1. INFORMATION FOR THE VACCINE AND RELATED BIOLOGICAL PRODUCTS ADVISORY COMMITTEE CBER, FDA (Seasonal Influenza and Zoonotic Influenza) FEBRUARY 28, 2012 Nancy J. Cox, Ph. D Director WHO COLLABORATING CENTER FOR SURVEILLANCE, EPIDEMIOLOGY AND CONTROL OF INFLUENZA Director, Influenza Division National Center for Immunization and Respiratory Diseases Coordinating Center for Infectious Diseases Centers for Disease Control and Prevention Atlanta, GA 30333

2. A(H1N1)pdm09 Viruses Sept 2011 – Feb 2012

3. A(H1N1)pdm09 Sept 2010 – Feb 2011 (maximum activity)

4. Percentage of influenza viruses by subtypes (From 4 September 2011 – 28 January 2012) Data source: FluNet, (www.who.int/flunet), Global Influenza Surveillance and Response System (13 February 2012)www.who.int/flunet

5. Number of A(H1N1)pdm09 viruses detected in GISRS Data source: FluNet (www.who.int/flunet), Global Influenza Surveillance and Response System (GISRS)www.who.int/flunet

6. A(H1N1)pdm09 viruses characterized during the past 2 northern hemisphere seasons

7. HI Reactions of Influenza A(H1N1)pdm09 Viruses

8. Influenza A(H1N1)pdm09 Isolates Characterized by CDC

9. A(H1N1)pdm09 low reactors in HI assays in WHO CCs WHO CCA/Cal/07/09Low (≥ 8 fold) CDC120 (98%)3 (2%) CNIC0 (0%) NIID1 (100%)0 (0%) NIMR12 (100%)0 (0%) VIDRL40 (87%) 6 (13%) Total 172 (95.1%) 9 (4.9%)

10. Since 2009Since August 2011 Antigenic cartography of A(H1N1)pdm09 viruses

11. Influenza A (H1N1)pdm09 HA Genes

12. Evolutionary Relationships Among Influenza A (H1N1pdm) Hemagglutinin (HA) Genes, 2011-12 Current Northern Hemisphere Vaccine Strain LR- Low Reactor to A/California/07/2009 (≥ 8 fold) F: Ferret Antisera # Egg Isolate $ CDC serology antigen @- Oseltamivir Resistant H275Y H1 Numbering October 2011 November 2011 December 2011 January 2012 February 2012 usafsam A/California/1254/2012 Jan usafsam A/Oklahoma/1324/2012 Feb A/Maine/01/2012 Jan A/Colorado/01/2012 Jan nor A/Norway/147/2012 Jan A/Mexico/52/2011 Dec A/Alabama/01/2012 Jan A/Texas/05/2012 Jan aus A/Brisbane/190/2011 Jun # A/Brisbane/70/2011 Feb # aus A/Brisbane/70/2011 IVR-162 # A/St Petersburg/100/2011 Mar # F A/Nonthaburi/78/2011 Jun F A/Puerto Rico/8233/2011 Nov aus A/Brisbane/141/2011 Apr # A/Hawaii/05/2011 Sep # A/Wisconsin/26/2011 Oct $ H1N1pdm HA Consensus 2011 usafsam A/Florida/382/2011 Nov A/Vermont/02/2012 Feb usafsam A/California/nhrcx83/2012 Jan nimr A/Norway/2379/2011 Dec A/Florida/01/2012 Jan A/Ontario/RV0003/2012 Dec aus A/Newcastle/132/2011 Jul @ A/Hong Kong/3973/2011 Jun A/Cape Town/60/2011 Jun # $ nimr A/Johannesburg/43/2011 Jun # aus A/Perth/533/2011 Sep # A/Florida/36/2011 Dec A/Valparaiso/17275/2011 Aug # F A/Bangladesh/2110/2011 Oct # A/Oregon/13/2011 Dec A/Minnesota/03/2011 Feb F A/Minnesota/03/2011 Feb # F A/Costa Rica/8107/2011 Oct @ swe A/Stockholm/1/2012 Jan nor A/Norway/302/2012 Jan nimr A/Hong Kong/5089/2011 Dec A/South Carolina/07/2011 Nov spn A/PaisVasco/RR8716/2011 Oct A/Voronezh/1/2011 Mar # F swe A/Stockholm/35/2011 Nov A/Argentina/656/2011 Aug LR aus A/Malaysia/478/2011 Apr # A/Florida/35/2011 Dec LR A/Paraguay/105/2011 Nov LR A/Florida/27/2011 Oct # $ A/Vermont/16/2011 Dec A/Brisbane/10/2010 Apr # F A/Christchurch/16/2010 Jul # A/Christchurch/16/2010 NIB-74 # A/Nigeria/5382/2011 Aug nimr A/Ghana/ARI1181/2011 Oct niid A/Ishikawa/70/2011 Mar @ A/New Mexico/07/2011 Mar A/Pennsylvania/02/2011 Feb # F A/California/07/2009 # F $ NYMC X179 A/California/07/2009 # LR F NYMC X179 A A/California/07/2009 # F NYMC X181 A/California/07/2009 # 0.001 7 6 5 4 8 3 2 1 S143G A197T N260D V520A S69T N129T S84G S185T S451N D97N H138R V249L D97N R205K I216V V249L H138Q E356A K488R N125D S203T E374K G155E K154K/E

