Presentation title | Presenter name 1 |

Asia-Pacific Workshop on surveillance, prevention and control of

zoonotic influenza

Paro, Bhutan, 29-31 August 2016

Global and Regional situation, and

Scientific updates on Zoonotic Influenza

Dr Frank Wong

OIE Reference Lab

Australian Animal Health Laboratory

How Predictable is the Next Influenza Pandemic? Tracking Evolution of Avian Influenza A Viruses – Global

& Regional Situation Update

Frank Wong (AAHL) – on behalf of the OFFLU VCM Team

Asia-Pacific Workshop on Surveillance, Prevention and Control of Zoonotic Influenza – Paro, Bhutan, 29-31 August 2016

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One of the world’s largest biosecure laboratories for the safe handling and containment of animal diseases - Viral diseases of livestock and zoonoses - Diagnosis, surveillance and research - BSL3/4 large animal facility (1000 m2)\BSL3

insectary - Small animal facility and farm facility

CSIRO Australian Animal Health Laboratory

Influenza Reference Activities: • OIE Reference Laboratory for Avian Influenza

(World Organisation for Animal Health)

• FAO Reference Centre for Animal Influenza (Food & Agricultural Organisation of the United Nations) • Reference Laboratory for OFFLU (Joint OIE/FAO Network of Expertise on Animal Influenza)

H5N1 HPAI – 20 years on!

Source: www.who.int/influenza/gisrs_laboratory/h5n1_nomenclature/en/ Smith et al. (2015) Influenza and Other Respiratory Viruses 9(5), 271–276.

2012-2015

Indonesia

Egypt

South Asia

China, SE Asia, West Africa, Middle-East

East Asia, SE Asia (Nth America/Europe)

Cambodia, Viet Nam

China, SE Asia

Egypt, Middle-East

China, Viet Nam

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2015 – An H5Nx HPAI year…

• H5Nx HPAI events increased in numbers and geographical extent

• HPAI H5 viruses have genetically diversified and re-assorted

• H5N1

• H5N2

• H5N6

• H5N8

• Endemic countries reported more outbreaks

• Previously unaffected countries detected H5Nx HPAI viruses in poultry and wild birds

Geographical Distribution of H5Nx HPAI viruses 26 October 2014 – 26 October 2015

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H5N1 HPAI 2015 = highest number of AI human cases in history

New introduction and significant spread of the virus in: • Israel – Gaza – West Bank • West Africa

Geographical Distribution of AI viruses 01 October 2014 – 18 November 2015

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If we go clade by clade …

• Clade 1 – Was persisting in southern Viet Nam and Cambodia

– Not seen recently (last time end of 2014)

– Replaced by clade 2.3.2.1.C

• Clade 2.1.3.x – Only persisting in Indonesia

– No genetic information publicly available from 2015

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If we go clade by clade …

• Clade 2.2.1 – Mainly in Egypt

– Some spill over to Israel and Gaza/West Bank

• Clade 2.3.2.1a – Persisting in South Asia

– Main clade in Bangladesh, India, Nepal

– No major genetic drift during recent years

• Clade 2.3.2.1b – Not observed recently

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If we go clade by clade …

• Clade 2.3.2.1c – Most widespread clade of H5N1

– Spread widely in SEA

– Introduced into Indonesia in 2012

– Also spread to India

– Found in wild birds in central Asia and Europe

• Clade 2.3.4.2 – Only reported in Myanmar, poultry outbreaks

– Continuous circulation since 2012?

– Unknown status in China

Clade 2.3.4.4 H5Nx HPAI

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Clade 2.3.4.4 : what do we know ?

