Background on Pandemic Influenza

Pandemic Influenza Working GroupJanuary 18, 2006

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

Avian Influenza

H5N1 is the strain causing recent deadly outbreaks in Asia

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

20th Century Influenza Pandemics

Year Strain Impact

1918-1919 H1N1 Killed 500,000 Americans and 20-50M worldwide

1957-1958 H2N2 Killed 70K Americans, 2M worldwide

1968-1969 H3N2 Killed 34,000 Americans, 1M worldwide

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)

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

WHO Epidemic Phases

Status Transmission Phase

Inter-pandemic phase Low risk of human cases 1

New virus in animals, no human cases

Higher risk of human cases 2

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

Pandemic Efficient and sustained human-to-human transmission

6

Bird Migration and H5N1

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

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

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

Comparison of Features

SARS “The Flu” Pandemic Influenza

Virus Coronavirus Influenza A or B Influenza A H5N1

Origin China Ubiquitous Asia, spread by migratory birds

Age All ages Elderly, very young

All ages*

Symptoms Flu symptoms, pneumonia

Fever, malaise, muscle pains

Flu symptoms, organ failure

Transmission Human to human Human to human Human to human

Incubation ? 10 days Short incubation 2-4 days

Management Supportive care Supportive care, anti-virals

Supportive care, anti-virals??

Mortality 10% < .01% 2.5 - 50%

Possible Interventions

• Preventive hygiene• Limiting movement• Vaccines• Anti-virals• Isolation• Quarantine

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

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

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?

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

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

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?