13. Current Northern Hemisphere Vaccine Strain LR- Low Reactor to A/California/07/2009 (≥ 8 fold) F: Ferret Antisera # Egg Isolate $ CDC serology antigen @- Oseltamivir Resistant H275Y H1 Numbering October 2011 November 2011 December 2011 January 2012 February 2012 Evolutionary Relationships Among Influenza A (H1N1pdm) Neuraminidase (NA) Genes, 2011-12 A/Alabama/01/2012 Jan A/Colorado/01/2012 Jan A/Maine/01/2012 Jan A/Mexico/52/2011 Dec A/Texas/05/2012 Jan A/Vermont/02/2012 Feb nimr A/Norway/2379/2011 Dec A/Wisconsin/26/2011 Oct $ H1N1pdm NA Consensus 2011 A/Hawaii/05/2011 Sep # A/Puerto Rico/8233/2011 Nov A/Nonthaburi/78/2011 Jun F A/Florida/01/2012 Jan A/Ontario/RV0003/2011 Dec A/Hong Kong/3973/2011 Jun aus A/Newcastle/132/2011 Jul @ aus A/Brisbane/70/2011 IVR-162 # aus A/Brisbane/190/2011 Jun # A/Brisbane/70/2011 Feb # aus A/Brisbane/141/2011 Apr # A/St Petersburg/100/2011 Mar # F A/South Carolina/07/2011 Nov A/Voronezh/1/2011 Mar # F swe A/Stockholm/1/2012 Jan nimr A/Hong Kong/5089/2011 Dec A/Minnesota/03/2011 Feb # F A/Minnesota/03/2011 Feb F A/Costa Rica/8107/2011 Oct @ aus A/Perth/533/2011 Sep # A/Capetown/60/2011 Jun # $ nimr A/Johannesburg/43/2011 Jun # A/Bangladesh/2110/2011 Oct # A/Oregon/13/2011 Dec A/Florida/36/2011 Dec A/Valparaiso/17275/2011 Aug # A/Florida/35/2011 Dec LR A/Vermont/16/2011 Dec A/Florida/27/2011 Oct # $ A/Paraguay/105/2011 Nov LR A/Nigeria/5382/2011 Aug nimr A/Ghana/ARI1181/2011 Oct A/New Mexico/07/2011 Mar niid A/Ishikawa/70/2011 Mar @ A/Argentina/656/2011 Aug LR swe A/Stockholm/35/2011 Nov aus A/Malaysia/478/2011 Apr # A/Pennsylvania/02/2011 Feb # F A/Brisbane/10/2010 Apr # F A/Christchurch/16/2010 Jul # A/Christchurch/16/2010 NIB-74 # A/California/07/2009 # F $ NYMC X179A A/California/07/2009 # F NYMC X179 A/California/07/2009 # LR F NYMC X181 A/California/07/2009 # 0.001 7 5 AND 6 5 2 1 8 4 N44S ADD GLY G41R V241I N369K N386S LOSS GLY D451G N386Y LOSS GLY N386S LOSS GLY N248D V106I 3

14. A(H1N1)pdm09 HA changes compared to A/California/7/2009

15. Influenza A(H1N1)pdm09, A(H3N2) and B circulated/co-circulated globally. No former seasonal A(H1N1) viruses were detected. Northern Hemisphere: –Low level of H1N1pdm09 activity levels, in general. –Except Mexico with widespread activity. Southern Hemisphere: –low levels in general. –Except few countries in South America and Oceania with regional activity. Summary of A(H1N1)pdm09 viruses (1)

16. HI tests using post-infection ferret sera indicated that H1N1pdm09 viruses remained antigenically homogeneous and closely related to the A/CA/7/09 vaccine virus. HA gene sequence analysis indicated that viruses fell in 8 genetic groups. A small proportion of viruses had reduced titers with antiserum against A/CA/7/09-like viruses and many of these had aa changes in HA positions 153-157. Summary of A(H1N1)pdm09 viruses (2)

