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. [email protected]
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
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
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.
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