INFORMATION FOR THE VACCINE AND RELATED BIOLOGICAL PRODUCTS ADVISORY COMMITTEE CBER, FDA Information Regarding Seasonal Influenza Viruses FEBRUARY 27, 2013 Nancy J. Cox, Ph. D. Director, Influenza Division Director, WHO COLLABORATING CENTER FOR SURVEILLANCE, EPIDEMIOLOGY AND CONTROL OF INFLUENZA Influenza Division National Center for Immunization and Respiratory Diseases Coordinating Center for Infectious Diseases Centers for Disease Control and Prevention Atlanta, GA 30333

Global Influenza Surveillance and Response Network (GISRS) All year around surveillance conducted by GISRS –6 WHOCCs, 140 NICs, 4 ERLs, H5 Reference Laboratories Feb 2013 WHO Consultation: Data review and analysis; write recommendations Co-Chaired by Dr. Nancy Cox, WHOCC CDC Atlanta and Dr. Masato Tashiro, WHOCC, NIID Tokyo –9 Advisers: Directors of WHOCCs and ERLS Disclosure of potential conflicts of interest 18 observers from NICs, H5 Reference Laboratories, WHOCCs, WHO ERLs, academic partners and the veterinary sector

Influenza B – September 2012-January 2013 maximum influenza activity

Percentage of influenza viruses by subtypes (From 2 September 2012 – 2 February 2013) A(H5), 6 human viruses Data source: FluNet, ( Global Influenza Surveillance and Response System (15 February 2013)

Type and Subtype OseltamivirZanamivir Tested (n) Normal Reduced Highly Reduced Tested (n) Normal Reduced Highly Reduced US viruses: b1b 2c2c A(H1N1)pdm A(H3N2) B Non-US viruses: A(H1N1)pdm A(H3N2) B a Viruses were tested in the fluorescent NA inhibition assay. Inhibition is based on fold difference in IC 50 of a test virus compared to the median IC 50 value for type/subtype. The WHO AVWG criteria: Type A viruses - Normal: 100-fold.Type B viruses - Normal: 50-fold. b Influenza B/Maryland/07/2012 virus, GISIAD acc.no for NA: EPI c H275Y was detected in two A(H1N1)pdm09 viruses. Susceptibility to Neuraminidase Inhibitors: Inhibition of Neuraminidase Activity a Virus collection period: Oct 01, Jan 21, 2013

A(H1N1)pdm09 Viruses Sept 2012 – Jan 2013

Number of A(H1N1)pdm09 Viruses Detected by GISRS Data source: FluNet, ( Global Influenza Surveillance and Response System (15 February 2013)

(H1N1)pdm09 Viruses Characterized During the Past 3Years, September to January

(H1N1)pdm09 low reactors in HI assays by WHO CCs WHO CCA/Cal/7/09Low (≥ 8 fold) CDC 152 (95%)8 (5%) CNIC 120 (98%) 2 (2%) NIID 8 (99%) 1 (1%) NIMR 94 (98%) 2 (2%) VIDRL 18 (100%) 0 (0%) Total 392 (96.8%) 13 (3.2%)

REFERENCE FERRET ANTISERA 567 EGGMDCKEGGMDCKHASEQ.DATE REFERENCE ANTIGENSCA/7FL/27MD/13BA/2021 WA/24 CO/14GROUPCHANGECOLL. PASS. 1A/CALIFORNIA/7/2009* /09/09 E3 2A/FLORIDA/27/ /30/11 E4 3A/MARYLAND/13/ /01/12 M1/C2 4A/BANGLADESH/2021/2012* N156S07/21/12 E4 5A/BANGLADESH/2021/ N156S07/21/12 C1/C4 6A/WASHINGTON/24/2012* /17/12 E4 7A/WASHINGTON/24/ /17/12 C3 8A/COLORADO/14/ /28/12 C1/C2 TEST ANTIGENS 9A/FLORIDA/60/ /18/12 C1 10A/MINNESOTA/28/ /09/12 C2 11A/MINNESOTA/30/ /23/12 C1 12A/OHIO/106/ /29/12 C2 13A/MINNESOTA/29/ /08/12 C2 14A/PENNSYLVANIA/30/ /04/12 C2 15A/WISCONSIN/49/ /11/12 C2 16A/WYOMING/30/ /19/12 C H275Y/NA12/26/12 C1 18A/NEW JERSEY/11/ /08/12 C2 19A/NORTH CAROLINA/29/ /27/12 M1/C1 20A/TEXAS/99/ /17/12 M1/C1 21A/CHIANG RAI/312/2012* /02/12 C2/C2 22A/INDIA/2181/ /21/12 C1 23A/INDIA/2192/ /22/12 E3 24A/INDIA/2243/ /28/12 C1 25A/BANGLADESH/0019/ /18/12 C2 26A/INDIA/2055/ /03/12E3 27A/INDIA/2055/ /03/12C1 28A/INDIA/2080/ /06/12C1 29A/INDIA/2192/2012* /22/12C1 30A/INDIA/2205/ /24/12E3 31A/INDIA/2227/ /25/12C1 32A/BANGLADESH/5011/ /26/12C2 33A/INDIA/2150/ /17/12C2 Sequence in GISAID * Serology Oseltamivir resistant All but 2 viruses tested were well inhibited by ferret antisera raised against A/California/07/2009 and other recent reference viruses. The 2 low reactors did not acquire changes at positions HEMAGGLUTINATION INHIBITION REACTIONS OF INFLUENZA A(H1N1)pdm09 VIRUSES (01/23/13)

