hpai - who · – 12clusters are with 2 cases per cluster – 1 cluster is with 3 cases...

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CHINESE CENTER FOR DISEASE CONTROL AND PREVENTION

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


H7 human cases（>100 cases) USA, UK, Italy, Netherland, Cananda

(H7N2, H7N3, H7N7)

HPAI

LPAI

1959

1/USA

H7N7

1977

1/USA

H7N7

1979-

1980

4/USA

H7N7

1996

1/England

H7N7

2002

1/ USA

H7N2

2003

1/ USA

H7N2 7/ Italy

H7N3

89/ Netherlands

H7N7 1 died

2004

1/ Canada

H7N3

1/ Canada

H7N3

2006

1/ Norfolk

H7N3

2007

4/ Wales

H7N2

2/ Mexico

H7N3

2012


H7 avian influenza viruses in China

(before 2013)

A/Baer's pochard/HuNan/414/2010(H7N1)

A/chicken/Hebei/1/2002(H7N2)

A/duck/Guangdong/1/1996(H7N3)

A/duck/Hubei/126/1985(H7N8)

A/duck/Jiangxi/1742/03(H7N7)




A/duck/Nanchang/1904/1992(H7N1)

A/duck/Nanchang/1944/92(H7N1)

A/duck/Zhejiang/10/2011(H7N3)



A/magpie-robin/China/28710/93(H7)

subtypes：H7N1,

H7N2, H7N3, H7N7,

H7N8

LPAI

No human H7cases


H7N9 avian influenza viruses

(before 2013)

Totally 25 isolates

all LPAI

All from wild birds

No human infection

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(H7N3)-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 2013


Human H7N9 Confirmed Cases in China (as of April,28,2014, Beijing time)

Provinces* 2014 Total

cases deaths cases deaths

Guangdong 98 33 104 34

Zhejiang 87 36 137 48

Hunan 20 7 22 8

Fujian 17 5 22 5

Jiangsu 24 8 53 17

Shanghai 8 7 41 25

Anhui 11 9 15 11

Guangxi 2 1 2 1

Beijing 2 1 4 1

Shandong 1 1 3 1

Jilin 1 - 1 -

Guizhou 1 1 1 1

Jiangxi 1 - 7 1

Henan - - 4 1

Hebei - - 1 1

Hongkong SAR 8 2 10 3

Taiwan 2 0 4 1

Total 283 111 431 159

*This table is counted by the provinces where cases were reported. CHINESE CENTER FOR DISEASE CONTROL AND PREVENTION

Epidemic Curve of Confirmed

Cases in Mainland China (n=417)

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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)

*First wave：before Oct 1, 2013; Second wave：after 0ct 1,2013

#CFR% in the second wave may be under estimated as some cases are still in

hospital.

Age(year)

Total First wave* Second wave#

cases death CFR(%) cases death CFR(%) cases death CFR(%)

0~ 24 0 0.0 6 0 0.0 18 0 0.0

15~ 24 7 29.2 6 1 16.7 18 6 33.3

30~ 73 13 17.8 20 3 15.0 53 10 18.9

45~ 104 32 30.8 31 7 22.6 73 25 34.2

60~ 192 103 53.6 71 33 46.5 121 70 57.9

total 417 155 37.2 134 44 32.8 283 111 39.2

Male 288 112 38.9 94 32 34.0 194 80 41.2

Female 129 43 33.3 40 12 30.0 89 31 34.8


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 transmission


Characterization of molecular markers of

avian influenza H7N9 viruses

HA NA PB2 PB1 PB1-F2 M2

RBS

69-73 del

Increased path in

mice

Enhance

transmission

Increased

transmission in

Ferret Increased path

Amantidine

resistant

186 226 627 701 368 31

G(2)/V(38) Q(2)/L(36)

/I(2)

Yes(39)

/No(1) E(12)/K(28) D(36)/N(4) I(7)/V(33)

90aa(30)/76aa(2)

/25aa(8) N(40)

HA NA PB2* PB1* PB1-F2* M2

RBS 69-73 del

Increased path

in mice

Enhance

transmission

Increased

transmission

in Ferret Increased path Amantidine resistant

186 226 627 701 368 31

V(69) L(69) Yes(69) E(13)/K(51)/mi

x(3) D(64)/N(3) V(68)

