Emerging Infectious Diseases: Does Nature strike back?

Malik Peiris Centre of Influenza Research HKU-Pasteur Research Pole The School of Public health

The University of Hong Kong

• “Human destiny is bound to remain a gamble, because at some unpredictable time and some unforeseeable manner, nature will strike back.”

Rene Dubos, 1959

“One can think of the middle of the 20th Century as one of the most important societal changes in history – the conquest and elimination of infectious diseases as a significant factor in society” - McFarlane Burnet, 1962

The germs are striking back!

Many are zoonoses

Most are RNA viruses

Genetic and Biological Factors

Physical Environmental Factors

Microbe

Human

Ecological Factors Social, Political and Economic Factors

The Convergence Model

One Health “Collaborative effects of multiple disciplines

working locally, nationally and globally to attain optimal health for people, animals and the environment.” – American Veterinary Association 2008

Animal Human

Environment

Sri Lanka

Jetavanaramaya dagaba 273-310AD

Japanese Encephalitis - Sri Lanka: 1985-7

But why now? Cx.tritaeniorhynchus 4/10,959 (0.036%) Cx. Gelidus, other

Sri Lanka

Maintain food production Minimise health risk

Emergence of a obscure nephropathy in areas

covered by the irrigation scheme

H5N1: First detected in Hong Kong 1997

Epidemic Curve of Influenza A (H5N1) Cases in HKSAR, May - Dec 1997

01234567

15-M

ay

06-J

un

11-J

un

06-J

ul

10-J

ul

03-A

ug

17-A

ug

31-A

ug

12-S

ep

16-S

ep

12-O

ct

26-O

ct

01-N

ov

09-N

ov

16-N

ov

23-N

ov

30-N

ov

07-D

ec

12-D

ec

21-D

ec

26-D

ec

29 D

ec

Dates of onset (Beginning of week)

No.

of C

ases

Recovered Deceased

Active surveillance Avian flu H5N1-Post 1997

• 2000 Reassortment in ducks

• 2001 Live poultry markets

• 2002 Farm outbreaks

HK/1997

• 2002 Wild birds

• Progressive implementation of evidence based interventions

• Avian flu task force: Convener Dr PY Leung

Live poultry markets maintain, amplify AND DISSEMINATE avian influenza viruses

Poultry farms Wholesale poultry market Retail poultry

Market

Kung et al Emerg Infect Dis 2007

Kung et al Avian Dis 2003; Lau et al EID 2007; Leung et al - 2012

0%

4%

8%

12%

Bef or e Af ter Bef or e After Bef or e After

July August September

Sims & Peiris Current Top Microbiol Infect 2012

Cultural resistance to close all live poultry markets

Evidence based interventions in live poultry markets Isolation rates of H9N2 viruses in chicken

1 rest day 2 rest days Ban holding live poultry overnight

1999-2011; monthly surveillance; 5-8 FEHD poutlry markets; 53,541 samples

Leung et al EID 2012

Live poultry markets: A “dead-end” for the poultry, not for the virus.

Poultry farms Wholesale poultry market Retail poultry

Market

Kung et al Emerg Infect Dis 2007

Sims & Peiris Current Top Microbiol Infect 2012

Lessons Active surveillance, evidence-based intervention

and applying a “One health” approach protected Hong Kong. Hong Kong: a “sentinel post” for the region. What if - - - - -? 15

2004 2004 – to date

As of Aug 2012, 608 human cases, 359 deaths

Qinghai Lake outbreak: April 2005

Qinghai Lake:April 2005 Bar headed geese, Brown headed gull Great black headed gull, Great cormorant

“There is a danger that it may spread to the south Asian subcontinent …. And Europe” Chen et al Nature July 2005 16

“Pet-bird” trade and H5N1 avian flu in Hong Kong

Ceremonial religious bird release brings “merit”

“fangsheng”

Epi-curve of human H7N9 cases by province: (as of April 22, 2013)

19 http://www.who.int/influenza/human_animal_interface/influenza_h7n9/ChinaH7N9JointMissionReport2013u.pdf

China-WHO Joint Mission on Human Infection with Avian Influenza A(H7N9) virus: April 2013

How long will the live poultry markets stay closed? • Cultural preference • Food security

Surveillance of H5N1 viruses in “HEALTHY” poultry in live poultry markets in China

(2000-2004)

Li et al Nature 2004; 430: 209-213

Transmissibility of A(H7N9) in ferrets

21 Zhu et al Science 2013, on line

H7N9

pdmH1N1

Influenza H7N9 vs. H5N1 infection in ex vivo cultures of human conjunctiva, bronchus and lung

H5N

1

H

7N9

Immunohistochemistry of infected tissues, 24 hours post infection with comparable viruses dose

Conjunctiva Bronchus Lung

Chan et al - unpublished

Viral load in throat swabs after commencement of antiviral therapy

ECMO

Ventilator

Pneumonia

Emergence of antiviral resistance correlates with rebound of viral load (2/14 patients).

