Similarities and differences between the novel H7N9 and H5N1 influenza A viruses

Ruben Donis, DVM, PhD

National Center for Immunization & Respiratory DiseasesInfluenza Division

Associate Director for Policy Evaluation and PreparednessInfluenza Division, NCIRD, Centers for Disease Control and Prevention

EMERGING VIRAL DISEASES – THE “ONE HEALTH” CONNECTIONForum on Microbial Threats, IOM, NAS

18‐19 March, 2014

Rob Webster sent a note with apologies and best wishes for a productive meeting. 

Influenza A Virus

8 RNA genes HA: receptor binding, 

fusion NA: virus release Evolution

• Error rate 10-4

o All possible changes in ~200,000 virions

• Genetic reassortment

HA NA

8 RNA genes

Host Species for HA and NA SubtypesH1

H2

H3

H4

H5

H6

H7

H8

H9H10 N10H11 N11H12

H13

H14

H15

H16H17

H18

N1N2

N3

N4

N5

N6

N7

N8

N9

Other Animals

Other Animals

Other Animals

Other Animals

Other Animals

Other Animals

Blue icons: lack of sustained transmission

Courtesy of Dr. Danielle Iuliano, Influenza Division

Human Cases Avian Influenza A (H7N9) March 13, 2014

†† Confirmed clusters are two or more confirmed cases of H7N9 that are close contacts of one another.

Cumulative counts by Report Date 30 Mar–30 Sept, 2013

1 Oct 2013– present Total

Countries affected China China, Malaysia

China,Malaysia

Number of provinces/municipalities/areas/SARs with confirmed cases – China

11 / 2 / 1 / 0 9 / 2 / 1 /1 13 / 2 / 1 / 1

Number of confirmed cases 135 254 389Number of confirmed cases hospitalized 131 253 384Number of fatal confirmed cases 45 79 124Cases of confirmed human to human transmission 0 0 0

Number of confirmed clusters†† 5 3 8Number of asymptomatic infections 1 0 1

• Most infections have caused severe disease, older adults– Limited evidence of mild illness, restricted to children

* Onset date unknown for 6 cases

0

2

4

6

8

10

12

14

2/18 3/18 4/18 5/18 6/18 7/18 8/18 9/18 10/18 11/18 12/18 1/18 2/18 3/18 4/18 5/18

Num

ber o

f Cases

Onset Date

Malaysia China

Epidemic Curve for Confirmed Cases of A(H7N9),18 Feb 2013 – 13 Mar 2014  (N=389)*

2013 2014

First wave Second wave

Courtesy of Dr. Danielle Iuliano, Influenza Division

22 new casesSince 2004:659 total cases/388 fatal

Human Cases Avian Influenza A (H5N1)September 17, 2013 - March 13, 2014

Cambodia Fatal

ChinaVietnamCanada

Indonesia

Oct Nov Dec Jan FebSept Mar

More than 10 human cases of H7N9 in China for each H5N1 case globally (in Asia and Africa)

Courtesy of Dr. Wenqing Zhang, WHO GISRS

Most cases had direct/close contact with poultry• Direct or indirect exposure to poultry

Most cases in urban centers• Exposed to poultry at live bird markets

Exposure historyo backyard poultry o live poultry markets

Difference in exposure reflects current patterns of H5N1 distribution in poultry populations• H5N1 more widespread in backyard poultry than H7N9

Human Cases of Avian Influenza A (H5N1) Virus

Human Cases of Avian Influenza A (H7N9) Virus

* Onset date unknown for 6 cases

0

2

4

6

8

10

12

14

2/18 3/18 4/18 5/18 6/18 7/18 8/18 9/18 10/18 11/18 12/18 1/18 2/18 3/18 4/18 5/18

Num

ber o

f Cases

Onset Date

Malaysia China

Epidemic Curve for Confirmed Cases of A(H7N9),18 Feb 2013 – 13 Mar 2014  (N=389)*

2013 2014

First wave Second wave

Live PoultryMarkets Close

Live PoultryMarkets Close

• Drastic drop in H7N9 cases after closure of live marketsCourtesy of Dr. Danielle Iuliano, Influenza Division

Closing the live bird markets

• HK 1997 H5N1: Human and avian cases fall to ~ zeroCourtesy of Dr. Rob Webster, St Jude Hospital.

