1. NS 2 Lipid Bilayer NA (Neuraminidase) HA (Hemagglutinin) M 2 (Ion channel) M 1 (Matrix protein) NP (Nucleocapsid) PB1, PB2, PA (Transcriptase complex) Infected cell protein NS 1 Influenza A Virus Structure

2. Natural History of Influenza Viruses Topley and Wilson’s Microbiology and Microbial Infections. 9th ed, Vol 1, Virology. Mahy and Collier, eds, 1998, Arnold, page 387, with permission. 1880189019001910192019301940195019601970198019902000 B H3N2 H1N1 H2N2 H3N8 H2N? H1N1 Serum antibody prevalence Virus isolation

3. Adapted from Levine AJ. Viruses. 1992;165, with permission. Hemagglutinin Subtypes of Influenza A Virus SubtypeHumanSwineHorseBird H1H2H3H4H5H6H7H8H9H10H11H12H13H14H15

4. CDC. Influenza Prevention and Control. Available at: http://www.cdc.gov/ncidod/diseases/flu/fluinfo.htm. Influenza Type A (H1N1) l Cause of 1918-1919 pandemic (swine) l Antigenic drift and subsequent epidemics l Disappeared in 1957 with appearance of H2N2 virus l Reappeared as the “Russian flu” in 1977 l Immunity in persons born before 1950

5. NEJM, June 2009

6. 6 Novel H1N1 Weekly Surveillance Pattern: 2008-09 Through July 11, 2009 CDC: http://www.cdc.gov/flu/weekly/weeklyarchives2008-2009/WhoLab27.htm. Accessed July 30, 2009. New Slide: Needs to be regularly updated

7. 7 Origins of Novel H1N1 Influenza  First described in April 2009 in Southern California and Mexico  By May 2009 had spread to 43 countries –>12,000 hospitalizations –>90 deaths  As of September 11, 2009 –>277,000 cases worldwide –At least 3200+ deaths New Slide Trifonov V. N Engl J Med.2009; 361:115-119. WHO. http://www.who.int/csr/don/2009_09_11/en/index.html. Accessed September 11, 2009.

8. 8 WHO Definitions  Epidemic: human-to-human spread of the virus into at least two countries in one WHO region  Pandemic: human-to-human spread of the virus with community level outbreaks in at least one other country in a different WHO region than initial epidemic  Attack rate: numbers of cases of infection per unit of population  Virulence: severity of illness caused by a particular virus WHO. http://www.who.int/csr/disease/avian_influenza/phase/en. Accessed July 28, 2009. Gallaher WR. Virology Journal. 2009, 6:51 doi:10.1186/1743-422X-6-51. New Slide

9. 9 Pandemic Severity Categories Monto AS. Clin Infect Dis. 2009;48:S20–25. New Slide

10. 10 US Hospitalization Rate per 100,000 Population by Age Group Through July 2009 Fiore A. Presentation to Advisory Committee on Immunization Practices (ACIP). July 29,2009.

11. 11 Cross-reactive Antibody to Novel H1N1 Influenza  Serum samples taken before and after vaccination with the 2005-06, 2006-07, 2007-08, or 2008-09 influenza season vaccines  Before vaccination cross-reactive antibody to the novel H1N1 virus seen in: –Children <18 years = 0% –18-64 years = 6%-9% –>60 years = 33%  Seasonal influenza vaccine did not elicit antibody response to novel H1N1 New Slide CDC. Morbid Mortal Weekly Report. May 22, 2009. 58(19);521-524.

12. Oseltamivir Treatment: Antiviral Effect in Adults Treanor JJ. JAMA. 2000;283:1016-1024. Hayden FG. JAMA. 1999;282:1240-1246. 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 -36-24-1201224364860728496108120132144156 Median log 10 Tissue Culture-Infective Dose per Millimeter Inoculation Time, hours Placebo Oseltamivir Drug Administration The viral titer area under the curve value was lower in the combined oseltamivir group (n=56) compared with placebo (n=13); P=0.02. Effect of Oral Oseltamivir Treatment on Vital Titers in Nasal Lavages Following Experimental Influenza A/Texas/36/91(H1N1) Infection Viral Titres

13. Oseltamivir Treatment for Influenza: Adults (16 to 65 Years) 21 hours** 32 hours* Treanor JJ. JAMA. 2000;283:1016-1024. *P<0.001; **P=0.004. Treatment initiated within 36 hours of onset of symptoms. Time to Resolution of All Flu Symptoms

14. Effects of Oseltamivir on Return to Normal Activities *P<0.001; **P=0.02. Treatment initiated within 36 hours of onset of symptoms. Health StatusActivity * ** 1.9d 2.8d 0 12 8 6 4 2 Placebo (n=129) Oseltamivir 75 mg bid (n=124) 10 Placebo (n=129) Oseltamivir 75 mg bid (n=124) Time to Return to Normal Health and Activity Days Treanor JJ. JAMA. 2000;283:1016-1024.

15. 15 Antiviral Treatment Recommendations  Treatment with oseltamivir or zanamivir is recommended for: –All patients requiring hospitalization –Patients at increased risk of complications Children 0-4 years Pregnant women Persons with immune suppression, chronic pulmonary (including asthma), cardiovascular (except hypertension), renal, hepatic, hematological (including sickle cell disease), neurologic, neuromuscular, or metabolic disorders (including diabetes mellitus) or > 65 years  Early treatment is key  Clinicians should not wait for confirmatory tests to treat  Postexposure prophylaxis should generally not be used –Consider for high-risk person with close unprotected exposure –Do not use if more than 48 hours after exposure New Slide

16. Inactivated Vaccine Effectiveness by Age and Risk Group Age/Risk groupOutcomeEffectiveness* 6m-16 years, healthyInfluenza50-90% 18-64 years, healthyInfluenza50-90% >65 years, communityInfluenza30-70% Elderly, nursing homeInfluenza30-40% Elderly, nursing homeHospitalization30-60% *Effectiveness may be lower when vaccine and circulating strains antigenically different. Source: CDC.

17. Impact of Vaccination of Japanese School Children on Mortality in the Elderly Reichert TA. N Engl J Med. 2001;344:889-896. Mandatory vaccination 70 60 50 40 30 20 10 0 14 12 10 8 6 4 2 0 Excess Deaths From All Causes (per 100,000 population) Excess Deaths Attributed to Pneumonia and Influenza (per 100,000 population) 1950195419581962196619721976198019841988199219962000 Japan, pneumonia and influenza Japan, all cause US, pneumonia and influenza US, all cause

18. 18 Host and Lineage Origins For The Gene Segments of 2009 A(H1N1) Virus Garten RJ. Science. 2009;325:197-201. New Slide

19. 19 Approved Monovalent Vaccines for Novel H1N1 Influenza New Slide CDC. http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Post- MarketActivities/LotReleases/ucm181956.htm. Accessed Sept. 28, 2009.