WORKING GROUP 1Influenza Virulence and

Antigenic Change

Chairperson – Robert WebsterBriefer – Peter Palese

Rapporteur – Robert Lamb

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

H3N2

H1N1 H1N1

H2N2

19001889

INFLUENZA A VIRUS SUBTYPES IN THEHUMAN POPULATION

YEAR

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

H3

H1 H1

H2

H1?

19001889

H3?

?

INFLUENZA A VIRUS SUBTYPES IN THEHUMAN POPULATION

YEAR

0

1000

1500

2000

<1 1-4 5-14 15-24 25-34 35-44 45-54 55-64 65-74 75-84 >85

Age Divisions

Sp

ecif

ic D

eath

Rat

e

500

1918 influenza mortality by age in the U.S.

0

1000

1500

2000

<1 1-4 5-14 15-24 25-34 35-44 45-54 55-64 65-74 75-84 >85

Age Divisions

Sp

ecif

ic D

eath

Rat

e

500

19181918 if no immunity in adults

Potential issues to consider:

What studies are needed to define the genetic loci for pathogenicity in avian and human influenza virus strains?

Identification of relevant strains

Better and different animal models

Use of reverse genetics to study strains/mutants

Transmission studies

2) What studies are needed to affirm the hypothesis that incremental acquisition of genetic changes can lead to influenza pandemics as compared with the sudden emergence of previous pandemics?

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

H3N2

H1N1 H1N1

H2N2

19001889

INFLUENZA A VIRUS SUBTYPES IN THEHUMAN POPULATION

YEAR

HYPOTHESES

ONLY REASSORTANTS BETWEEN HUMAN AND ANIMAL (AVIAN) STRAINS CAN “MAKE IT”

GRADUAL/INCREMENTAL CHANGES IN AN ANIMAL STRAIN CAN RESULT IN A NEW PANDEMIC VIRUS

3) What studies are needed to track the rate of antigenic change in avian and human influenza virus strains and to predict changes that may occur?

Better immunological markers are needed

Sequencing of strains is appropriate

Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6263-8.

–  

Hemagglutinin sequence clusters and the antigenic evolution of influenza A virus.

–Plotkin JB, Dushoff J, Levin SA.

Department of Ecology and Evolutionary Biology, Princeton University, Princeton, NJ 08540, USA. plotkin@ias.edu

THE NEW ENGLAND JOURNAL OF MEDICINE Volume 352:686-691 February 17, 2005

Fatal Avian Influenza A (H5N1) in a Child Presenting with Diarrhea Followed by Coma

Menno D. de Jong, M.D., Ph.D., Bach Van Cam, M.D., Phan Tu Qui, M.D., Vo Minh Hien, M.D., Tran Tan Thanh, M.Sc., Nguyen Bach Hue, M.D., Marcel Beld, Ph.D., Le Thi Phuong, M.D., Truong Huu Khanh, M.D., Nguyen Van Vinh Chau, M.D., Tran Tinh Hien, M.D., Do Quang Ha, M.D., Ph.D., and Jeremy Farrar, F.R.C.P., D.Phil.

4) What studies are needed to determine whether pandemic risk can be predicted by virulence factors and/or antigenic characteristics?

Acknowledgements

Armed Forces Institute of Pathology

Jeffery K. Taubenberger Ian Wilson

Adolfo Garcia-Sastre, PI Christopher F. Basler

Peter Palese

CDC, Atlanta Terrence M. Tumpey Michael Katze

Mount Sinai School of Medicine

David E. Swayne

Southeast Poultry Research Laboratory

TSRI

University of Washington

FDA-approved Antiviral Drugs against Influenza

Generic/(Trade Name) Route

• Amantadine ORAL

• Rimantadine ORAL

• Oseltamivir/(Tamiflu) ORAL

• Zanamivir/(Relenza) Inhalation

Oseltamivir/Tamiflu

0

20

40

60

80

100

0 5 10

Days Post-Infection

Oselt. only

1918 HA/ 1918 NA &Oselt.

1918 HA/ 1918 NA &PBS

Oseltamivir Protects Mice from a Lethal Challenge with 1918 HA/1918 NA Virus

Tumpey et al. PNAS, 99,13849,2002

Copyright ©2004 by the National Academy of Sciences

Tumpey, Terrence M. et al. (2004) Proc. Natl. Acad. Sci. USA 101, 3166-3171

H1N1-INACTIVATED VACCINE PROTECTS AGAINST LETHAL CHALLENGE WITH 1918 HA/NA INFLUENZA VIRUS

AVIAN INFLUENZA THE NEXT PANDEMIC?

MAYBE NOT

Table 7. Serological Evidence for Human Exposure to Avian Influenza Viruses in the Hypothetical Influenza Epicenter and Occurrence of these

Viruses in Domestic Ducks There

Percent Seropositivity of Human Sera From:

HA Subtype Pearl River Delta

(n = 400)*

Jiangsu Province (n = 300)

Taichung Taiwan (n = 150)

Urban Hong Kong

(n = 100)

Percent Isolation

Rate From Domestic

Ducks

H1 NT 19 NT NT <1

H2 NT 58 NT NT 1

H3 47 46 48 45 25

H4 11 4 10 2 29

H5 2 7 2 0 4

H6 12 1 13 1 22

H7 5 38 4 0 <1

K.F. Shortridge. Seminars in Respiratory Infections, 7, 11, 1992

Table 7. Serological Evidence for Human Exposure to Avian Influenza Viruses in the Hypothetical Influenza Epicenter and Occurrence of these

Viruses in Domestic Ducks There

Percent Seropositivity of Human Sera From:

HA Subtype Pearl River Delta

(n = 400)*

Jiangsu Province (n = 300)

Taichung Taiwan (n = 150)

Urban Hong Kong

(n = 100)

Percent Isolation

Rate From Domestic

Ducks

H1 NT 19 NT NT <1

H2 NT 58 NT NT 1

H3 47 46 48 45 25

H4 11 4 10 2 29

H5 2 7 2 0 4H6 12 1 13 1 22

H7 5 38 4 0 <1

K.F. Shortridge. Seminars in Respiratory Infections, 7, 11, 1992

• Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi. 1999 Jun 30;13(2):105-8.Related Articles, –

[Discovery of men infected by avian influenza A (H9N2) virus][Article in Chinese]

Guo Y, Li J, Cheng X.

China National Influenza Center, Institute of Virology, Chinese Academy of Preventive Medicine, Beijing 100052.

OBJECTIVE: To understand whether the avian influenza A(H9N2) virus can infect men or not. METHODS: Seroepidemiological surveys for avian (H9N2) virus in human, chickens and pigs were conducted. The specimens for viral isolation were taken from throat of patients with influenza like disease, as well as from chickens, then the specimens were inoculated into embryonated chicken eggs. Afterward, the idsolates were identified with HI and NI tests. Meanwhile, the patients who would be studied individually were found to carry H9N2 virus. RESULTS: Approximately 19% of human had antibody to H9N2 virus with HI titers > or = 20, 5 strains of influenza A (H9N2) virus were isolated from the patients. CONCLUSION: Avian influenza A(H9N2) virus can infect men.

Nature Medicine  10, S82 - S87 (2004)

Influenza: old and new threats

Peter Palese

Department of Microbiology, Mount Sinai School of Medicine, New York,

New York 10029, USA.

IT’S TOUGH TO MAKE PREDICTIONS,

ESPECIALLY ABOUT THE FUTURE

Yogi Berra