1. WORKING GROUP 1 Influenza Virulence and Antigenic Change Chairperson – Robert Webster Briefer – Peter Palese Rapporteur – Robert Lamb

2. 1918 194019601980 2000 1918 194019601980 2000 1918 194019601980 2000 1918 194019601980 2000 H3N2 H1N1 H2N2 19001889 INFLUENZA A VIRUS SUBTYPES IN THE HUMAN POPULATION YEAR

3. 1918 194019601980 2000 1918 194019601980 2000 1918 194019601980 2000 1918 194019601980 2000 H3 H1 H2 H1? 19001889 H3? ? INFLUENZA A VIRUS SUBTYPES IN THE HUMAN POPULATION YEAR

4. 0 1000 1500 2000 <11-4 5-14 15-24 25-34 35-44 45-54 55-64 65-74 75-84 >85 Age Divisions Specific Death Rate 500 1918 influenza mortality by age in the U.S.

5. 0 1000 1500 2000 <11-4 5-14 15-24 25-34 35-44 45-54 55-64 65-74 75-84 >85 Age Divisions Specific Death Rate 500 1918 1918 if no immunity in adults

6. 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

7. 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?

8. 1918 194019601980 2000 1918 194019601980 2000 1918 194019601980 2000 1918 194019601980 2000 H3N2 H1N1 H2N2 19001889 INFLUENZA A VIRUS SUBTYPES IN THE HUMAN POPULATION YEAR

9. 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

10. 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

11. 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

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

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

14. 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

15. FDA-approved Antiviral Drugs against Influenza Generic/(Trade Name) Route Amantadine ORAL Rimantadine ORAL Oseltamivir/(Tamiflu) ORAL Zanamivir/(Relenza) Inhalation

16. Oseltamivir/Tamiflu

17. Oseltamivir Protects Mice from a Lethal Challenge with 1918 HA/1918 NA Virus Tumpey et al. PNAS, 99,13849,2002

18. 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

19. AVIAN INFLUENZA THE NEXT PANDEMIC? MAYBE NOT

20. 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 SubtypePearl River Delta (n = 400)* Jiangsu Province (n = 300) Taichung Taiwan (n = 150) Urban Hong Kong (n = 100) Percent Isolation Rate From Domestic Ducks H1NT19NT <1 H2NT58NT 1 H34746484525 H411410229 H527204 H612113122 H753840<1 K.F. Shortridge. Seminars in Respiratory Infections, 7, 11, 1992

21. 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 SubtypePearl River Delta (n = 400)* Jiangsu Province (n = 300) Taichung Taiwan (n = 150) Urban Hong Kong (n = 100) Percent Isolation Rate From Domestic Ducks H1NT19NT <1 H2NT58NT 1 H34746484525 H411410229 H527204 H612113122 H753840<1 K.F. Shortridge. Seminars in Respiratory Infections, 7, 11, 1992

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

23. 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.

24. IT’S TOUGH TO MAKE PREDICTIONS, ESPECIALLY ABOUT THE FUTURE Yogi Berra