• Emerged from Asian clade 2.3.4 H5N1 HPAI reassorting with LPAI viruses, resulting in various subtypes: H5N8, H5N6, H5N2, H5N1, …

• No/little pathogenicity in wild ducks

• Spread both to west and east

• Clade 2.3.4.4 H5-HA is already greatly diversified into multiple lineages

• Efficacy of current vaccines against this clade is unknown but antigenically distant to previous 2.3.4 H5N1 viruses

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H5N2 HPAI Asian reassortant - endemic in Chinese Taipei (Taiwan)

American reassortant: Asian H5N8 reassorted with Nth Am LPAIV PB1, NP and N2 genes. Caused largest H5 HPAI outbreak ever recorded in the USA in 2015 (48 million birds affected)

No human case despite massive environmental contamination

Geographical Distribution of AI viruses October 2014 – November 2015

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H5N6 HPAI New H5N6 HPAI first detected in Southern China – H5N1 and H6N6

reassortant

Spread to Lao PDR and Viet Nam via cross-border poultry movement

>14 confirmed human cases since 2014; new pandemic concern?

Geographical Distribution of AI viruses October 2014 – November 2015

OFFLU-WHO agreement initially

signed in 2011 for 3 years; further

extended from 2014 – 2018

What & how does OFFLU Lab

Network contribute to the WHO

VCM process? • Focus on sharing timely genetic (HA gene) data from zoonotic influenza

viruses circulating in birds and animals to track virus evolution and identify

emergence (Asian HP-H5N1/H5Nx, HP-H7, H7N9, H9N2, novel subtypes)

• Fills crucial surveillance gap where human health sector does not have

access to human isolates

• Collate associated epidemiological and sample metadata

• Key OFFLU Ref Labs produce HI data from H5 HPAI viruses using

standardised antigenic panels produced by WHO-CCs that represent the

circulating lineages/clades & CVVs (consist of strain specific ferret antisera

and corresponding homologous virus antigens)

• Speed up production of human vaccines against emergent zoonotic

and potentially pandemic influenza viruses

• Assess animal influenza viruses for zoonotic potential, before

spillover occurs (analysis of key genetic residues)

WHO-VCM selection of candidate test vaccine seed viruses for pandemic preparedness against zoonotic influenza viruses

http://www.who.int/influenza/vaccines/virus/characteristics_virus_vaccines/en/

A(H5N6) – antigenically divergent from existing H5 HPAIs JWE/HK/

1038/06 DK/Laos/ 3295/06

Anhui/ 1/05

CM/HK/ 5052/07

BS/HK/ 1161/10

Hubei/ 1/10

DK/VNM/ NCVD-2848/13

CK/BGD/ 15205/12

ENV/BGD/ 15121/12

DK/BGD/ 19097/13

CK/BGD/ 42010/12

DK/VNM/ NCVD-1584/12

DK/VNM/

NCVD-129-7/11

Clade 2.3.4 2.3.4 2.3.4 2.3.2.1 2.3.2.1b 2.3.2.1a 2.3.2.1c 2.3.2.1a 2.3.2.1a 2.3.2.1a 2.3.2.1a 2.3.2.1c 2.3.2.1b

Reference antigen: A/JWE/HK/1038/06 2.3.4 80 80 80 <40 <40 NT NT <40 NT ND ND ND ND