90aa(64)/57aa(3)/25a

a(1) N(69)

HA# NA PB2 PB1 PB1-F2 M2

RBS

69-73 del

Increased path

in mice

Enhance

transmission

Increased

transmission

in Ferret Increased path

Amantidine

resistant

186 226 627 701 368 31

V(60)/A(1) Q(11)/L(48)

/mix(2) Yes(61) E(58)/K(2) D(60) V(60)

90aa(45)/36aa(1)/2

5aa(14) N(60)

First wave

Second wave

Non-human

4


November

2013

December

2013

January 2013

February 2014

HA NA

HA NA


November

2013

December

2013

January 2013

February 2014

PB2 PB1 PA


November

2013

December

2013

January 2013

February 2014

NP MP NS


Genoty

pes isola

ted o

n m

ore

than o

ne s

am

plin

g o

ccasio

n AnH1

SH7

SH13

ZJ2

ZJ410

SD1

SH1080

SH1

JS1

JS537

ZJHZ1

ZJ4

ZJ007SH5

HB1

SH1439

SH1436 HZ109

SH1438

SH1437

HZ48

GD1

HK1

GX8970

GD2

(1)

(1) (3) (2) (6) (11) (18) (7) (9) (5)

(2)

(3)

(7) (1) (1) (8) (5)

(10) (3) (2) (1) (1) (1)

(1)

(1)

(1)

(1)

(1)

(1)

(1)

(2)

(1)

(1)

(1)

(1)

(1)

(2)

(1) (1)

(1)

(1)

(1)

(1) (2)

(2)

(1)

(1)

(1)

(1)

(1)

(2)

Tra

nsie

nt geno

types

Collection

DateFeb.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

Clade A

Clade B

Clade C

Clade D

Clade E

Clade F

Clade G

Clade H

HA

NA

NA(del)

RZ871

(1)

A

5


The geographic distribution of Genotypes

China

12

9

6

4

3

2

1

★ AnH1

SH7

JS1

★

★

★

★

★

★

★

★

★

B


Six internal genes:

domestic-poultry–derived H9N2,

chicken or wild-bird

Novel H7N9

Morens DM et al, NEJM, 2013 D liu et al., Lancet, 2013


Taijiao Jiang et al, Cell Host Microbes, 2013


Genetic tuning

mediated the interspecies transmission

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Receptor Binding Profile

α2,3 &

α2,6

α2,6

α2,6 α2,6 α2,6

α2,3 α2,3 α2,3

α2,3

Zhou JF, et al. Nature, 2013 HA G186V, Q226L


Growth Properties of H7N9 virus

in mammalian cell lines

Human Canine

Porcine CA04:A/California/04/2009 (2009pdmH1N1)

SH1: A/Shanghai/1/2013 (H7N9)

AH1: A/Anhui/1/2013 (H7N9)

Zhou JF, et al. Nature, 2013


Growth Properties of H7N9 virus

in different temperature

Watanabe T. et al, Nature, 2013

Belser JA. et al., Nature, 2013


Ex vivo infection of H7N9 virus

in trachea or lung tissue


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host infectivity Transmissibility pathogenicity

chicken ✔ ✔ ✗

duck ✗ ✗ ✗

Pigeon ✗ ✗ ✗

quail ✔ ✔ ✗

pig ✔ ✗ ✔ mild

mice ✔ NA ✔ mild

ferret ✔ ✔ ✔mild

monkey ✔ NA ✔mild

Guinea pig ✔ ✔ ✔mild

Animal model studies


Why severe case?

Fatality risk for all age: 36%

Yu, H et al Lancet 2013


Bian T. et al., NEJM, 2013

Demographic

Characteristics

Study subjects N(%)

N=1544

Shanghai Zhejiang Jiangsu Anhui

Age group, years

0-15 0 1(0.2%) 1(0.2%) 1(0.3%)

16-24 34(8.5%) 12(2.7%) 2(0.5%) 2(0.7%)