Hu et al Lancet on line 2013

First detected April 2009

April 2009

May 2009

June 2009

WHO, 2009. Pandemic (H1N1) 2009, situation update, available at: http://www.who.int/csr/don/2009_07_06/en/index.html (accessed 6 July 2009)

July 6 2009

1–10 11–50 51–500

500–5000

Cumulative cases

>5000

In a few weeks, the 2009 H1N1 pandemic spread around the world affecting all countries * Reports up to July 2009

25

Reverse zoonosis of pandemic H1N1 to pigs worldwide global perturbation of swine influenza, leading to emergence of novel reassortants in pigs

Science 2010; 328: 1529

USA: July 2012 – Present: 309 human cases; 10 states, 16 hospitalized, 1 fatal.

http://newshopper.sulekha.com/pig-scramble_photo_1921995.htm

26

Different genotypes detected in swine: Hong Kong / China (2010-2012)

PB2 PB1 PA HA NP NA M NS isolates

pH1N1 pH1N1 pH1N1 pH1N1 pH1N1 pH1N1 pH1N1 pH1N1 32 pH1N1 pH1N1 pH1N1 H3-VTN pH1N1 N2-VTN pH1N1 pH1N1 53 pH1N1 pH1N1 pH1N1 H3-VTN TR-VTN N2-VTN pH1N1 pH1N1 3 pH1N1 TR pH1N1 H3-VTN pH1N1 N2-VTN pH1N1 pH1N1 5 pH1N1 pH1N1 pH1N1 pH1N1 pH1N1 N2-early pH1N1 pH1N1 1 pH1N1 pH1N1 pH1N1 H3-VTN pH1N1 TR-N2 pH1N1 pH1N1 1 pH1N1 pH1N1 pH1N1 pH1N1 pH1N1 TR-N2 pH1N1 pH1N1 22 pH1N1 pH1N1 pH1N1 pH1N1 TR TR-N2 pH1N1 pH1N1 5 pH1N1 pH1N1 pH1N1 TR-H1 pH1N1 TR-N2 pH1N1 pH1N1 4

TR TR pH1N1 TR-H1 pH1N1 TR-N2 pH1N1 pH1N1 7 pH1N1 pH1N1 pH1N1 H1 pH1N1 TR-N2 pH1N1 TR 1 pH1N1 pH1N1 pH1N1 EA pH1N1 TR-N2 pH1N1 pH1N1 1 pH1N1 pH1N1 pH1N1 EA TR TR-N2 EA pH1N1 1

TR TR TR EA TR pH1N1 TR TR 1 pH1N1 pH1N1 pH1N1 EA pH1N1 EA pH1N1 pH1N1 29

EA EA EA EA EA EA pH1N1 EA 4 EA EA EA H1 EA N2 EA EA 5 EA EA EA EA EA EA EA EA 37 EA EA EA EA EA EA EA TR 25 TR TR TR EA TR EA EA TR 2 TR TR TR EA TR TR-N2 EA TR 7 TR TR TR EA TR EA TR TR 1 TR TR TR TR TR TR-N2 EA TR 7 TR TR TR TR-H1 TR TR-N2 TR TR 7

261 isolates 64.9% with pH1N1 gene 24 genotypes

Peiris & Guan - Unpublished

SARS

Peiris et al 2003; Drosten et al 2003; Ksiazek et al 2003

Lau et al PNAS 2005; Li et al Science 2004

Guan et al 2003

? ?

Body equilibrium and food

The novel human MERS coronavirus/2012: Closely related to bat coronaviruses

Chan & Poon mBio 2013

55 human cases 31 deaths • Jordan, Qatar, Saudi

Arabia, UAE • Travel associated

cases in France, Germany, Italy, Tunisia, UK

Ex vivo human lung and bronchus experimentally infected with coronaviruses

Chan et al J Virol 2013

HCoV-EMC ≥ SARS CoV

Cellular localization of HCoV-EMC in the ex vivo lung

Type 1 alveolar epithelium: YES

Alveolar macrophage: NO

Bronchiolar epithelium : YES Bronchus: ciliated

cells: NO

Type II alveolar epithelium: YES Pulmonary endotheilal cells: YES

HCoV-EMC (compared with H5N1) fails to induce an interferon response in alveolar

epithelial cells A549

Chan et al - submitted

SARS Legacy: Outbreak reporting is expected and respected

David L Haymann, John S MacKenzie, Malik Peiris. Lancet 2013; 381: March 9th; pp 779-781

“How the global public health and animal health communities respond to the recent emerging coronavirus threat will be a test of what has been achieved and whether the one-health notion can move beyond words to practical action.”