A/DK/Laos/3295/06 2.3.4 <40 160 80 <40 <40 <40 <40 <40 <40 <40 <40 <40 <40

A/Anhui/1/05 2.3.4 <40 320 320 <40 <40 <40 <40 <40 40 <40 <40 <40 <40

A/CM/HK/5052/07 2.3.2.1 <40 40 80 160 <40 <40 80 <40 640 80 80 80 40

A/BS/HK/1161/10 2.3.2.1b <40 <40 80 80 320 <40 80 <40 640 160 80 80 80

A/Hubei/1/10 2.3.2.1a <40 <40 40 80 <40 80 40 <40 640 160 <40 40 <40

A/DK/VNM/NCVD-2848/013 2.3.2.1c <40 <40 <40 40 160 <40 160 <40 640 160 40 80 <40

A/CK/BGD/15205/12 2.3.2.1a <40 <40 40 <40 160 <40 <40 80 1280 320 320 80 40

A/ENV/BGD/15121/12 2.3.2.1a <40 <40 <40 40 160 <40 40 <40 640 160 80 80 <40

A/DK/BGD/19097/13 2.3.2.1a <40 <40 <40 40 <40 <40 40 <40 640 160 80 40 <40

A/CK/BGD/42010/12 2.3.2.1a <40 40 40 80 320 <40 80 80 1280 320 160 80 40

A/DK/VNM/NCVD-1584/12 2.3.2.1c <40 <40 40 80 320 <40 40 <40 640 320 160 80 <40

A/DK/VNM/NCVD-129-7/11 2.3.2.1b <40 <40 <40 40 320 <40 80 <40 640 80 80 40 80

Test antigen: A/CK/Laos/LPQ001/14(H5N6) 2.3.4.6 <40 <40 <40 <40 <40 <40 <40 <40 <40 <40 <40 <40 <40

A/DK/Laos/LPQ002/14(H5N6) 2.3.4.6 <40 <40 <40 <40 <40 <40 <40 <40 <40 <40 <40 <40 <40

A/CK/Laos/XBY003/14(H5N6) 2.3.4.6 <40 <40 <40 <40 <40 <40 <40 <40 <40 <40 <40 <40 <40

A/DK/Laos/XBY004/14(H5N6) 2.3.4.6 <40 <40 40 <40 <40 <40 <40 <40 <40 <40 <40 <40 <40

Antigenically unrelated to older 2.3.4 H5N1 reference viruses; >30 aa differences in HA1 subunit Concerns for diagnostic serodetection and coverage of current vaccine virus candidates for pandemic preparedness

A(H5N6) clade 2.3.4.4 Lao PDR 2014

Vaccine Candidate

New viruses OFFLU (since Feb 2014)

Annotation

Mat

ure

H5

HA

1

A/A

nh

ui/

1/2

00

5

A/d

uck

/Lao

s/3

29

5/2

00

6

A/c

hic

ken

/Lao

s/LP

B0

01

/20

14

(H5

N6

)

A/d

uck

/Lao

s/X

BY0

04

/20

14

(H5

N6

)

A/c

hic

ken

/Sic

hu

an/J

1/2

01

4(H

5N

6) A

/ch

icke

n/N

ingx

ia/S

6/2

01

4(H

5N

6)

Clade 2.3.4.6

40 K . R R . . Antigenic site C 45 D . N N N N 53 R . K K K K 72 N . R R R R 82 K . R R R R 95 F . L L L L 114 I . T T . . 115 Q . L L L L 123 S . P P T T Antigenic site B 124 D . N N N N 127 A . T T T T 129 S . L L L L

133 S . A A A A Antigenic site A; receptor binding 140 T . M M T T Antigenic site A 151 I . T T . . Antigenic site B; receptor binding 155 N . D D D D Antigenic site B 156 T . A A A A Antigenic site B 162 R . M M I I 169 Q . R R . . 183 D . N N N N Antigenic site B 189 K . N N N N Antigenic site B; receptor binding 192 Q . K K K K Antigenic site B 198 I . V V . . 210 V . E E . . Antigenic site D 218 K . Q Q Q Q 223 S . R R R R Antigenic site D 240 N . H H H H 263 A . T T T T 265 V I M M M M 269 V . M M . . 273 N . H H H H Antigenic site C

31 aa

31 aa

24 aa

24 aa

Framework for Assessing Influenza Virus Pandemic Risk – eg. IRAT

Virus Properties - Genomic Variation - Receptor Binding Properties - Transmissibility in Animal Models - Antiviral susceptibility Host Properties: - Population Immunity - Disease Severity - Antigenic Relationship to Vaccines Ecology & Epidemiology: - Human Infections - Infections in Animals - Global Distribution in Animals

Source: Trock SC, Burke SA, Cox NJ. EID. 2015. http://dx.doi.org/10.3201/eid2108.141086

