Arnold S. Monto University of Michigan School of Public Health Ann Arbor, Michigan USA

1. New WHO Phases: Issues Related to the Pandemic of a Novel A(H1N1) Virus Arnold S. Monto University of Michigan School of Public Health Ann Arbor, Michigan USA

2. Proposed 2008 Phases 1 - 3 Phases 5-6 Sustained H-2-H transmission Time Predominantly animal infections; Limited infections of people Geographic spread 5 - 6 4 Post Peak Post Pandemic

3. First Detection of Community Level Outbreaks Will Require Several Urgent Decisions Sustained H-2-H transmission Consider rapid containment Consider Phase Change to 4 Consider switch to pandemic vaccine Other

4. WHO Pandemic Phase Descriptions Phase Estimated probability of pandemic Description Main actions in affected countries Main actions in not-yet-affected countries Phase 4 Medium to high Human-to-human transmission of an animal or human-animal influenza reassortant virus able to sustain community-level outbreaks has been verified Rapid containment Readiness for pandemic response Phase 5 High to certain The same identified virus has caused sustained community level outbreaks in at least two countries in one WHO region Pandemic response: Each country to implement actions as called for in their national plans. Readiness for imminent response Phase 6 Pandemic in progress In addition to the criteria defined in Phase 5, the same virus has caused sustained community level outbreaks in at least one other country in another WHO region.

8. Progress of Asian Influenza Pandemic, February, 1957-January, 1958 Langmuir AD,Am Rev Resp Dis. 1961; 83:3.

9. Status of Asian Influenza in the United States and Major Routes of Spread through July 22, 1957 Military Civilian   Confirmed Sporadic Cases   Confirmed Outbreaks   Suspect Outbreaks Arrows indicate probable spread from Foci of infection.                           Langmuir AD,Am Rev Resp Dis. 1961; 83:5.

10. Influenza Attack Rates by Age in Tangipahoa Parish, Louisiana – August, 1957 Langmuir AD,Am Rev Resp Dis. 1961; 83:5.

11. Weekly Incidence of Respiratory Illnesses (all ages) Per 100,000, July, 1957-June 1958 Langmuir AD,Am Rev Resp Dis. 1961; 83:8. 1957 1958 6,000 5,000 4,000 3,000 2,000 1,000 0 Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr May Jun

12. Clinical Influenza Attack Rates (Kansas City, 1957) and Annual Mortality Rate Pneumonia and Influenza (U.S. 1957) - 300 - 250 - 200 - 150 - 100 - 50 0 Mortality Rate per 100,000 Modified from Monto AS. Am J Med . 1987; 82:20-5.

13. Comparison of Amantadine and Rimantadine Structures NH 2 NH 2 Amantadine Rimantadine

14. Protective Efficacy of M2 Inhibitors Against Laboratory-Confirmed Clinical Influenza Monto AS, et al . JAMA. 1979; 241:1003-7. Dolin R, et al. N Engl J Med . 1982; 307:580-4.

15. Cases of Influenza-like Illnesses and Resistant Viruses Isolated From Case-Patients at Nursing Home B, by Living Unit Mast et al. Am J Epidemiol. 1991; 134:988-97. January February Val to Ala, position 27 Ala to Val, position 30 Ser to Asn, position 31 Demonstrated Amino Acid Changes

16. Trend of Adamantane-Resistant H3N2 Viruses, 1994-2005 China Japan US Hong Kong South Korea Overall 90 80 70 60 50 40 30 20 10 0 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 Season of Isolate Collection Resistance Frequency (%) Bright RA, et al . Lancet . 2005;366:1175-81.

17. Zanamivir

18. Oseltamivir Carboxylate

19. Efficacy of Seasonal Prophylaxis of Influenza with Zanamivir (4 weeks) and Oseltamivir (6 weeks) Monto AS, et al. JAMA . 1999; 282:31-5. Hayden FG, et al. NEJM . 1999; 341-1336-43.

20. Efficacy of Oseltamivir in Preventing Lower Respiratory Tract Complications (LRTCs) Leading to Antibiotic Use Percent Reduction Overall n=2413 55%* 52% 61% 55% 54% Otherwise Healthy n=1644 67% 60% 77% 63% 71% At Risk n=769 34% † 34% 30% 34% 25% LRTCs Leading to Antibiotic Use All LRTC Bronchitis Pneumonia Influenza A Influenza B * Comparison of oseltamivir vs placebo, P<.001. † Comparison of oseltamivir vs placebo, P=.02. Kaiser L, et al. Arch Intern Med . 2003; 163:1667-72.

21. Influenza Prevention in Household Studies with NAI’s * Prophylaxis is given ≥ 5 years. † Excludes contacts positive for influenza prior to prophylaxis. Antiviral (Study) Season (Virus) Reduction in Secondary Cases % Resistance Transmission No Treatment of Index Zanamivir (Monto et al, 2002) Oseltamivir (Welliver et al, 2001) 2000-01 (A/H3N2, B) 1998-99 (A/H3N2, B) 81% 89% — — With Treatment of Index Zanamivir* (Hayden et al, 2000) † Oseltamivir (Hayden et al, 2004) 1998-99 (A/H3N2, A/H1N1) 2000-01 (A/H3N2, B) 79% 85% No No

23. Comparisons of Infectivity and Transmissibility of WT and MUT Pairs for NA Genotypes Isolated During Treatment Studies Herlocher, et al. 2002. Antiviral Research , 54: 99-111. Herlocher, et al. 2004. J Infect Dis , 190:1627-30. Wild type [WT] and Mutant [MUT] pairs isolated from pre- and follow-up specimens from the same subject Infectious dose Donor infection status Recipient infection status Sequence confirmation of WT or MUT NA genotype A/Sydney/5/97-like (H3N2) R292 - WT 2.3 TCID50/0.5 ml 4 of 4 12 of 12 WT *R292K – MUT Same 2 of 4 3* of 6 *Reversion to WT A/Wuhan/359/95-like (H3N2) E119 - WT 1.0 x 10 -6 Dilution of stock 4 of 4 11 or 11 WT E119V - MUT 1.0 x 10 -6 Dilution of stock 4 of 4 11 or 11 MUT A/New Calendonia (H1N1) H274 – WT 1.5 x 10 -6 Dilution of stock 4 of 4 12 or 12 WT H274Y – MUT 1.5 x 10 -5 Dilution of stock 0 of 4 @ day 7 0 of 12 @ day 7 1.5 x 10 -3 Dilution of stock 4 of 4 12 of 12 MUT

24. Antiviral Resistance in USA (Week 14, 2008-2009) CDC, Apr 11, 2009 Isolates tested (N) Resistant Viruses, n (%) Isolates tested (N) Resistant Viruses, n (%) Oseltamivir Zanamivir Adamantanes Influenza A (H1N1) 748 743 (99.3%) 0 729 3 (0.4%) Influenza A (H3N2) 112 0 0 108 108 (100%) Influenza B 227 0 0 N/A* N/A*