1. Influenza Today Joseph Mester, Ph.D. September 24, 2009

2. Control of Infectious Diseases

3.  Sanitation  Diagnosis  Antimicrobials  Vaccines  Still, an ongoing effort

4. Influenza Surveillance: CDC & WHO Monitor prevalence of circulating strains and detect new strains Rapidly detect outbreaks Assist disease control through rapid preventive action Estimate influenza-related morbidity, mortality and economic loss

5. On the Web http://www.flu.gov/ http://www.cdc.gov/H1N1FLU/ http://www.fda.gov/NewsEvents/PublicHealthFocus/ ucm150305.htm

6. Influenza Virus: Morbidity and Mortality Debilitating illness lasting 5-7 days  Most severe when there is underlying cardiac or pulmonary disease In the USA:  ~150,000 influenza-associated hospitalizations per year  ~7,000-70,000 average deaths per year  Up to 10x this number of deaths during pandemics  >500,000 (USA) and 20 Million deaths (world wide) in 1918 pandemic

7. PeriodYearsAvg. Deaths Per year Pandemic1918-1920225,000 Interpandemic1920-193328,300 Interpandemic1933-195710,100 Pandemic1957-196039,000 Interpandemic1960-196814,300 Pandemic1968-197228,000 Interpandemic1972-198122,000 Interpandemic1981-199120,000 Influenza in the USA Glezen, Epidemiology Revs. 1996. 18:64-76

8. Influenza Pathogenesis Respiratory & contact transmission Replication in respiratory epithelium with subsequent destruction of cells Viremia rarely documented Viral shedding in respiratory secretions for 5- 10 days

9. Virus Variables Virulence of Strain(s) e.g., H5N1 (pandemic) vs. H1N1 (seasonal) Influenza Immune suppression? Immune over-activation? Tissue invasiveness Speed of replication Amount of necrosis Dose Co-infection / multiple infection

10. Influenza Virus Strains Type A- moderate to severe illness - all age groups - humans and other animals Type B- milder epidemics - humans only - primarily affects children Type C- rarely reported in humans - no epidemics

11. Influenza Virus A/Moscow/21/99 (H3N2) Neuraminidase Hemagglutinin Type of nuclear material Virus type Geographic origin Strain number Year of isolation Virus subtype

12. Influenza Virus  Enveloped RNA Virus  Capsid with helical symmetry  Polymorphic shape  Segmented Genome  8 Negative sense RNAs

13. Influenza Virus Evolution Genetic Variability  Virus is prone to accrue nucleotide misincorporations  error-prone viral RNA-dependent RNA polymerase with no proof-reading function  Misincorporation rate for Influenza A virus:  1 x 10 -4 - 10 -5 changes/ nucleotide position/ replication cycle

14. Antigenic Drift

15. Replication in Animals (Other Than Man) Agricultural Animals - Hogs - Horses - Cattle - Sheep - Goats - Chickens - Turkeys Aquatic/Wild Birds - Ducks - Geese - Quail - Pheasants Companion Animals - Dogs - Cats

16. Antigenic Shift: Reassortment

17. Shift Timeline

18. Triple-Reassortant Swine Influenza A (H1) 11 sporadic cases 2006-2008 NEJM 2009

19. Pandemic Flu 40 million deaths world-wide 675,000 in US Mortality 2.5% Flu killed more than WWI (1918) Estimated that half of the US WWI casualties were due to Flu 1957 Asian Flu (H2N2) 1968 Hong Kong (H3N2) 1976 Swine Flu (H1N1) 2009 Swine Flu (H1N1) Avian Flu’s 1997 H5N1 Hong Kong 1999 H9N2 Hong Kong 2004 H5N1 1918 (H1N1) Others San Francisco

20. Phases of the Immune Response to Influenza

21. Influenza Vaccines Inactivated subunit (TIV) Intramuscular Trivalent Live attenuated vaccine (LAIV) Intranasal Trivalent

22. Composition of the 2009-10 Seasonal Influenza Vaccine A/Brisbane/10/2007 (H3N2) A/Brisbane/59/2007 (H1N1) B/Brisbane/60/2008

23. Vaccine Attenuation

24. Influenza Antiviral Agents Amantadine and rimantadine effective against influenza A only approved for treatment and prophylaxis Zanamivir and oseltamivir neuraminidase inhibitors “generally” effective against influenza A and B Most currently circulating seasonal influenza A strains are resistant! oseltamivir approved for prophylaxis