18. A(H3N2) Viruses Sept 2011 – Feb 2012

19. GISRS: Percentage of influenza viruses by subtypes (From 4 September 2011 – 28 January 2012) Data source: FluNet, (www.who.int/flunet), Global Influenza Surveillance and Response System (13 February 2012)www.who.int/flunet

21. Number of A(H3N2) viruses detected by GISRS Data source: FluNet, (www.who.int/flunet), Global Influenza Surveillance and Response System (13 February 2012)www.who.int/flunet

22. H3N2 viruses characterized during the past 2 Northern Hemisphere seasons

23. H3 HA gene evolution

24. Evolutionary Relationships Among Influenza A (H3N2) Hemagglutinin (HA) Genes, 2011-12 Current Northern Hemisphere Vaccine Strain LR- Low Reactor to A/Perth/16/2009 (≥ 8 fold) # Egg Isolate F - CDC Reference Antigen $- CDC Serology Antigen October 2011 November 2011 December 2011 January 2012 February 2012 A/Christchurch/28/2011 Aug # F $ aus A/Brisbane/299/2011 IVR-164 # A/Brisbane/299/2011 Aug F $ A/Iowa/19/2010 Dec # F A/Iowa/19/2010 Dec F A/Georgia/01/2011 Feb F usafsam A/Alaska/1250/2012 Jan A/Wisconsin/01/2012 Jan usafsam A/Puerto Rico/1216/2012 Jan A/Texas/06/2012 Jan LR A/Chile/64/2011 May F A/Kentucky/05/2011 Nov F $ A/Kentucky/05/2011 Nov # LR cnic A/Guangdong-Jinping/1334/2011 Sep A/California/01/2012 Jan LR A/Perth/10/2010 # F A/Montana/05/2011 Mar # F A/Ontario/RV0064/2011 Jan F usafsam A/Florida/633/2011 Dec A/Alabama/04/2011 Dec aus A/Victoria/8/2010 Aug # A/Rhode Island/01/2010 Jan # F nimr A/Baden-Wurttemberg/1/2012 Jan A/Pennsylvania/15/2011 Nov spn A/Valencia/S01030G/2012 Jan A/Washington/01/2012 Jan A/Idaho/02/2012 Jan A/Saskatchewan/RV0019/2011 Dec LR usafsam A/Japan/1307/2012 Jan usafsam A/Korea/1078/2012 Jan usafsam A/Ohio/1325/2012 Feb A/British Columbia/4791/2011 Dec LR H3N2 HA Consensus 2011-12 A/Bangladesh/5071/2011 May F $ A/Nebraska/01/2012 Jan LR A/Utah/12/2011 Nov F A/California/34/2011 Nov LR nimr A/Finland/190/2011 Nov A/Texas/10/2012 Jan usafsam A/Illinois/1263/2012 Jan A/Oregon/09/2011 Oct F A/South Australia/03/2011 Jun F $ A/Victoria/361/2011 Oct # F $ A/Hong Kong/4913/2011 Nov LR A/Chiang Rai/277/2011 Sep LR F $ cnic A/Hunan-Yueyanglou/1320/2011 Oct A/Nonthaburi/279/2011 Sep LR A/Minnesota/25/2011 Dec nimr A/Berlin/3/2012 Jan usafsam A/Korea/1222/2012 Jan usafsam A/Kyrgyzstan/1407/2012 Jan A/Shanghai-Luwan/1440/2011 Nov LR A/Victoria/208/2009 Jun # A/Alabama/03/2011 Apr A/Perth/16/2009 # F $ A/Victoria/210/2009 Jun # F A/Victoria/210/2009 X-187 # F cnic A/Shanghai-Luwan/188/2011 Feb # A/Chungbuk/644/2011 Nov niid A/Incheon/668/2011 Dec 0.002 6 5 3B 3C 3A 4 2 1 7 A/Victoria/208/2009-like A/Perth/16/2009 -like K158N N189K T212A D53N Y94H I230V E280A K173Q I361R A198S N312S S45N ADD GLY T48I D487N N144D LOSS GLY N145S D487N V223I N145S Q33R N278K N145S S45N ADD GLY S199A I217V E62K N144K LOSS GLY K158N N189K I260M R261Q P162S S9G N171K F193S Y195Y/N

