1. Influenza Branch VACCINES AND RELATED BIOLOGICAL PRODUCTS ADVISORY COMMITTEE CBER, FDA February 16-17, 2005, Bethesda, MD Nancy COX, Ph.D. WHO COLLABORATING CENTER FOR SURVEILLANCE, EPIDEMIOLOGY AND CONTROL OF INFLUENZA Influenza Branch Division of Viral and Rickettsial Diseases National Center for Infectious Diseases Centers for Disease Control and Prevention Atlanta, GA 30333

2. Influenza Branch Influenza A(H5N1) December 2003 – February 2005 H5N1 –outbreaks in birds reported H5N1 – outbreaks in birds and humans H5N1 –outbreaks in birds, controlled and final report submitted to OIE

3. Influenza Branch Human H5N1 Cases, 2004-2005 Country H5N1 Cases Deaths Case Fatality Cambodia11100% Thailand171271% Vietnam372978% Total554276%  High case fatality regardless of age  Clinical symptoms similar to earlier cases, including lymphopenia  Diarrhea prominent in some cases  Second wave of infections in Aug 2004-present  Thai family cluster; probable H-to-H transmission

4. Influenza Branch 320 160 80 20 640 80 80 1280 40 640 40 640 HK/213/03 CK/KOR/ES/03 HK/97 TH/353/04 VN/1203/04 VN/1194/04 5120 20 320 ND 20 <10 HK/213/03 CK/KO/03 320 40 320 <10 <10 <10 HK/97 VN/1203/03 Antigenic Characterization of H5N1 Influenza Viruses VIRUSES FERRET H5N1 ANTISERA

5. Influenza Branch  Avian influenza viruses can pose a major risk to global public health (H5N1, H7N7, H9N2, etc.)  Early detection H-2-H transmission of novel influenza viruses is essential  2003/05 Asian viruses are heterogeneous in AV susceptibility and pathogenicity; more lethal in mammals than 1997 strains  Ongoing vaccine development, antiviral stockpiling and pandemic preparedness  Surveillance in animals (birds, swine and other susceptible hosts) is critical  Research agenda needed to enhance our understanding of the genesis of pandemic influenza viruses  Global recognition of need for better communication between human and veterinary health authorities Conclusions

6. Influenza Branch Influenza: An Emerging Disease that Rolls On

7. Influenza Branch InfluenzaVirusIsolates Characterized by CDC andOtherWHO Collaborating Centers and Laboratories * (October 2004– February 2005) North America Europe Asia Cent/So America Africa, Oceania Total (%) A(H1N1) 2 115 74 2 193 (8%) A(H3N2) 616 402 212 4 458 1692 (75%) B/Yamagata 98 62 30 1 112 303 (14%) B/Victoria 18 28 16 3 9 74 (3%) Total 734 607 332 8 581 2262 Preliminary Data 02/14/2005 * Data based on cumulative influenza virus isolates antigenic characterization data provided by WHO Collaborating Centers in Atlanta,London, Melbourne, Tokyo, reports from European Influenza Surveillance Scheme and National Influenza Center, Canada

