1. Pandemic Influenza; A Harbinger of Things to Come Michael T Osterholm PhD, MPH Director, Center for Infectious Disease Research and Policy Associate Director, DHS National Center for Food Protection and Defense and Professor, School of Public Health University of Minnesota

3. 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

4. Influenza Virus Change and Pandemic Potential Reassortment Recombination: point mutations

6. Influenza Virus Change and Pandemic Potential Reassortment Recombination: point mutations

7. 1968 2004 People 790 million 1.3 billion Pigs 5.2 million508 million Poultry 12.3 million 13 billion People, Pigs and Poultry in China

8. 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

9. 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”

10. Comparison of Mortality Impact in the Three Influenza Pandemics of the 20 th 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?~500,000530 1957-58 A(H2N2)H + N~ 60,000 40 1968-69 A(H3N2)H only~ 40,000 18 Simonsen et al

11. 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

12. 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

15. Projected Number of Deaths Due to Future Pandemic Influenza Based on the 1918-1920 Pandemic AreaNo. Deaths Twin Cities SMA18,538 Minnesota30,498 United States1,763,664 Worldwide30,000,000 - 384,000,000

16. CIDRAP, 8/2005 17 Human Cases 12 Deaths 94 Human Cases 42 Deaths 4 Human Cases 4 Deaths 4 Human case 3 Deaths

17. Influenza Pandemic Preparedness Prevention –vaccine and antivirals Treatment –health-care delivery system “Collateral damage response” –global just-in-time economy

18. Prevention Vaccination Antiviral therapy and prophylaxis

19. 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

20. 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

21. Influenza Antiviral Drugs Approved for Human Use Viral M2 Protein Inhibitors amantadine rimantadine Selective Neuraminidase Inhibitors oseltamivir phosphate zanamivir

22. Treatment and Corpse Management Facilities and staffing Worker and patient protection Medical devices and therapy Ethical issues Use of “recovered” volunteers Corpse management

23. Collateral Damage Response Implications of the global just-in-time economy –other pharmaceutical products –food –equipment parts International security

24. 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