1. Background on Pandemic Influenza Pandemic Influenza Working Group January 18, 2006

2. The Influenza Virus Three types of influenza (A, B, and C) Only A – among which is avian flu – causes severe illness in humans Characterized by so-called H and N proteins, which line surface of the virus There are 16 known H proteins and 9 known N proteins, creating 144 theoretical subtypes Most prevalent human flu viruses are H1N1 and H3N2, both transferable from person to person

3. Avian Influenza H5N1 is the strain causing recent deadly outbreaks in Asia

4. Influenza Virus Mutations Flu virus has eight genes that mutate rapidly, creating strains that move rapidly through susceptible populations via: Replication errors: Slight copying errors resulting in “antigenic drift” Reassortment: Exchange of genetic material by two simultaneous viruses, resulting in “antigenic shifts,” the cause of last two global pandemics Recombination: Gene swaps between human and avian flu viruses, resulting in entirely new gene

5. 20 th Century Influenza Pandemics YearStrainImpact 1918-1919H1N1Killed 500,000 Americans and 20- 50M worldwide 1957-1958H2N2Killed 70K Americans, 2M worldwide 1968-1969H3N2Killed 34,000 Americans, 1M worldwide

6. Incidence of H5N1 According to WHO: 148 cases through January 14, 2006, including 79 fatalities (53% case fatality rate), including recent Turkish cases Vietnam (93), Thailand (22), Indonesia (17)

7. Epidemiology Natural reservoirs: Wild aquatic birds Virus replicates in intestinal tracts of aquatic birds, sheds fecal/oral, spreads to turkeys and ducks, then chickens Aquatic birds probably have no symptoms, but rapid evolution occurs in new host Mammalian infection is highly associated with co-mingling of poultry and humans Pigs and domesticated poultry are intermediate hosts Thus far 1 documented human-to-human transmission, others debatable

8. WHO Epidemic Phases StatusTransmissionPhase Inter-pandemic phaseLow risk of human cases1 New virus in animals, no human cases Higher risk of human cases2 Pandemic alert New virus causing human cases No or very limited human-to-human transmission 3 Evidence of increases human-to- human transmission 4 Evidence of significant human-to- human transmission 5 PandemicEfficient and sustained human-to- human transmission 6

9. Bird Migration and H5N1

10. Avian Flu Is Not the Same as Pandemic Flu Birds have probably had influenza viruses for centuries Vast majority of avian influenza viruses do not affect humans Pandemic potential comes from an influenza virus: –Acquiring the ability to infect humans –Recombining or otherwise mutating into strains capable of person-to-person transmission –Developing the “efficiency” to cause serious disease, particularly into an immunologically “naïve” population

11. Pandemic Flu Requires Efficient Human to Human Transmission Transmission of human influenza: inhalation of aerosols and droplets, direct contact, and contaminated objects Incubation period: –Most cases occur 2-4 days; recent reports range up to 8 days –Case-to-case intervals in household clusters have generally been 2 to 5 days, but the upper limit has been 8 to 17 days Affects all ages, in contrast to conventional influenza, which places “immuno-incompetent” populations, elderly and very young at increased risk Source: NEJM, Avian Influenza A (H5N1) Infection in Humans, Sept 29, 2005

12. Symptoms of Pandemic Influenza There is a body of evidence suggesting the human immune system may have deleterious effects –Individuals with robust immune systems may develop more serious disease –Organ involvement reminiscent of other human diseases exacerbated by over-aggressive immunity Symptoms: –High fever –Diarrhea –Pneumonia –Liver and kidney impairment –Death

13. Comparison of Features SARS“The Flu”Pandemic Influenza VirusCoronavirusInfluenza A or BInfluenza A H5N1 OriginChinaUbiquitousAsia, spread by migratory birds AgeAll agesElderly, very young All ages* SymptomsFlu symptoms, pneumonia Fever, malaise, muscle pains Flu symptoms, organ failure TransmissionHuman to human Incubation? 10 daysShort incubation2-4 days ManagementSupportive careSupportive care, anti-virals Supportive care, anti-virals?? Mortality10%<.01%2.5 - 50%

14. Possible Interventions Preventive hygiene Limiting movement Vaccines Anti-virals Isolation Quarantine

15. Vaccine Issues Customary development technique using chicken eggs are inefficient; virus can be lethal to eggs Cell-based and DNA-based vaccines being explored Even if vaccine were available: –Difficult to target the correct strain –Needed production would be problematic –Timeliness would be critical issue –Distribution priorities and channels uncertain

16. Anti-Viral Medications Benefit of anti-virals: –Useful in treatment and prevention Issues: –Resistance to amantidine, least expensive and most widely available drug –? Emerging resistance to Tamiflu –Use of Relenza limited to specific populations –No guarantee that eventual pandemic strain would retain its sensitivity to existing drugs

17. Isolation and Quarantine Isolation: Separation of infected individuals Quarantine: Separation of individuals known/suspected to have been exposed Obstacles: –Given short incubation, shedding of virus before illness, and absence of definitive diagnostic tests, difficult to take appropriate steps in timely fashion –How would these measures be enforced?

18. Planning Considerations Influenza pandemic would likely occur in waves, lasting 3-4 months or longer Significant impact on workforce due to illness and fear of infection Proper hygiene and anti-viral environmental cleaning Need for food, utilities, and essential services would continue Delivery of critical goods and services limited by illness, fear of exposure and travel limitations

19. Overall Implications Death and disease: Conservative CDC model predicts 66M cases in US, 2.4M hospitalizations, >500K deaths Surge impacts on healthcare system Threat to the social fabric Massive disruptions of government services, interstate commerce, transportation, education, recreation Staggering economic impacts

20. Significant Uncertainty Remains How quickly, if at all, will the virus develop the ability to “jump” from person to person? In the event of a pandemic, what will be the mortality rate? Will an effective vaccine be developed, manufactured, and distributed in a timely fashion? Will the viral strain causing a pandemic be susceptible to existing drugs?