25. Current Northern Hemisphere Vaccine Strain LR- Low Reactor to A/Perth/16/2009 (≥ 8 fold) # Egg Isolate F - CDC Reference Antigen $- CDC Serology Antigen October 2011 November 2011 December 2011 January 2012 February 2012 Evolutionary Relationships Among Influenza A (H3N2) Neuraminidase Genes, 2011-12 A/Kentucky/05/2011 Nov F LR $ A/Kentucky/05/2011 Nov # LR cnic A/Guangdong-Jinping/1334/2011 Sep A/Iowa/19/2010 Dec F A/Iowa/19/2010 Dec # F A/Perth/10/2010 # F A/Georgia/01/2011 Feb F A/Ontario/RV0064/2011 Jan F niid A/Hiroshima-C/53/2011 Oct A/Montana/05/2011 Mar # F A/Chile/64/2011 May F A/California/01/2012 Jan LR A/Texas/06/2012 Jan LR A/Christchurch/28/2011 Aug # F $ aus A/Brisbane/299/2011 IVR-164 # A/Brisbane/299/2011 Aug F $ aus A/Victoria/8/2010 Aug # A/Rhode Island/01/2010 Jan # F A/Oregon/09/2011 Oct F A/Washington/01/2012 Jan A/Idaho/02/2012 Jan A/Saskatchewan/RV0019/2011 Dec LR A/Utah/12/2011 Nov F A/California/34/2011 Nov LR H3N2 NA Consensus 2011 niid A/Kobe/241/2011 Oct A/Bangladesh/5071/2011 May F $ A/British Columbia/4791/2011 Dec LR A/Nebraska/01/2012 Jan LR nimr A/Finland/190/2011 Nov A/Texas/10/2012 Jan A/Victoria/361/2011 Oct # F $ A/South Australia/03/2011 Jun F $ A/Shanghai-Luwan/1440/2011 Nov LR A/Hong Kong/4913/2011 Nov LR cnic A/Hunan-Yueyanglou/1320/2011 Oct A/Minnesota/25/2011 Dec A/Chiang Rai/277/2011 Sep LR F $ nimr A/Berlin/3/2012 Jan A/Nonthaburi/279/2011 Sep LR A/Alabama/04/2011 Dec spn A/Valencia/S01030G/2012 Jan A/Pennsylvania/15/2011 Nov nimr A/Baden-Wurttemberg/1/2012 Jan A/Chungbuk/644/2011 Nov niid A/Incheon/668/2011 Dec cnic A/Shanghai-Luwan/188/2011 Feb # A/Perth/16/2009 # F $ A/Victoria/210/2009 Jun # F A/Victoria/210/2009 X-187 # F A/Alabama/03/2011 Apr A/Wisconsin/15/2009 Jun # F A/Victoria/208/2009 Jun # 0.002 3A 3B 3C 1 AND 2 5 AND 6 4 7 D147N D151/D/N/V/G/S/A (N ADD GLY) I215V D127N I307M L338F N342D N402D LOSS GLY L81P D93G N402D LOSS GLY S367N ADD GLY K369T I464L

26. HI Reactions of Influenza A(H3N2) Viruses (Guinea Pig Red Blood Cells; 02/22/12)

27. HI Reactions of Influenza A(H3N2) Viruses (Guinea Pig Red Blood Cells with 20 nM Oseltamivir) NIMR

28. Virus Neutralization: Plaque Reduction Assay for Influenza A(H3N2) Viruses (CDC)

29. Influenza A(H3N2) Isolates Characterized by CDC

30. H3 low reactors in HI assays in WHO CCs WHO CCA/Perth/16/09Low (≥ 8 fold) CDC 375 (83%)76 (17%) CNIC 36 (92%) 3 (8%) NIID 41 (100%)0 (0%) NIMR61 (67%)30 (33%) VIDRL 274 (99%) 3 (1%) Total827 (89%)112 (13%)

31. Antigenic Cartography: CDC

33. Antigenic Cartography: NIMR

35. Recent Group 3 180° rotation S214I T212A A198S K62E K144N* L183H V223I N312S Q33R N278K S45N T48I H3 Hemagglutinin Structure

36. Influenza A(H3N2) Activity Influenza A(H3N2) viruses circulated in many countries during this period In northern Africa, regional and widespread activity was reported from December onwards In Asia, regional activity was reported in several countries with widespread reported in January in Japan In Europe, activity increased in January with regional and widespread activity reported in Spain and other countries In North America, spordic and local activity was reported in Canada and Mexico while the USA reported regional activity from November onwards

37. Influenza A(H3N2) Virus Summary A(H3N2) viruses analyzed from Sept. 2011- Jan. 2012 were antigenically and genetically heterogeneous An increasing proportion of viruses showed reduced reactivity with ferret serum against A/Perth/16/2009-like viruses and higher titres with antisera against A/Vic/361/2011 and A/Brisbane/299/2011 reference viruses in HI and PRMN assays The HA genes of most recent H3N2 viruses fall in genetic groups 3 and 6 H3N2 viruses were resistant to adamantanes and sensitive to neuraminidase inhibitors

