1918

1. The reason we are so concerned about a pandemic is the experience of the 1928 pandemic of influenza. 1918 H1N1

2. Mortality in the 1918 pandemic was so great that the life expectancy in the United States dropped dramatically in that period.

3. Usually flu deaths are in the very young and the very old, usually because of secondary bacterial pneumonia The dotted line shows the expected mortality from influenza that is normally seen with deaths in the very young and the elderly. These patients usually died in the second week of illness due to secondary bacterial pneumonia.

4. The 1918 virus resulted in severe, often fatal primary viral pneumonitis. • In 1918 the big difference was deaths in young adults between the ages of 15 and 40. • These patients died of acute viral pneumonia and died between 24 and 48 hours of onset of symptoms. • This is what is reported from Mexico City and what has been seen with bird (avian) flu. This is the reason for major concern.

5. 1928 epidemic: rate of progression across the United States This map shows how rapidly the 1928 epidemic progressed across the United States at a time when there was no air travel, few cars, and only the railroad. You can see it all happened in four short weeks. It started in the ports where the soldiers from World War I were returning, and spread rapidly to the rest of the country. This is a lesson about the efficiency of the spread of influenza virus.

6. This is an electron micrograph of the influenza virus. You will see that it has a coat with spikes. These spikes are the Hemagglutinin (H) and the Neuraminidase (N) of the virus. These are the H and the N we hear about. These are the proteins against which our bodies make antibodies. These antibodies protect us against influenza. Influenza virus

8. Note: H16 recently identified in black-headed gulls

9. HA from another virus reassorts in a single cell SHIFT HA NP DRIFT Critical point mutation creates antigentically mutated HA Epidemic vs. Pandemic 1918, Swine flu, Bird flu Major mutation = pandemic Regular winter flu Minor mutation = epidemics

10. Reassortment (in humans) Migratory water birds PANDEMICS SHIFT Source: WHO/WPRO

11. Reassortment (in pigs) SHIFT Migratory water birds Source: WHO/WPRO

12. The Role of The Pig The original avian virus hemagluttinin (H5) can only attach to bird cells which have α2,3 receptors in their respiratory and gastrointestinal tracts α2,3 α2,3 α2,3 α2,6 andα2,3 α2,6 The virus reassorts in pigs which have α2,3 AND α2,6 receptors. When it does this it may aquire the ability to attach to α2,6 human respiratory tract cells

13. However, the human respiratory tract does have some α2,3 linkages of sialic acid residues to galactose particularly lower down in the tract. NOSE SINUS BRONCHUS ALVEOLUS Green = α2,6 BRONCHIOLE Red = α2,3 Kyodo Shinya et al. Nature 2006

15. Pulmonary histology of infected mice 1918 clone A = necrotising bronchiolitis severe alveolitis B = severe alveolar edema histiocytic alveolitis scattered neutrophils C = alveolitis (neutrophilic) hemorrhage 1918 5:3 Tx/91 D = moderate alveolitis moderate edema Tx/91 HA:1918 E = mild peribronchial inflammation minimal alveolitis Tx/91 F = paucicity of lesions Tumpey et al, Science 2005:310:77-80

16. Anti-influenza Drugs • Neuraminidase Inhibitors • Target - NA • Zanamivir=Relenza • Oseltamivir=Tamiflu • M2 – blockers • Target - M2 • Amantadine=Symmetrel® • Rimantadine=Flumadine ® • Most 2004 H5N1 are resistant against M2-blockers Slide courtesy of Erich Hoffmann, Division of Virology, Department of Infectious Diseases, St.Jude Children’s Research Hospital Memphis, TN, USA

17. Safe and effective vaccines are likely to be the single most important public health tool.