and high pathogenic New CVVs engineered by reverse genetics (antigenicity and yield) IDCDC-RG56B (LP), antisera inhibits diverse LP viruses Clinical trial starting IDCDC-RG56N (HP), antisera broadly cross-reactive Others against HP becoming available

28 Acknowledgments Virology, Surveillance and Diagnosis Branch David Wentworth Vivien Dugan Larisa Gubareva Becky Garten Steve Lindstrom Xu Xiyan John Barnes Sam Shephard Zoonotic Virus Team, Todd Davis Yunho Jang Atanaska Marinova-Petkova Sharmi Thor Han Di Natosha Zanders Patrick Yang Joyce Jones Erin Hodges Vaccine Preparedness Team, Vivien Dugan (acting TL) Guaniri Mateu-Petit Pavani Bondugula Jaber Hossain Adam Johnson Xudong Lin Callie Ridenour Li Wang Terianne Wong International Research and Epidemiology Team, EPB Eduardo Azziz-Baumgartner James Kile Danielle Iuliano Katherine Roguski National Veterinary Services Laboratory, USDA Mia Torchetti Nicole Hines Influenza Division, OD Dan Jernigan Jackie Katz James Stevens Sue Trock Alicia Fry Director, Influenza Program U.S. CDC-China Office Carolyn Greene China CDC Shu Yuelong Dayan Wang Taiwan CDC Ji-Rong Yang Centre for Health Protection, Hong Kong Janice Lo University of Hong Kong Yi Guan Tommy Lam Zhu Hua Chen

29 Extra

Mar 16, 2018 Geographic Distribution Geographic Distribution of Sixth Epidemic Confirmed Avian Influenza A(H7N9) Virus Infections of Humans, Reported by WHO or in Chinese Provincial or Hong Kong CHP

30 Mar 16, 2018 Geographic Distribution Geographic Distribution of Sixth Epidemic Confirmed Avian Influenza A(H7N9) Virus Infections of Humans, Reported by WHO or in Chinese Provincial or Hong Kong CHP Press Releases, October 1, Feb 2018 (N=3)* Mongolia Inner Mongolia Jilin Heilongjian g Russi a Nepa l India Xinjiang 1 Tibet Bhuta n Banglades h India Qinghai Sichuan Yunnan 1 Gansu Chongqing Guizhou Shaanxi Guangxi Henan Shandon g Liaonin g Myanmar Vietnam Macao Hong Kong Thailan Laos Human Infections of A(H7N9) with HPAI d mutation identified by China CDC or Taiwan CDC * LPAI human infections are by Province of Reporting; HPAI human infections are by Province of Exposure Ningxi a Shanxi Hubei Hunan Hebei Jiangxi Guangdong 1 Anhui Fujian Beijin g Tianjin Zhejian g Taiwan Jiangsu North Korea Shangha i South Korea Japa n

31 HPAI H5 outbreaks animals - Reported to OIE and/or FAO; data is from OIE and FAO open sources that are available online H5N6 Ireland It Laboratory Zoonotic Influenza March 6-12, 2018 H5NX Bulgaria (1) H5N8 Italy(1) Iraq (2) Ir I H5N6 China(1) H5N6 Japan (3) H5N2 Taiwan (1) H5NX H5N1 H5N2 H5N3 H5N5 H5N6 H5N8 H5N1 India (1) Captive Birds Domestic Poultry Wild bird

32 Laboratory Zoonotic Influenza Reported February 27- March 5, 2018 A(H5) and A(H9N2) - No influenza A(H5) or A(H9N2) viruses were isolated or characterized antigenically Newly detected HPAI H5 outbreaks in animals Country Number of Outbreaks/reports Observation Date *Reported to OIE and/or FAO; data is from OIE and FAO open sources that are available online Species Description Bulgaria (H5) 1 2 March 2018 Domestic poultry India (H5N1) 1 11 Feb 2018 Domestic poultry China (H5N6) 1 22 Feb 2018 Domestic poultry Japan (H5N6) 3 1,2,3 March 2018 Wild bird Ireland (H5N6) 1 23 Feb 2018 Wild bird Iraq (H5N8) 2 4,5 March 2018 Domestic poultry Italy (H5N8) 1 2 March 2018 Domestic poultry Taiwan (H5N2) 1 24 Feb 2018 Domestic poultry

Antigenic and genetic characteristics of zoonotic influenza viruses and development of candidate vaccine viruses for pandemic preparedness

Antigenic and genetic characteristics of zoonotic influenza viruses and development of candidate vaccine viruses for pandemic preparedness February 2014 The development of representative candidate influenza