1918 Spanish Influenza. Avian Flu: The Risks of Pandemic. Avian Flu: The Risks of Pandemic Outbreak. The Influenza Epidemics of Great Britain

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1 Pediatric Challenges and Opportunities in the st Century - April, 6 Avian Flu: The Risks of Pandemic Outbreak Avian Flu: The Risks of Pandemic Robert G. Webster, PhD Division of Virology Department of Infectious Diseases St. Jude Children s s Research Hospital Memphis, TN Robert Webster, PhD Member, St. Jude Faculty Infectious Diseases St. Jude Children s s Research Hospital Negative sense RNA virus segmented genomes Each segment encodes a different protein Smallest RNAs encode proteins Epidemics Of: The Influenza Epidemics of Great Britain First epidemic in Britain Annuals of Influenza in Great Britain (8) 98 Spanish Influenza million persons killed Total sequence now known Taubenberger Closely related to classic HN swine influenza Avian source of all gene segments Brevig Mission 98 Spanish Influenza Letter carrier taken home by dog team. Nov - : 7 of 8 people in Brevig died. Children survived.

2 98 Spanish Influenza Reconstructed 98 Spanish Influenza Brevig Mission The Complete Sequence Lethal for mice and embryonated eggs Replicates in the absence of trypsin High growth in human bronchial epithelial cells Jeffery Taubenberger Johan Hultin Tumpey et al., Science, October Influenza A Virus Host Range H H H H H H6 H7 H8 H9 H H H H H H H6 The Ecology of Influenza Viruses That there are a limited number of host specific lineages of influenza viruses There is geographical separation into Eurasian and American lineages Laos China Spread of HN Influenza in Asia - Thailand Vietnam Cambodia Indonesia South Korea Japan s of millions of birds culled Human Cases: 9 Human Deaths: 9 Vietnam: deaths Thailand: deaths Cambodia: 6 deaths Indonesia: deaths China: deaths Turkey: deaths Iraq: deaths Azerbaijan: deaths Egypt: deaths

3 Genesis of HN Influenza In Asia 996 Goose/Guangdong//96 (HN) 997 Emergence of HN Bird Flu A reassortant Goose X Quail X Duck HN H9N H6N 6 of 8 infected persons died 997- Multiple genotypes - Pathogenic for aquatic birds Spread across Asia Wood Duck Bar-headed Goose Common Shel duck Ruddy Duck Puna Teal Duck Numbers Coscoroba Swan HN Influenza Outbreak Kowloon Park, Hong Kong Dead Sick Chiloe Wigeion Duck Ringed Teal Duck Rosybill Duck Greater Flamingo Red-crested Pochard December, January, Victoria Crowned Pigeon Hawaiian Goose Tufted Duck Bahama Pintail White-faced Whistling Duck Black-necked Swan Brazilian Duck The Spread of HN in Asia Poultry Market Surveillance Southern China - Shantou HN Influenza Viruses Isolated From Live Poultry Markets In Southern China -.9%.8%.%.% % Positive Isolation of HN Viruses From Live Poultry Markets in S. China Aug Sept Oct Nov Dec Jan Feb Mar Apr May Jun Aug SeptOct Nov Dec Jan Feb Mar Apr May Aug Sept Oct Nov Dec Jun Jan Feb Mar Apr May Jun Based on numbers (%) from August to June

4 Human HN in China Isolation of HN in Hong Kong 6 Migrating Bird Routes Spread of HN Influenza Viruses by Migratory Birds RUSSIA Qinghai Lake L. QINGHAI CHINA L. POYANG May Outbreak INDIA of H.P. HN Jan., March H.P. HN VIETNAM INDONESIA Pathogenicity of HN Viruses for Ducks and Geese Virus Date of Isolation Lethality for: Ducks Geese Spread of HN Mallard duck/jx/ Bar-headed goose/qh/ January/ May/ /9 /9 6/6 6/6

5 The Role of Ducks Domestic Migratory The Trojan Horses Rapid Evolution of HN in Ducks Long term shedding despite antibody Retain HPAI characteristics Antigenic drift Increased environmental stability HN Stability in Fecal Samples Wet feces -- 7ºC HN Thermal Stability Virus titers-eid /ml A/ck/AP/ A/Viet/6/ A/ck/Viet// A/ck/AA/8/ A/HK/6/ HN in cooling coils remained viable for days Days post-infection How Pathogenic Is This Virus? A/Vietnam// (HN) Kills chickens in less than one day Kills ducks in - days High risk of death in humans Diarrhea Respiratory symptoms High Risk of death in ferrets Respiratory symptoms Diarrhea Hind Leg paralysis Human HN Cases in Vietnam Multiple organ dysfunction More virus in the lower respiratory tract Diarrhea in majority of patients Virus isolation /7 RNA /7 Detection of RNA in human serum /7 Median virus load 6 days for HN, days for HN Menno de Jong, Ho Chi Minh City, Vietnam, Oxford University Clinical Research Unit