39. Influenza B viruses Sept 2011 – Feb 2012

40. In recent years viruses of the B/Victoria lineage vastly predominated over viruses of the B/Yamagata lineage in many regions of the world. This situation seems to be changing. Introduction

42. Influenza B viruses received in the WHO CCs

43. B/Yamagata and B/Victoria isolations B/Victoria – Blue, B/Yamagata- Red – from August 2011

45. HI Reactions of Influenza B/Victoria Viruses

46. HI Reactions of Influenza B/Yamagata Viruses

47. Influenza B Isolates Characterized by CDC

48. HI reactions of recent influenza B (Yamagata lineage) viruses

49. Influenza B/Victoria lineage antigenic cartography - 3

50. WHO information meeting on influenza vaccine composition for northern hemisphere 2012-2013 23 February 2012 EB Room WHO HQ Geneva B low reactors in HI assays in WHO CCs WHO CCVictoria (Br/60) Yamagata (Wisc/1/2010) CDC Low Reactors 148 (76%) 4 (3%) 47 (24%) 0 (0%) CNIC Low Reactors 1311 (89%) 256 (19%) 192 (11%) 8 (4%) NIID Low Reactors 6 (13%) 0 (0%) 39 (87%) 3 (8%) NIMR Low Reactors 18 (38%) 0 (0%) 30 (62%) 9 (30%) VIDRL Low Reactors 91 (82%) 27 (30%) 20 (18%) 1 (5%) Total Low Reactors 1594 (93%) 287 (18%) 328 (17%) 21 (6.4%)

51. Evolutionary Relationships Among Influenza B (Victoria) Hemagglutinin (HA) Genes, 2011-12 Current Northern Hemisphere Vaccine Strain LR- Low Reactor to B/Brisbane/60/2008 (≥ 8 fold) F - CDC Reference Antigen # Egg Isolate $- CDC Serology Antigen ____ 165N October 2011 November 2011 December 2011 January 2012 B/India/5875/2011 Dec B/Ontario/RV0011/2011 Dec B/British Columbia/4787/2011 Nov LR B/Wisconsin/01/2012 Jan B/Florida/01/2012 Jan nimr B/Sachen Anhalt/1/2012 Jan nimr B/Ireland/12m2515/2012 Jan gre B/Athens/12/2012 Jan B/Nevada/03/2011 Feb # F B/Nevada/03/2011 Feb F B/Bangladesh/5004/2011 Sep LR B/Uganda/2920/2011 Nov B/Wisconsin/02/2011 Jan # nimr B/Hong Kong/767/2011 Jun B/California/02/2012 Jan B/Newfoundland/RV0032/2012 Jan B/Brisbane/60/2008 BX-31B # B/Brisbane/60/2008 BX-35 # B/Brisbane/60/2008 Aug # F $ B/Mexico/3087/2011 Jul # LR B/Mexico/3750/2011 Dec B/Georgia/07/2010 Nov # F B/Michigan/09/2011 Sep # F B/Dominican Republic/5486/2011 Jul # $ B/Georgia/07/2010 Nov F niid B/Taiwan/371/2011 May # B/Paraguay/0241/2011 Dec B/Wisconsin/06/2011 Dec gre B/Athens/11532/2011 Dec gre B/Athens/90/2012 Jan nimr B/Israel/15/2011 Dec B/Delaware/01/2012 Jan B VIC HA Consensus 2011-12 B/Nigeria/5451/2011 Jan B/St Petersburg/05/2011 Feb # B/Kansas/01/2012 Jan B/Shanghai-Jingan/1392/2011 Apr # B/Jiangsu-Pingjiang/1603/2011 Nov cnic B/Guangdong-Luohu/1351/2011 Sep # B/Chongqing-Yuzhong/1651/2011 Oct # $ B/Hiroshima/09/2010 Sep # LR F cnic B/Shanghai-Chongming/1458/2011 Nov cnic B/Shanghai-Songjiang/176/2011 Feb # cnic B/Shanghai-Xuhui/1374/2011 Sep # B/Sichuan-Bazhou/1249/2011 Nov B/Shanghai-Putuo/1623/2011 Nov nimr B/Hong Kong/1129/2011 Dec nimr B/Hong Kong/1153/2011 Dec aus B/Victoria/304/2006 # B/Bolivia/1526/2010 # LR F B/Bolivia/1526/2010 LR F B/Malaysia/2506/2004 # B/Uruguay/12/2008 Jun # LR B/Fujian/Gulou1272/2008 Mar # F B/Hunan-Yuhu/311/2009 Mar F niid B/Taiwan/318/2011 Apr # B/Vietnam/92/2011 Mar LR F B/Cambodia/1412/2011 Oct # LR B/Cambodia/1412/2011 Oct LR B/Ohio/01/2005 Feb # LR F 0.002 1 5 6 2 4 3 N75K N165K S172P V15I V146I T37I N165K K167R T182K Intra-clade Reassortants HA-1/NA-3 Intra-clade Reassortants HA-1/NA-4

