PANDEMIC INFLUENZA VIRUSES:

PAST AND FUTUREPETER PALESE

DEPARTMENT OF MICROBIOLOGY MOUNT SINAI SCHOOL OF MEDICINE,

NEW YORK

2010 DOE ISM Champions Workshop , Sept. 15, 2010

YoshiKawaoka

TakeshiNoda

YoshiKawaoka

TakeshiNoda

H1N1

THE BURDEN OF SEASONAL INFLUENZA

• 250,000 to 500,000 deaths globally/year

• More than 200,000 hospitalizations/year in US; deaths vary, more than 3,000 in 1986-7 and more than 48,000 in 2003-4

• $37.5 billion on economic costs/year in US related to influenza and pneumonia

• Ever-present threat of pandemic influenza

Sources: CDC, WHO, Am. Lung Assoc.

INFLUENZA VIRUSES CIRCULATINGIN THE HUMAN POPULATION

1918 1940 1960 1980 20001918 1940 1960 1980 20001918 1940 1960 1980 2000

H3N2

H1N1 H1N1

H2N2

Year

A

A

A ?H1N1

INFLUENZA VIRUSES CIRCULATINGIN THE HUMAN POPULATION

1918 1940 1960 1980 20001918 1940 1960 1980 20001918 1940 1960 1980 2000

H3N2

H1N1 H1N1

H2N2

Year

A

A

A ?H1N1

B

35

45

55

65

75

85

1900 1920 1940 1960 1980 2000

Alte

r

Jahr

LIFE EXPECTANCY IN THE UNITED STATES 1900-2001: BOTH SEXES

YEAR

AG

E

NIH PROGRAM PROJECT GRANT

The Scripps Research Institute

Ian Wilson Jim Paulson

Adolfo Garcia-SastreChris BaslerPeter Palese

CDC, Atlanta Terrence M. Tumpey

Mount Sinai School of Medicine

University of WashingtonMichael Katze

Viral RNA expression plasmids Protein expression plasmids

PB2PB1PANP

PB2PB1PAHANPNAMNS

Transfection

Cells

Recombinant influenza virus

REVERSE GENETICS

Tumpey et al., Science, 310, 77, 2005THE LANCET PAPER OF THE YEAR 2005

Texas/36/91

>6

Tx/91: PB2, PB1, PA, NP, M, NS1918: HA, NA

4.75

Virulence of the 1918 virus in mice: MLD50 log pfu

1918 “Spanish” flu

3.3

Texas/36/91

>7

Tx/91: PB2, PB1, PA, NP, M, NS1918: HA, NA

Virulence of the 1918 virus in chick embryos: ELD50 log pfu

1918 “Spanish” flu

1.5

>7

Single gene reassortants identify a critical role for PB1, HA and NA in the high virulence of the 1918 pandemic influenza virus

Claudia Pappas, Patricia V. Aguilar, Christopher F. Basler, Alicia Solórzano, Hui Zeng, Lucy A. Perrone, Peter Palese, Adolfo García-Sastre, Jacqueline M. Katz, Terrence M. Tumpey

PNAS 105, 3064, 2008

Virulence of 7:1 Reassortants (1918:Texas/91)

Virus stock

LD50

1918 3.25

1918:Tx PA

3.5

1918:Tx PB1

5.5

1918:Tx PB2

3.75

1918:Tx HA

> 6

1918:Tx NP

3.5

1918:Tx NA

5.5

1918:Tx M 3.5

1918:Tx NS

3.25

Tx/91 > 6

Pandemic Influenza: What’s Next?

AVIAN INFLUENZA IS A THREAT

Confirmed Human H5N1 Cases Updated August 31, 2010

Cases DeathsAzerbaijan 8 5Bangladesh 1 0Cambodia 10 8China 39 26Djibouti 1 0Egypt 112 36Indonesia 168 139Iraq 3 2Lao 2 2Myanmar 1 0Nigeria 1 1Pakistan 3 1Thailand 25 17Turkey 12 4Viet Nam 119 59

Total 505 300 WHO

INFLUENZA VIRUSES CIRCULATINGIN THE HUMAN POPULATION

1918 1940 1960 1980 20001918 1940 1960 1980 20001918 1940 1960 1980 2000

H3N2

H1N1 H1N1

H2N2

YEAR

A

B

A

A ?H1N1

Swine origin H1N1 to date

• First confirmed cases reported to WHO in late April 2009

• Global spread prompted WHO to declare pandemic 11 June 2009

• As of March 2010 the CDC estimates up to 80 million cases, as many as 362,000 hospitalizations and 14,460 H1N1-related deaths in the US

• 90% of hospitalizations and 88% of deaths occurred in individuals younger than 65 years of age

• On August 10, 2010, the WHO declares an end to the 2009 H1N1 pandemic

ORIGIN OF GENES OF THE 2009 SWINE H1N1 INFLUENZA VIRUS

Amino Acid Differences (%) in influenza A Virus Hemagglutinins (HA1)

A/Brisbane/59/2007SEASONAL

A/South Carolina/1918

A/California/04/2009PANDEMIC

19%29%A/USSR/90/1977

A/New Jersey/1976.