8. Influenza Branch Influenza A(H1N1)

9. Influenza Branch HEMAGGLUTINATION INHIBITION REACTIONS OF INFLUENZA H1 VIRUSES REFERENCE FERRET ANTISERA Date REFERENCE ANTIGENSBJ/262NC/20FUJ/156NEI/52CI/8885PE/3135collectedPassage 1A/BEIJING/262/95640 160320 4001/09/95E3/E3 2A/N. CALEDONIA/20/99 *160640320 16006/09/99E4/E2 3A/FUJIAN/156/200080640320 1608008/25/00E2/E2 4A/NEIMENGGU/52/2002403201603201604001/25/02E2/E4 5A/CHILE/8885/200240320160 3202007/03/02E1/E4 6 7 A/PERU/3135/20031604080201064004/09/03X/C3 TEST ANTIGENS 8 A/FLORIDA/04/2004 *3201280 64032012/20/04X1/C1 9 A/FLORIDA/03/20043201280640 320 12/09/04X2/C1 10 A/PRACHINBURI/1749/20043201280 32064009/18/04C1/C1 11 A/BANGKOK/1757/20043201280 640 09/20/04C1/C1 12 A/PRACHINBURI/1817/20043201280 640 09/23/04C1/C1 13 A/BANGKOK/1876/20043201280 64032009/27/04C1/C1 14 A/SUPHANBURI/2131/20043201280 64032010/04/04C1/C1 15 A/BANGKOK/1752/200432012806401280320 09/20/04C1/C1 16 A/SUPHANBURI/2130/200416012806401280320 10/04/04C1/C1 17 A/BANGKOK/1822/200416012806401280320 09/23/04C1/C1 18 A/RATCHABURI/1847/20043201280640 320 09/24/04C1/C1 19 A/BANGKOK/1544/2004 *16064032064032016008/31/04E3/E1 20 A/SUPHANBURI/2129/2004160640 32016010/04/04C1/C1 21 A/SAKAEW/2132/2004160640320640320 10/04/04C1/C1 22 A/SINGAPORE/14/20041601280640 32016003/31/04E4/E1 23 A/N. CALEDONIA/9/20041601280640 320 06/11/04E2/E1 24 A/N. CALEDONIA/3/2004160640 32016004/19/04E2/E1 25 A/MALAYSIA/1513/200416064032064016032007/10/04E2/E1 26 A/HONG KONG/4555/2004160640 32016009/25/04C2/C1 27 A/HONG KONG/4580/2004160640 32016010/08/04C2/C1 A/HONG KONG/4596/20041601280 64032010/25/04C2/C1 * Serology antigens

10. Influenza Branch Influenza A(H1) Isolates Characterized by CDC

11. Influenza Branch Evolutionary Relationships Among Influenza A(H1) HA Genes 0 5 nucleotides (LR) Low reactor in HI # - Egg Isolate * Serology Antigen Jan-Feb-Mar Apr-May-Jun Jul-Aug-Sep Oct-Nov-Dec Date Collected

12. Influenza Branch Evolutionary Relationships Among Influenza N1 NA Genes Nucleotides *Serology antigen (LR) Low reaction to HI # Egg isolate 0 Scale 3

13. Influenza Branch HI Antibody Response to 2004-2005 Vaccine (adults) % w/HI titer >40 Sera N Antigen % Rise Pre GMT Post GMT Pre Vaccine Post Vaccine 30 A/New Caledonia/20/99 23 21 44 43 67 30 A/Bangkok/1544/2004 17 26 54 53 77 30 A/Florida/04/2004 17 27 54 53 73 Japan 30 A/Netherlands/128/2004 27 59 57 77 25 A/New Caledonia/20/99 32 19 54 44 76 25 A/Bangkok/1544/2004 32 23 57 40 76 25 A/Florida/04/2004 24 53 48 80 USA 25 A/Netherlands/128/2004 24 26 66 52 80

14. Influenza Branch H1 Summary: October 2004 to February 2005  Relatively few H1 viruses have been detected worldwide  The majority of H1N1 viruses were closely related antigenically to the A/New Caledonia/20/99 vaccine strain and no significant variants of H1N1 viruses were detected  No H1N2 viruses were detected  N1 neuraminidase genes of recent H1 viruses were similar to those of viruses isolated prior to October 2004