(H5N1) Outbreak in Hong Kong, 1997The Role of LBMs

Close down the live bird market system• Only temporary solution

One clean day per month H9N2 fell to low levels, then increasedfailed

Additional clean daysfailed No overnight carry over ‐ daily all out

H5N1 and other subtypes eliminated

Lam TT et al. 2013 Nature 

Genesis of H7N9 in China

• Since 2013, multiple reassortments with related H9N2 viruses

HA

Internal genes

NA

H5 and H7 Diverged Extensively

HA subtypes evolved into two major groups; 1 and 2

S - S

HA1 HA2

S - S

HA2Host Protease

HA0

HA Cleavage Site

HA1

HA cleavage is required for

virus infectivity

Cleavage site

Human Arg Glu Thr Arg . Gly

Low Path AvianH7N9

Arg Glu Thr Arg. Gly

Highly pathogenic H5 and H7 viruses Arg Arg Arg Arg . Gly H5N1

Multiple basic amino acids

Low Pathogenicity of H7N9 is “Subject to Change Without Notice”

H7N9 is a “low path” virus that can become highly pathogenic with a few mutations at cleavage site• When that happens, it is expected to resemble H5N1

Low Pathogenicity of H7N9 has Major Implications for Detection and Control 

Detection• No H7N9 chicken die-offs as is the norm for H5N1• Human cases of H7N9 have been sentinels for virus detection in

poultry in China

Control• Consumer reaction to human H7N9 cases: buy pork!!

o Drop in retail price of chicken → economic loss to entire value chain o $16 B U.S. dollars loss in one year

Reference: http://www.caaa.cn/show/newsarticle.php?ID=329866]

Contact

Contact

Contact

Inoculated

Inoculated

Inoculated

Respiratory Droplet (RD)

Droplet Transmission of H7N9 and H5N1: Ferret Model

Human virus: 100% droplet transmission to contacts

H7N9 virus: ~30% 

H5N1 virus: 0%

Belser J et al 2013, Nature. Chen HL et al 2013; Richard M, et al. Nature. 2013, 501(7468):560‐3

Molecular Basis of Inefficient Droplet Transmission of H7N9

Courtesy of Doug Jordan, Influenza Division

HA Receptor Binding Preferences

Sialylated glycan ReceptorAvian-like Human-like

VirusHuman Minimal StrongH5N1 Strong MinimalH7N9 Strong Moderate

Location Human Lung Human Nasal/Trachea

JCFM Dortmans et al. Scientific Reports 3, Article number: 3058 doi:10.1038/srep03058

H7N9: “dual” receptor specificity, but predominantly avian• Q226L and G186V mutations in HA

Differences in the Ecology of A(H5N1) and A(H7N9)

H5N1 Kaplan 2013 #3929; H7 Pantin‐Jackwood et al 2014,  Ku et al. 2013  

H5N1 H7N9

Unlike H5N1, H7N9• Transmits more efficiently among gallinaceous birds than ducks• No transmission to mammalian species or wild migratory birds

Kilpatrick AM Proc Natl Acad Sci U S A. 2006 Dec 19;103(51):19368‐73. Epub 2006 Dec 7.

Spread of A(H5N1): 2003‐2005Purple circles= wild bird spread

• If H7N9 becomes transmissible in wild migratory birds, it will likely spread to many countries

A Reservoir of H5N1 and H7N9 In Siberia?

Wintering

Breeding

Frozen lakes in Siberia serve as virus reservoirs

Conclusions A(H5N1) vs. (H7N9)

Similarities:• Both viruses acquired “internal” genes from H9N2 • Neither established sustained circulation in swine or other

mammals• No reassortment with swine or human viruses• Share reservoirs in gallinaceous birds• Hypercytokinemia correlated with more severe outcomes

Conclusions A(H5N1) vs. (H7N9)

Differences:• H5N1 HA multibasic cleavage site – absent in H7N9

o Lethal for gallinaceous poultry, H7N9 is subclinicalo H5N1 die-offs serve as sentinels for human infectionso H7N9 human infections are indicators of virus in poultry

• H5N1 binds avian-like receptor preferentiallyo Targets lower respiratory tract of humans

• H7N9 dual avian-human receptor binding specificityo Target both upper and lower respiratory tract

• H7N9 is partly droplet transmissible in ferrets, H5N1 is not• H7N9 appears to be more transmissible to humans than H5N1

Thanks!

rdonis@cdc.gov