..

THE 2009 SWINE H1N1 INFLUENZA VIRUS:

• TRANSMITS WELL• HAS H1 (HEMAGGLUTININ) AND N1

(NEURAMINIDASE) SURFACE GLYCOPROTEINS SUGGESTING THAT THE HUMAN POPULATION HAS PARTIAL HERD IMMUNITY.

• DOES NOT EXPRESS THE VIRULENCE GENE, PB1-F2.

• IS SENSITIVE TO NEURAMINIDASE INHIBITORS.

The Guinea Pig as a Transmission Model for Influenza

• Anice Lowen• Samira Mubareka• Terry Tumpey (CDC)• Adolfo García-Sastre• Peter Palese

Lamb, F.H., and Brannin, E.B. (1919). The epidemic respiratory infection at Camp Cody. JAMA, April 12, 1056.

Transmission cage

Environmental chamber

EXPOSED INFECTED

AIR FLOW

EXPOSED INFECTED

EXPOSED INFECTED

EXPOSED INFECTED

Transmission of A/California/04/2009 virus (S-OIV) by the aerosol route

ExposedInoculated

Nas

al w

ash

titer

(log

10PF

U/m

l)

Day post-inoculation

012345678

0 2 4 6 8

4/4 exposed guinea pigs were infected

Transmission of conventional swine and human influenza viruses

Day post-inoculation

012345678

0 2 4 6 8Day post-inoculation

012345678

0 2 4 6 8

Nas

al w

ash

titer

(log

10PF

U/m

l)

A/Swine/Texas/1998 A/Panama/2007/99

1/4 infected 4/4 infected

Aerosol transmission of influenza virus from guinea pig to guinea pig is most

efficient at low temperature%

Tra

nsm

issi

on

% Relative humidity

100

00 100

5°C

30°C

ANICE LOWEN

TRANSMISSION SUMMARY

• THE GUINEA PIG TRANSMISSION MODEL WAS DEVELOPED

• THE H5N1 AVIAN INFLUENZA VIRUS DOES NOT TRANSMIT IN THIS SYSTEM

• AEROSOL TRANSMISSION OF INFLUENZA VIRUSES IS MOST EFFECTIVE AT LOW TEMPERATURE AND LOW RELATIVE HUMIDITY – PARTIAL EXPLANATION FOR SEASONALITY

VACCINES

KILLED (INACTIVATED)

LIVE (ATTENUATED)

TRIVALENT INFLUENZA VIRUS VACCINE

2009-2010

A/BRISBANE/10/2007 (H3N2)A/BRISBANE/59/2007 (H1N1)B/BRISBANE/60/2008

MONOVALENT INFLUENZA VIRUS VACCINE

(PANDEMIC H1N1, NOVEL H1N1, SWINE-ORIGIN)

2009/2010

A/CALIFORNIA/7/2009 (H1N1)

Source: CDC ILI and Vaccine Distribution Data

Percentage of Visits for ILI and H1N1 Vaccine Distribution, Sep 2009 – May 2010

TRIVALENT INFLUENZA VIRUS VACCINE

2010-2011

A/CALIFORNIA/7/2009 (H1N1)A/PERTH/16/2009 (H3N2)B/BRISBANE/60/2008

ANTIVIRAL RESISTANCE OF INFLUENZA VIRUS SUBTYPES

Centers for Disease Control and Prevention

NA INHIBITORSM2 INHIBITORS(Adamantanes) (Oseltamivir)

SEASONALB

SEASONALA/H3N2

SEASONALA/H1N1

PANDEMICA/H1N1

2007

N/A 0% 0%

0%0%

0.7%100%

1.3%0.5%

100%92%

25% 0%

100% 99.8%

‘08 ‘09 ‘10 2007 ‘08 ‘09 ‘10

� PANDEMIC INFLUENZA VIRUSES: �PAST AND FUTURESlide Number 2Slide Number 3THE BURDEN OF SEASONAL INFLUENZASlide Number 5Slide Number 6Slide Number 7Slide Number 8Slide Number 9Slide Number 10Slide Number 11Slide Number 12Slide Number 13Slide Number 14Pandemic Influenza: What’s Next?Slide Number 16Confirmed Human H5N1 Cases�Updated August 31, 2010Slide Number 18Swine origin H1N1 to dateSlide Number 20Slide Number 21Slide Number 22THE 2009 SWINE H1N1 INFLUENZA VIRUS:The Guinea Pig as a Transmission Model for InfluenzaSlide Number 25Slide Number 26Transmission of A/California/04/2009 virus (S-OIV) by the aerosol routeTransmission of conventional swine and human influenza virusesSlide Number 29TRANSMISSION SUMMARY Slide Number 31Slide Number 32Slide Number 33Slide Number 34Slide Number 35Slide Number 36

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