52. Evolutionary Relationships Among Influenza B (Victoria) Neuraminidase (NA) Genes, 2011-12 Current Northern Hemisphere Vaccine Strain LR- Low Reactor to B/Brisbane/60/2008 (≥ 8 fold) F - CDC Reference Antigen # Egg Isolate $- CDC Serology Antigen October 2011 November 2011 December 2011 January 2012 B/Ohio/1/2005 # LR F B/Bolivia/1526/2010 # LR F B/Bolivia/1526/2010 LR F B/Uruguay/12/2008 Jun # LR B/Paraguay/0241/2011 Dec B/Georgia/07/2010 Nov # F B/Mexico/3087/2011 Jul # B/Mexico/3750/2011 Dec B/Dominican Republic/5486/2011 Jul # $ B/Georgia/07/2010 Nov F B/Wisconsin/06/2011 Dec B/Michigan/09/2011 Sep # F aus B/Brisbane/99/2011 Sep niid B/Taiwan/371/2011 May # B/Cambodia/1412/2011 Oct # B/Cambodia/1412/2011 Oct LR niid B/Taiwan/318/2011 Apr # B/Vietnam/92/2011 Mar LR F B/Kansas/01/2012 Jan cnic B/Guangdong-Luohu/1351/2011 Sep # B/Jiangsu-Pingjiang/1603/2011 Nov B/Chongqing-Yuzhong/1651/2011 Oct # $ B/Shanghai-Jingan/1392/2011 Apr # B VIC NA Consensus 2011-12 cnic B/Shanghai-Songjiang/176/2011 Feb # cnic B/Shanghai-Xuhui/1374/2011 Sep # cnic B/Shanghai-Chongming/1458/2011 Nov nimr B/Hong Kong/1153/2011 Dec B/Shanghai-Putuo/1623/2011 Nov B/Sichuan-Bazhou/1249/2011 Nov B/Hunan-Yuhu/311/2009 Mar F B/Fujian/Gulou1272/2008 Mar # F B/Malaysia/2506/2004 # 0.005 nimr B/Ireland/12m2515/2012 Jan nimr B/Sachen Anhalt/1/2012 Jan B/Wisconsin/01/2012 Jan B/Florida/01/2012 Jan B/Oman/65/2012 Jan B/Ontario/RV0011/2011 Dec B/British Columbia/4787/2011 Nov B/India/5875/2011 Dec B/California/02/2012 Jan B/Bangladesh/5004/2011 Sep LR B/Nevada/03/2011 Feb # F $ B/Nevada/03/2011 Feb F B/Newfoundland/RV0032/2012 Jan nimr B/Hong Kong/767/2011 Jun B/Uganda/2920/2011 Nov B/Wisconsin/02/2011 Jan # B/Brisbane/60/2008 Aug # F $ B/Brisbane/60/2008 BX-31B # B/Brisbane/60/2008 BX-35 # nimr B/Israel/15/2011 Dec B/Hiroshima/09/2010 Sep # LR F B/Nigeria/5451/2011 Jan B/St Petersburg/05/2011 Feb # B/Delaware/01/2012 Jan 1 3 Intra-clade Reassortants HA-1/NA-3 6 4 5 Intra-clade Reassortants HA-1/NA-4 aus B/Victoria/304/2006 # 2 D329N N340D N220K S295R E358K Q61H M375K L73F S397R T8M A389T S41P N125K D320E D463N T8M S15L S34L Y210F P42S V271I E320D K404E K272Q E320K D342G M375K D384N A465T ADD GLY