Conclusions • Proactive surveillance short term pain / long term gain stay “ahead-of-the-curve” • Risk-assessment

– Animal health – Human health

• Evidence-based interventions “One Health” pays!!

軒轅黃帝 The superior physician

• The superior physician helps before the early budding of the disease 上工救其萌牙

• The inferior physician begins to help when the disease has already developed; he helps when the destruction has already set in. And since his help comes when the disease has already developed, it is said of him that he is ignorant.

下工救其已成，救其已敗， 救其已成者，言不知三部，九之相失。

黃帝內經素問 Wong Dae Noi Ging Sou Men

(2697-2597 BCE) The Yellow Emperor's Classic of

Internal Medicine

Slide courtesy of Gabriel Leung

School of Public Health; The University of Hong Kong Centre of Influenza Research / HKU Pasteur Research Pole Yi Guan, Leo Poon, Michael Chan, Renee Chan, H Yen, Huachen Zhu, Ken Shortridge Department of Pathology: John Nicholls Depts of Agriculture & Food / Environmental Hygiene, Health: Les Sims, Trevor Ellis, Geraldine Luk, Miranda Lee (PY Leung) St Jude Children’s Research Hospital, Memphis: RG Webster, R Webby

Michael Chan

John Nicholls

H Yen Renee Chan Yi Guan

Ben Cowling Joe Wu

Gabriel Leung

Leo Poon

Ex vivo human lung and bronchus experimentally infected with coronaviruses

Chan et al J Virol 2013

HCoV-EMC ≥ SARS CoV

Cellular localization of HCoV-EMC in the ex vivo lung

Type 1 alveolar epithelium: YES

Alveolar macrophage: NO

Bronchiolar epithelium : YES Bronchus: ciliated

cells: NO

Type II alveolar epithelium: YES Pulmonary endotheilal cells: YES

HCoV-EMC (compared with H5N1) fails to induce an interferon response in alveolar

epithelial cells A549

Chan et al - submitted

Interferon α and β suppresses HCoV EMC virus replication

Chan et al - submitted

Interventions • Changes in wholesale and retail poultry

marketing system – Modifications to wholesale poultry market. – No live ducks and geese in live poultry markets

since 1998. – Ducks and geese slaughtered separately and sold

as freshly killed poultry carcasses. – Surveillance tests on all imported poultry for

evidence of H5N1 infection.

41

Transient

Reconstructing the emergence of the pandemic

Seven gene segments “pandemic-like”. But phylogeny suggests NOT pandemic precursor

• What are the viral genetic determinants of transmission in humans?

Vijaykrishna et al Nature 2011

2009 Pandemic

a Nasopharyngeal

Transmission in ferrets Yen et al PNAS 2011 Chan et al J Virol 2011

Transmission in ferrets Transmission risk to humans

Pandemic 2009 H1N1

Nasopharynx Bronchial Alveoli

915/04 (H1N2); Differs in NA

201/10 (H1N1); Differs in HA

TRIG (H1N2); Differs in NA/M

✔ ✔ ✔

✔ ✔

✔ RG-sw915 x HK415742NA

Yen et al PNAS 2011 Chan et al J Virol 2011

Tropism in ex vivo cultures of human respiratory tract

Classical swine (H1N1) Differs in PB2/PB1/PA/NA/M

Pandemic H1N1 Classical swine H1N1

Triple reassortant

A/Sw/HK/4167/99 (H1N1)

A/Sw/Arkansas/2976/02 (H1N2) Seasonal influenza

A/Sw/HK/915/04 (H1N2) A/Sw/HK/201/10 (H1N1)

A/HK/415742/09 A/CA/04/09

Differed by NA Differed by HA, M

Differed by NA, M

Differed by PB2, PB1, PA, NA, M

Eurasian swine H1N1 A/Sw/NS29/2009 (H1N1)

Differed by PB2,PB1,PA, HA,NP,NS

Yes

Yes/Weak

Yes

No/No

No/No

No/No No/No

Correlation between upper respiratory tract virus tropism in ex-vivo cultures and ferret transmission studies

AGREE !

Chan et al J Virol 2011; Yen et al PNAS 2011

Nature Jan 5, 2012

The real world