Emergent LP AIV (to poultry) of zoonotic concern

A(H7N9) A(H10N8) A(H9N2)

Zoonotic A(H7N9) situation update Human cases: (to 20 July 2016)

• 795 confirmed; 314 deaths (39% CFR)

• Reported cases generally severe illness (eg. ARS)

• Although viruses have undergone genetic drift, they remain antigenically related

• Remains restricted to poultry in China

Source: FAO EMPRES

Novel Zoonotic A(H10N8), China - Summary

Sources: (1) Chen H et al, 2014, Clinical and epidemiological characteristics of a fatal case of avian influenza A H10N8 virus infection : a descriptive study. The Lancet. Published online February 5, 2014 http://dx.doi.org/10.1016/S0140-6736(14)60111-2; (2) Liu M, et al. Genetic diversity of avian influenza A(H10N8) virus in live poultry markets and its association with human infections in China. Sci. Rep. 5: 7632. DOI:10.1038/srep07632 (2015).

hu

• First report of A(H10N8) infection in humans in Nanchang, Jiangxi Province in Dec 2013

• 3 human cases reported from Jiangxi Province since Feb 2014

• All infected individuals had severe disease with 2 fatalities

• All cases had contact with poultry or associated contaminated environment (LBM/LPM)

• Zoonotic A(H10N8) characterised; genes of AI origin with internal genes (PB2, PB2, PA, NP, M, NS) derived from A(H9N2) viruses circulating widely in chickens in China

(reassortment with H9N2 genetic backbone similar to H7N9)

• Presence of a complex picture of A(H10N8) genotype variants indicate prior extended circulation of related viruses in the regional poultry population

Ecology of AIV leading to novel reassortants, Asia

Large free-ranging and backyard domesticated duck populations

Intermingling of poultry hosts in LAMs/LPMs

Wild waterfowl reservoir hosts of AIV subtypes

Modified from Su et al. 2015. J Virol 89:8671–8676.doi:10.1128/JVI.01034-15.

• A(H7N9) has provided a new awareness of the zoonotic potential of LPAI of miscellaneous subtypes circulating in poultry (difficult to detect as no clinical signs in birds)

• Increased interest in A(H9N2) host infection dynamics and genome mechanics

• Reassortant HPAI viruses of Asian clade 2.3.4.4 H5 lineage with different NA subtypes have emerged and spread globally, threatening both poultry-dependant livelihoods and human health

• OFFLU/FAO implementing risk-based regional AI surveillance in at-risk & affected countries to enable early detection of incursion or spread of zoonotic subtypes and novel genotypes

Summary

• Not very likely! Current focus is on pandemic preparedness, not prediction

• Large gaps in both virological and epidemiological surveillance data in key regions, limiting pandemic risk assessments

• Current poultry systems and LAM/LBMs facilitate the generation of novel reassortant viruses (alphabet soup!)

[Let’s not forget about pigs! Even less surveillance data!]

• An emergent (novel) virus with pandemic potential needs to:

- Be able to cause disease in humans

- Presents little to no immunity in the human population

- Have the capacity for sustained human-to-human transmission

• Known virus genetic markers that facilitate infection, tropism and transmission in the mammalian(human) host are useful for surveillance, but there are still more unknowns than known!

• What are the key(s) to sustained human-human (airborne) transmission? Are only H1-H3’s able to?

Still unclear.

• WHO PIP activities aim to better prepare us for the next pandemic;

(a new pandemic virus will still likely spread around the globe within a week of emergence)

So…How Predictable is the Next Flu Pandemic?

Acknowledgements

OFFLU:

Ian Brown, Giovanni Cattoli, Peter Daniels, Gounalan Pavade, David Swayne

FAO, Rome:

Gwenaelle Dauphin, Sophie Dobschuetz

FAO Regional office for Asia/Pacific, Bangkok:

Filip Claes

OFFLU Network Reference Laboratories and Regional National Animal Health Laboratories

www.offlu.net