53. B/Victoria lineage viruses Phylogenetic analysis of HA gene sequences

54. Evolutionary Relationships Among Influenza B (Yamagata) Hemagglutinin (HA) Genes, 2011-12 LR- Low Reactor to A/Wisconsin/01/2010 (≥ 8 fold) F - CDC Reference Antigen # Egg Isolate $- CDC Serology Antigen October 2011 November 2011 December 2011 January 2012 B/California/15/2011 Dec niid B/Yamanashi/4/2012 Jan niid B/Sakai/41/2011 Nov niid B/Sakai/36/2011 Nov niid B/Niigata/30/2012 Jan niid B/Kanagawa/38/2011 Dec niid B/Kobe/293/2012 Jan usafsam B/California/nhrcx86/2011 Nov usafsam B/California/nhrcx87/2011 Nov B/British Columbia/RV1383/2011 Sep B/Connecticut/04/2011 Dec B/Arizona/01/2012 Jan B/Hunan-Yuhua/1555/2011 Nov B YAM HA Consensus 2011-12 B/Fujian-Gulou/1553/2011 Aug # nimr B/Berlin/147/2011 Dec B/Hawaii/05/2011 Dec B/New Mexico/06/2011 Oct B/Iowa/01/2012 Jan B/Utah/01/2012 Jan cnic B/Fujian-Gulou/1669/2011 Oct # cnic B/Jiangsu-Tianning/1470/2011 Nov B/Wisconsin/01/2010 Feb # F $ B/Wisconsin/01/2010 BX-41A # B/Wisconsin/01/2010 BX-41 # B/Hubei-Wujiagang/158/2009 BX-39A # B/Hubei-Wujiagang/158/2009 BX-39 # B/Hubei-Wujiagang/158/2009 # F B/Texas/06/2011 Feb # F B/Texas/06/2011 Feb F niid B/Kobe/299/2012 Jan nimr B/Ireland/12M1522/2012 Jan B/Stockholm/12/2011 Feb # nimr B/Sweden/2/2011 Nov nimr B/Paris/1900/2011 Nov swe B/Stockholm/1/2012 Jan spn B/Catalonia/S4361/2012 Jan nimr B/Ghana/FS-11-1995/2011 Nov gre B/Athens/97/2012 Jan nimr B/Israel/20/2011 Dec B/Bangladesh/3333/2007 Aug # F B/Missouri/01/2012 Jan B/New Mexico/08/2011 Dec niid B/Hiroshima/64/2011 Nov niid B/Taiwan/1056/2011 Oct # gre B/Athens/70/2012 Jan niid B/Sapporo/72/2011 Dec B/Finland/39/2010 Dec # F B/California/12/2011 Nov B/Idaho/06/2011 Dec B/New Hampshire/01/2012 Jan B/New Hampshire/02/2012 Jan B/Taiwan/1242/2011 Nov # F B/Texas/10/2011 Dec # B/Washington/01/2012 Jan niid B/Osaka-C/1038/2011 Dec niid B/Taiwan/928/2011 Oct # B/Florida/04/2006 Nov # F B/Pennsylvania/07/2007 Mar # 0.002 3 2 1 R48K P108A T182A S230G S150I N166Y S230D E479D N203S N116K E183G T182K V29A L173Q M252V

55. LR- Low Reactor to A/Wisconsin/01/2010 (≥ 8 fold) F - CDC Reference Antigen # Egg Isolate $- CDC Serology Antigen October 2011 November 2011 December 2011 January 2012 Evolutionary Relationships Among Influenza B (Yamagata) Neuraminidase (NA) Genes, 2011-12 niid B/Sakai/36/2011 Nov niid B/Sakai/41/2011 Nov niid B/Kobe/293/2012 Jan niid B/Fukui/48/2011 Nov B/Connecticut/04/2011 Dec B/California/15/2011 Dec B/British Columbia/RV1383/2011 Sep B/Arizona/01/2012 Jan niid B/Kanagawa/38/2011 Dec niid B/Niigata/30/2012 Jan niid B/Yamanashi/4/2012 Jan B/Hawaii/05/2011 Dec B/New Mexico/06/2011 Oct B/Iowa/01/2012 Jan B/Utah/01/2012 Jan B/Hunan-Yuhua/1555/2011 Nov B YAM NA Consensus 2011-12 B/Fujian-Gulou/1553/2011 Aug # nimr B/Berlin/147/2011 Dec cnic B/Fujian-Gulou/1669/2011 Oct cnic B/Jiangsu-Tianning/1470/2011 Nov B/Wisconsin/01/2010 BX-41 # B/Wisconsin/01/2010 BX-41A # B/Wisconsin/01/2010 Feb # F $ B/Hubei-Wujiagang/158/2009 BX-39A # B/Hubei-Wujiagang/158/2009 BX-39 # B/Hubei-Wujiagang/158/2009 # F B/Texas/06/2011 Feb # F B/Texas/06/2011 Feb F niid B/Kobe/299/2012 Jan nimr B/Ireland/12M1522/2012 Jan nimr B/Paris/1900/2011 Nov nimr B/Sweden/2/2011 Nov swe B/Stockholm/1/2012 Jan B/Stockholm/12/2011 Feb # spn B/Catalonia/S4361/2012 Jan nimr B/Ghana/FS-11-1995/2011 Nov nimr B/Israel/20/2011 Dec B/Bangladesh/3333/2007 Aug # F niid B/Sapporo/72/2011 Dec niid B/Hiroshima/64/2011 Nov niid B/Taiwan/1056/2011 Oct # B/California/12/2011 Nov B/Finland/39/2010 Dec # F B/Idaho/06/2011 Dec B/Taiwan/1242/2011 Nov # F B/Washington/01/2012 Jan niid B/Osaka-C/1038/2011 Dec niid B/Taiwan/928/2011 Oct # B/Texas/10/2011 Dec # B/New Hampshire/01/2012 Jan B/New Hampshire/02/2012 Jan B/Missouri/01/2012 Jan B/New Mexico/08/2011 Dec B/Florida/04/2006 Nov # F B/Pennsylvania/07/2007 # 0.002 3 2 1 Q42R A68T T125K K186R D340N T106I I248V S295R R65H D463N A465T ADD GLY L73P T106N S295N ADD GLY S27L