25-59 296(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 0 0 33(8.0%) 0

Collection date

Jan-May, 2012 0 439 415 166

Oct-Nov, 2012 399 0 0 125

Total 399 439 415 291

1

Retrospective serological study

No Positive


Infected Healthy Infected Healthy

H5N1 H7N9

P=0.0002

P=0.0002

P=0.0004

P<0.0001


H5N1 H7N9


H5N1 H7N9


H5N1 H7N9

P=0.0112 P=0.0032

P=0.0072 P=0.0001

P=0.0001

P<0.0001

P=0.0001 P=0.0007

P=0.0001 P=0.0427

P=0.0007

P=0.0034

A B C D

E F G H

Elevated cytokine levels in acute

infected patients

IP10 MIG MIP-1ß MCP-1

IL-6 IL-8 IFN-α


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Antigenicity analysis of avian influenza

A(H7N9 ) viruses Reference antigens Passage history subtype

Ferret anti sera AH1* SH2# PC0360 MN12

1 A/Anhui/1/2013 E2 H7N9 160 640 80 640 2 A/Shanghai/2/2013 E1 H7N9 320 2560 160 2560 3 A/wild gs/Dongting/PC0360/2012 E3 H7N7 40 320 160 640 4 A/mallard/Netherlands/12/2000 EX+E1/E1 H7N3 40 160 40 320

Test antigens 5 A/Shanghai/02619/2014 E1 H7N9 320 640 160 640 6 A/Guangdong/02620/2014 E1 H7N9 320 1280 160 1280 7 A/Guizhou/01502/2014 E1 H7N9 320 1280 160 1280 8 A/Guangdong/02125/2014 E1 H7N9 160 640 160 1280 9 A/Fujian/1/2014(H7N9) E1 H7N9 640 2560 320 2560 10 A/Zhejiang/07807/2014 E1 H7N9 320 2560 160 1280 11 A/ Zhejiang /07802/2014 E1 H7N9 640 2560 160 1280 12 A/Hunan/07833/2014 E1 H7N9 160 1280 80 640 13 A/Hunan/08963/2014 E1 H7N9 320 1280 160 1280 14 A/Guangxi/08970/2014 E1 H7N9 320 2560 160 1280 15 A/Guangxi/08971/2014 E1 H7N9 320 2560 80 1280 16 A/Environment/Guangdong/25003/2013 E1 H7N9 160 640 80 640 17 A/Environment/Zhejiang/07818/2014 E1 H7N9 320 1280 160 1280 18 A/Environment/Hunan/07836/2014 E1 H7N9 160 640 40 320

remain antigenically similar to the candidate vaccine viruses

derived from A/Anhui/1/2013-like viruses


Virus susceptibility of human H7N9 viruses to

Neuraminidase Inhibitors

Viruses IC50( Mean± SDa )

Oseltamivir Zanamivir

A/Shanghai/1/2013 (H7N9) 0.7±0.04 1.04±0.016

A/Shanghai/2/2013 (H7N9) 1.08±0.05 0.84±0.016

A/Shanghai/3/2013 (H7N9) 0.69±0.01 0.87±0.05

A/Shanghai/4/2013 (H7N9) 1.03±0.02 0.79±0.03

A/Shanghai/5/2013 (H7N9) 1.27±0.3 0.67±0.06

A/Anhui1/2013 (H7N9) 2±0.24 0.73±0.01

A/Jiangsu/1/2013 (H7N9) 1.15±0.07 0.51±0.07

A/Zhejiang/1/2013 (H7N9) 1.05±0.13 0.7±0.11

A/Pigeon/Shanghai/S1069/2013 (H7N9) 1.47±0.19 0.81±0.03

A/Chicken/Shanghai/S1053/2013 (H7N9) 1.47±0.1 0.67±0.05

A/Environment/Shanghai/S1088/2013 (H7N9) 0.67±0.21 0.9±0.04

A/Environment/jiangxi/2009 (H11N9) 1.62±0.4 0.85±0.13

A/Washington/1/2007(H3N2, WT) <10e-9 3.79±0.04

A/Texas/12/2007(H3N2, E119V) 100.46±8.54 0.27±0.04

A/California/7/2009 (2009pdmH1N1, WT) 0.979±0.52 0.1±0.01

A/NorthCarolina/39/2009 ( 2009pdmH1N1, H275Y) 239.7±76.02 0.24±0.02

Zhou JF, et al. Nature, 2013 Sensitive to Oseltamivir and Zanamivir


Hu Y. et al., Lancet, 2013

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

transmission

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

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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!

hpai - who · – 12clusters are with 2 cases per cluster – 1 cluster is with 3 cases...

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