15. Influenza Branch Influenza A(H3N2)

16. Influenza Branch HEMAGGLUTINATION INHIBITION REACTIONS OF INFLUENZA H3 VIRUSES STRAIN DESIGNATIONREFERENCE FERRET ANTISERA Date REFERENCE ANTIGENSWY/3WEL/01ND/01CA/7SN/37collectedPassage 1 A/WYOMING/03/2003 X-147 *64080160 4002/13/03X/E1 2 A/WELLINGTON/01/2004 *160320 01/26/04E3/E2 3 A/NORTH DAKOTA/01/20048016064032016010/20/04SpfCK1E4 4 A/CALIFORNIA/07/2004 *16080320 16009/16/04SpfCK1E3 6 7 5A/SINGAPORE/37/2004160 640 6/7/2004E4/E1 TEST ANTIGENS 8 A/KENTUCKY/6e/2004320 6401280 11/27/04SpfC1KE3 9 A/NEW YORK/57/2004320160640 16012/28/04X2/C1 10 A/VIRGINIA/02/2005320 1280640 01/06/05M1/C1 11 A/WISCONSIN/21e/2004160 320 16011/29/04SpfCK3E3 12 A/NEW YORK/39e/2004160 640 32011/09/04SpfCK2E4 13 A/NEW YORK/02/200516080320 16001/05/05X1/C1 14 A/NEW YORK/03/200516040320 8001/03/05X1/C1 15 A/TEXAS/12/200416080320 16012/29/04M1/C1 16 A/MASSACHUSETTS/01/20051608032064016001/05/05M1/C1 17 A/ALASKA/16/2004160803201608012/12/04X/C1 18 A/NEW YORK/55e/200480 320 16011/18/04SpfCK2E2 19 A/N. HAMPSHIRE/04/20048040160 12/27/04X/C1 20 A/WISCONSIN/16e/200440803201608011/22/04SpfCK3E2 21 A/WEST VIRGINIA/01/20058040160 4001/05/05C1/C1 22 A/VIRGINIA/03/200580 3201608001/07/05M1/C1 23 A/ARIZONA/03/20058040160 8001/05/05M2/C1 24 A/GEORGIA/01/20058040160 8001/06/05M1/C1 25 A/CANADA/707/200416080320 8011/16/04X1/C1 26 A/VICTORIA/523/200480160320 64011/03/04E5/E1 27 A/MADRID/RR1734/2004320160640 32012/01/04C1/C1 28 A/UNITED KINGDOM/305/200516080320 8001/05/05X/C1 29 A/NORWAY/1103/20048020801604011/22/04C2/C1 30 A/IRAQ/01/20048040160 8012/29/04X/C1 A/SINGAPORE/68/2004160 320 nd 11/09/04C1/C2 A/HONG KONG/4465/20048020160 4009/15/04C2/C1 * Serology antigens

17. Influenza Branch (guinea pig red blood cells) HEMAGGLUTINATION INHIBITION REACTIONS OF INFLUENZA H3 VIRUSES

18. Influenza Branch Influenza A(H3N2) Isolates Characterized by CDC

19. Influenza Branch Evolutionary Relationships Among Influenza A(H3) HA Genes

20. Influenza Branch Evolutionary Relationships Among Influenza N2 NA Genes Ningbo/982/2004 Ningbo/1043/2004 Ningbo/1042/2004 Ningbo/1032/2004(LR)* Ningbo/1114/2004 Ningbo/1018/2004 Hong Kong/2874/2004 HongKong/2976/2004 HongKong/2982/2004 Hong Kong/2874/2004 Ningbo/1119/2004 Hunan/L200-3/2004(LR)* Ningbo/1049/2004 Tennessee/6/2004(LR)* N. Dakota/01/2004# nimr-Lisbon/3/2004 NewYork/55/2004# nimr-Baleares/720/2004 nimr-Ireland/9195/2004 Texas/6/2004 Ningbo/997/2004 Ningbo/1001/2004 NewYork/40/2004# Washington/1/2004 California/7/2004(LR)#* Wellington/1/2004(LR)#* Singapore/15/2004 NewCaledonia/7/2004# Argentina/126/2004 Brazil/1759/2004 nimr-Reunion/581/2004 Hunan/L201-2/2004 Japan/120/2004# Singapore/21/2004 Singapore/36/2004(LR)#* Nepal/1646/2004 Korea/770/2002 Wyoming/3e/2003#* Fujian/411/2002 nihj-Nagasaki/52/2003 Canada/578/2004(LR)* Ningbo/1005/2004 Wuhan/269/2004 FrenchGuyana/12/2004 Uruguay/3173/2004 Peru/1296/2004 Victoria/505/2004# Panama/2007/99 Sydney/5/97 Nucleotides *Serology antigen (LR) Low reactor in HI # egg isolate 0 Scale 7 K221E I392T N92D, EI99K Q432E S18A, F23L, I30V, Y40H, F42C V143G, K172R, V216G, T265I, I307V, N385K, D399E, L437W

