Pandemic Influenza; A Harbinger of Things to Come

Michael T Osterholm PhD, MPHDirector, Center for Infectious Disease

Research and PolicyAssociate Director, DHS National Center for

Food Protection and Defenseand

Professor, School of Public HealthUniversity of Minnesota

• 16 different hemagglutinin antigens (HA) and nine different neuraminidase (NA) antigens

• Human disease historically been caused by three subtypes of HA (H1, H2, H3) and two subtypes of NA (N1 and N2)

• All known subtypes of influenza A can be found in birds, but only subtypes H5 and H7 have caused severe outbreaks of disease in birds

Type A Influenza

Influenza Virus Change and Pandemic Potential

• Reassortment

• Recombination: point mutations

Influenza Virus Change and Pandemic Potential

• Reassortment

• Recombination: point mutations

1968 2004

People 790 million 1.3 billion

Pigs 5.2 million 508 million

Poultry 12.3 million 13 billion

People, Pigs and Poultry in China

Understanding Pandemic Influenza

• Pandemic – An epidemic that becomes very widespread and affects a whole region, a continent or the world.

• Definition of pandemic influenza “somewhat fuzzy”• Influenza pandemics;

– at least 10 pandemics recorded in last 300 years– 1918-1920; 50,000,000-100,000,000 deaths worldwide– 1830-1832 was similarly severe in smaller population

Understanding Pandemic Influenza

• Pandemics occur when a novel influenza strain emerges that has the following features:– readily transmitted between humans– genetically unique (i.e., lack of preexisting immunity in

the human population– increased virulence

• Pandemics have differed in terms of population-specific mortality rates and can not be characterized by a “single risk predictive model”

Comparison of Mortality Impact in the Three Influenza Pandemics of the 20th

Century in the United States

Antigenic shift (pandemic event

Antigenic shift

(Pandemic event)

Number of Excess Deaths in the

pandemic season (All-cause deaths)

Total Excess Mortality rate per

100,000 population (crude)

(All-cause deaths)

1918-19 A(H1N1) All novel? ~500,000 530

1957-58 A(H2N2) H + N ~ 60,000 40

1968-69 A(H3N2) H only ~ 40,000 18

Simonsen et al

• 1918-1919 (Spanish flu)

– H1N1 strain

– 200 million to 1 billion people were infected; more than 50-100 million died

– killed a disproportionate number of healthy young adults (W curve)

• A summary of 13 studies in 1918-19 involving pregnant women demonstrated that the case-fatality rate ranged from 23 to 71%

Pandemic Influenza

Understanding Pandemic Influenza• Recent studies in mice using genetically

engineered influenza strains similar to the 1918 H1N1 pandemic strain suggest that macrophage activities with high levels of cytokine production maybe a factor in the lung and other organ damage (cytokine storm). Kobasa et al; Nature 2004;431:703

• The clinical picture and epidemiology, as well as current studies of H5N1 cases in SE Asia suggest a similar “cytokine storm” phenomena. Peiris et al; Lancet 2004;363:617

Projected Number of Deaths Due to Future Pandemic Influenza Based on the

1918-1920 Pandemic

Area No. Deaths

Twin Cities SMA 18,538

Minnesota 30,498

United States 1,763,664

Worldwide 30,000,000 - 384,000,000

CIDRAP, 8/2005

17 Human Cases12 Deaths

94 Human Cases42 Deaths

4 Human Cases 4 Deaths

4 Human case 3 Deaths

Influenza Pandemic Preparedness

• Prevention– vaccine and antivirals

• Treatment– health-care delivery system

• “Collateral damage response”– global just-in-time economy

Prevention

• Vaccination

• Antiviral therapy and prophylaxis

Vaccination• Current “standard” vaccine reflects 1950’s

technology– grown in chicken eggs– takes 6 months or more to produce

– use of “reverse genetics” to develop prototype vaccine virus

• Recent approval of live, attenuated vaccine

• Need an immediate and comprehensive international program to develop a cell culture system for vaccine production with surge capacity

Influenza Vaccine Crisis• Current annual international capacity for

influenza vaccine production using egg culture is approximately 300 million trivalent doses (900 million monovalent)

• Almost all of the world’s influenza vaccine is produced in nine countries (12% of the world’s population)

• Production capacity will NOT increase significantly in the next several years

• New and more timely methods for production desperately needed

Influenza Antiviral Drugs Approved for Human Use

Viral M2 Protein Inhibitors• amantadine• rimantadine

Selective Neuraminidase Inhibitors

• oseltamivir phosphate• zanamivir

Treatment and Corpse Management

• Facilities and staffing

• Worker and patient protection

• Medical devices and therapy

• Ethical issues

• Use of “recovered” volunteers

• Corpse management

Collateral Damage Response

• Implications of the global just-in-time economy

– other pharmaceutical products– food– equipment parts

• International security

What Do We Do?

• Pray, plan and practice (In that order)

• Not a matter of if, just when and where

• Lack of international political will and support

• At minimum, assume we will virtually no vaccine for the first 6-8 months and then supplies will remain limited

• The 1918-20 experience provides many important lessons