6 Human HN Influenza in Vietnam High levels of cytokines (IP, IL6, IL8, INTγ) Receptor Distribution in Humans IP and IL8 correlates with virus load Menno de Jong, Ho Chi Minh City, Vietnam, Oxford University Clinical Research Unit Shinya et al Nature 6 Does HN/ Replicate and Transmit in Pigs? Expanding Host Range for Influenza Infected Contact HN in Thailand Vietnam// lll Ck/Vietnam/C-8/ lll DK/TH/DAT/ GS/TH/G7CS/ lll lll Experimental transmission in domestic cats Choi et al Kuiken et al, Science Control Strategies: HN Poultry Prevention and Control ERADICTION Culling Quarantine Biosecurity 6

7 Changes in poultry The Hong marketing Kong Model in Hong Kong 998 Control Strategies: HN Poultry Vietnam: The ongoing experiment. One clean day per month Vaccination Eradication of Virus Eradication of Symptoms Residual Virus Inactivated vaccine used to ring vaccinate HN infected farms Additional clean day per month Inactivated vaccine used on all farms increased biosecurity sentinal unvaccinated poultry No HN Control Strategies: HN Poultry China: Changing strategies? (Indonesia) Vaccination Disease control - Poultry Continued low level virus circulation no disease New vaccine strategies? (Biosecurity??) Antivirals Sensitivity of Human HN Influenza Viruses to Amantadine Reduction of A/Vietnam// (HN) Virus Replication after Prophylactic Treatment of Mice with Oseltamivir Year 997 Virus A/HK/6/97 A/HK// A/Vietnam// A/Vietnam/9/ Sensitivity Yes No No No Amino acid change on M protein Ser Ser Asn Ser Asn Ser Asn Virus titer (logeid/ml 6. Control Oseltamivir dosage (mg/kg/day) Lungs Brain Spleen 7

8 Survival of Mice After A/Vietnam// (HN) Infection Vaccines A/Vietnam// (HN) Studies on r.g. HN Vaccines in Ferrets r.g. Hong Kong// (HN) Complete protection from homologous challenge Cross protection from challenge with A/Vietnam// Virus shedding reduced Weight loss No virus in brain No disease signs Vaccine Reverse Genetics Hoffmann et al. Poultry Vaccines Good Ones Provide protection despite antigenic drift Can reduce virus load below level of transmission Bad Ones Protect against disease signs Birds shed transmissible levels of virus Treatment Vaccine-x Vaccine -- boost Control Efficacy of HN Vaccine in Khaki Campbell Ducks Disease/Death /Total // // /8/ Outcome Virus Shedding / / / Transmission to Nonvaccinated Contacts / / Thaweesak Songserm-SJCRH SJCRH Vaccine: Chicken/Vietnam/C8/ (H); dk/germany//7 (N); PR/8/ internal genes Dose:.µgm HA antigen Schedule: Vaccinate day, boost day, challenge 8 days Challenge: DK/Thailand/DAT/ (HN) Ducks: weeks old at day 8

9 Humans The Current Situation New human cases in: Indonesia, Turkey, Azerbaijan, Egypt, Iraq, Cambodia, China Antigenically and genetically different viruses in Indonesia, China, Europe ( clades) Duck Blood Salad Poultry Wild birds HN causing asymptomatic infection in ducks but killing swans Highly pathogenic HN is endemic and spreading globally Leuad Peng Pet The Consequence of a HN Influenza Pandemic Will HN Acquire Transmissibility? Collapse of the global economy Exhaustion of all materials made off shore!!! Vaccines Antivirals Masks Needles Much more!! HAPPY NEW YEAR OF THE DOG Support: AI97, NIAID, ALSAC St. Jude Children s s Research Hospital Richard Webby, Elena Govorkova, Erich Hoffmann, Diane Hulse, Katharine Sturm-Ramirez, Aleksandr Lipatov and The Influenza Support Staff Hong Kong University Drs. Yi Guan, Malik Peiris, Leo Poon, K.Y. Yuen, Honglin Chen Influenza Research Group Indonesian Ministry of Research & Technology Dr. Amin Soebandrio Vietnamese Ministry of Agriculture and Rural Health Development Dr.. TD Nguyen Thailand Bureau of Disease Control and Veterinary Services Dr. Chantanee Buranathai Kasetsart University, Kamphaengsaen Campus Dr. Thaweesak Songserm 9

10 ?? Questions and Answers Some questions were asked without a microphone nearby and may be difficult to hear, but they are presented here. Questions and Answers Some questions were asked without a microphone nearby and may be difficult to hear, but they are presented here.? End Questions and Answers Some questions were asked without a microphone nearby and may be difficult to hear, but they are presented here. Robert Webster, PhD More medical education materials are available at: You may print and download content for personal educational use only. All material is copyrighted by the author of the content or St. Jude Children s Research Hospital. See legal terms and conditions at