21. Influenza Branch H3 Summary: October 2004 to February 2005  Influenza A (H3N2) viruses circulated in many countries in the Americas, Asia, Europe and Oceania.  In HI tests, A(H3N2) viruses were antigenically heterogeneous. Viruses isolated early in the season were often more closely related to A/Fujian/411/02 and A/Wyoming/3/03.  An increasing proportion of recent isolates were antigenically distinguishable from the A/Wyoming/3/03 and A/Wellington/1/04 vaccine strains and were most closely related to the A/California/7/04 reference virus.  Sequence analysis of N2 neuraminidase genes of recent H3N2 viruses indicates that NAs of recent viruses were genetically distinguishable from that of the Wyoming/3/03 virus (N93D, E199K, Q432E) but were similar to the NAs of A/Wellington/1/04 and A/California/7/04.

22. Influenza Branch Influenza B

23. Influenza Branch HEMAGGLUTINATION INHIBITION REACTIONS OF INFLUENZA B VIRUSES

24. Influenza Branch Influenza B Isolates Characterized by CDC

25. Influenza Branch Evolutionary Relationships Among Influenza B/Yamagata HA Genes

26. Influenza Branch Evolutionary Relationships Among Influenza B/Victoria HA Genes 0.01 Hawaii/20/2004 # LR Nevada/1/2005 LR Washington/1/2004 Hawaii/33/2004 # Hawaii/32/2004 # Hawaii/31/2004 # Hawaii/11/2004 # Hawaii/13/2004 # * Aus -Phitsanulok/2053/2004 * Aus -Surin/1597/2004 Aus -Perth/33/2004 Aus -Perth/12/2004 Kyonggi/501/2004 LR Brazil/1921/2004 LR New York/9/2004 Saint Lucia/2185/2004 LR Florida/1/2004 NIID -Sichuan/12/2003 # Taiwan/1558/2004 Talcahuano/6830/2004 # LR Wulumuqi/26/2004 # Hong Kong/318/2004 LR Aus -Malaysia/2276/2004 Hong Kong/312/2004 LR Hong Kong/310/2004 LR Aus -Malaysia/20/2004 NIMR -Israel/12/2004 Paraguay/636/2003 LR Aus -Brisbane/32/2002 # Kazakhstan/222/2004 NIID -Akita/9/2003 # NIMR -Madagascar/72134/2004 Shanghai/47/2003 # Beijing/243/97 # Shandong/7/97 # Fujian/203/2003 # NIID -Longyan/11/2003 # Hong Kong/1434/2002 # Hong Kong/330/2001 # Taiwan/217/97 LR - Low reactor to B/Hong Kong/330/2001 Vaccine Strain # - egg isolate * - Reference antigen K 299 R A 217 S K 80 E K 48 E K 80 R K 129 N I 121 T H 116 R I 121 N D 164 E K 129 E

27. Influenza Branch Evolutionary Relationships Among Influenza B NA Genes Shd/Sic Reassortants

28. Influenza Branch B Summary: October 2004 to February 2005   Influenza B viruses continued to circulate in many countries   The majority of analyzed B viruses belonged to the B/Yamagata/16/88 lineage and were closely related antigenically to the B/Shanghai/361/2002 vaccine strain   Most B/Victoria/2/87 lineage viruses analyzed were reassortants, bearing a B/Hong Kong/330/2001-like HA gene and a B/Sichuan/379/99-like NA gene.   B/Victoria/2/87 lineage viruses were antigenically distinguishable from B/Hong Kong/330/2001, the previous vaccine strain from this lineage

29. Influenza Branch InfluenzaVirusIsolates Characterized by CDC andOtherWHO Collaborating Centers and Laboratories * (October 2004– February 2005) North America Europe Asia Cent/So America Africa, Oceania Total (%) A(H1N1) 2 115 74 2 193 (8%) A(H3N2) 616 402 212 4 458 1692 (75%) B/Yamagata 98 62 30 1 112 303 (14%) B/Victoria 18 28 16 3 9 74 (3%) Total 734 607 332 8 581 2262 Preliminary Data 02/14/2005 * Data based on cumulative influenza virus isolates antigenic characterization data provided by WHO Collaborating Centers in Atlanta,London, Melbourne, Tokyo, reports from European Influenza Surveillance Scheme and National Influenza Center, Canada