56. B/Yamagata lineage viruses Phylogenetic analysis of HA gene sequences

57. Influenza B activity has been low except for China. In China viruses of the B/Victoria lineage > B/Yamagata lineage Elsewhere previously B/Victoria lineage viruses predominated BUT now The proportion of B/Yamagata lineage viruses is increasing. B/Victoria lineage viruses are predominantly similar genetically and antigenically to B/Brisbane/60/2008 The majority of B/Yamagata lineage viruses are antigenically and genetically similar to the egg propagated reference viruses: B/Wisconsin/1/2010 B/Stockholm/12/2011 B/Texas/6/2011 B/Hubei-Wujiagang/158/2009 Summary

58. WHO recommendation on influenza vaccine composition for northern hemisphere 2012-2013

59. Method of work All year around surveillance conducted by GISRS –WHOCCs, NICs, ERLs, H5 Reference Laboratories A WHO Consultation 20-22 Feb 2012: Review, analysis and conclusion –Chaired by Dr Masato Takato, WHOCC, NIID Tokyo –9 Advisers: Directors of WHOCCs and ERLS Disclosure DOI at the beginning of the Consultation –20 observers from NICs, H5 Reference Laboratories, WHOCCs, ERLs, academia and veterinary sector

60. Summary of A(H1N1)pdm09 viruses A(H1N1)pdm09 viruses –Continued to circulate; at low levels in general Except Mexico and a couple of countries in SH –Antigenically similar to A/California/7/2009. –Genetically falling into 8 groups, but antigentically indistinguishable. –Vaccines containing A/California/7/2009-like antigens stimulated anti-HA antibodies of similar titres against the vaccine virus and recent A(H1N1)pdm09 viruses. No former seasonal A(H1N1) viruses detected

61. Summary of influenza A(H3N2) Predominant in Europe and some other countries in NH; outbreaks in several countries; activity increasing currently in Europe. Genetically recent viruses falling into 2 groups; group 3 viruses (majority) represented by A/Victoria/361/2011 and group 6 by A/Brisbane/299/2011. Antigenically many recent viruses were similar to the vaccine virus A/Perth/16/2009. An increasing proportion of 2012 viruses showed reduced reactivity to antisera against A/Perth/16/2009, but higher titers with antisera against reference viruses in group 3 and 6. Vaccines containing A/Perth/16/2009-like antigens stimulated anti-HA antibodies of lower titres against recent A(H3N2) viruses than the vaccine virus.

62. Summary of influenza B (1) Influenza B activity has been low in general except China Both B/Victoria/2/87 and B/Yamagata/16/88 lineages co-circulated –In the past couple of years, B-Vic viruses predominated –In the past few months, similar proportions in some countries B-Vic predominant, notably in mainland China –Increasing prevalence of B/Yamagata lineage viruses The majority of recent B/Victoria/2/87 lineage viruses were antigenically and genetically closely related to B/Brisbane/60/2008

63. Summary of influenza B (2) Most recent B/Yamagata/16/88 lineage viruses –Antigenically distinguishable from the previous vaccine virus B/Florida/4/2006 –More closely related to B/Wisconsin/1/2010, B/Hubei- Wujiagang/158/2009, B/Texas/6/2011 and B/Stockholm/12/2011 –Genetically HA of most recent viruses are in clade 3 Current vaccines containing B/Brisbane/60/2008 antigens stimulated anti-HA antibodies that had similar titers against the vaccine viruses and recent viruses of the B/Victoria/2/87 lineage; however, titers were lower to recent viruses of the B/Yamagata/16/88 lineage

64. Recommendation It is recommended that the following viruses be used for influenza vaccines in the 2012-2013 influenza season (northern hemisphere): – an A/California/7/2009 (H1N1)pdm09-like virus; – an A/Victoria/361/2011 (H3N2)-like virus; and – a B/Wisconsin/1/2010-like virus.