REFERENCE FERRET ANTISERA 567 X-179HASEQ.DATE REFERENCE ANTIGENSCA/7 FL/27MD/13BA/2021 WA/24 CO/14GROUPCHANGECOLL.PASS. 1A/CALIFORNIA/07/2009* /09/09E3 2A/CALIFORNIA/07/2009 X G155EREASS.EX/E2 3A/FLORIDA/27/ /30/11E4 4A/MARYLAND/13/ /01/12M1/C2 5A/BANGLADESH/2021/2012* /21/12E4 6A/BANGLADESH/2021/ /21/12C1/C4 7A/WASHINGTON/24/2012* /17/12E5 8A/WASHINGTON/24/ /17/12C3 9A/COLORADO/14/ /28/12C1/C2 TEST ANTIGENS 10A/GEORGIA/01/ /02/13C1 11A/MASSACHUSETTS/01/ /02/13M1/C1 12A/MASSACHUSETTS/02/ /02/13M1/C1 13A/PENNSYLVANIA/34/ /20/12C2 14A/TENNESSEE/09/ /31/12C3 15A/TEXAS/106/ /15/12C1 16A/WISCONSIN/01/ /06/13C1 17A/WISCONSIN/02/ /02/13C1 18A/HAWAII/42/ /02/12M2/C1 19A/HAWAII/43/ /04/12M2/C1 20A/NEW YORK/01/ /07/13C2 21A/NEW BRUNSWICK/RV0041/ /02/12X1/C1 22A/ONTARIO/RV0013/ /12/12X1/C1 23A/ONTARIO/RV3144/ /03/12X1/C1 24A/ONTARIO/RV3149/ /12/12X1/C1 25A/NEW BRUNSWICK/RV0040/ /03/12X1/C1 26A/INDIA/2139/ /17/12C2 27A/TANZANIA/2085/ /10/12C2 28A/INDIA/2019/ /26/12C1 29A/INDIA/2080/ /06/12E4 30A/INDIA/2171/ /19/12E4 31A/INDIA/2181/ /21/12E4 32A/INDIA/2192/ /22/12E4 33A/TANZANIA/2074/ /05/12C2 34A/TANZANIA/2081/ /03/12C2 35A/TANZANIA/332/ /11/12C1 36A/TANZANIA/339/ /18/12C1 37A/INDONESIA/PAL102/ G155E08/24/12C2/C1 Sequence in GISAID * Proposed serology antigen HEMAGGLUTINATION INHIBITION REACTIONS OF INFLUENZA A(H1N1)pdm09 VIRUSES (01/29/13)

Antigenic Cartography of A(H1N1)pdm09 Viruses Sept 2012 to Feb 2013 – Gold, Aug 2011 to Aug 2012 – Blue, Earlier – Grey A/California /07/2009

A/California/07/2009 Apr # F $ NYMC X179A A/California/07/2009 # F NYMC X181 A/California/07/2009 # nimr A/Dakar/20/2012 Dec A/Cote DIvoire/1575/2013 Jan A/Nigeria/7781/2012 Oct A/Minnesota/16/2012 Oct A/Minnesota/03/2011 Feb F A/Minnesota/03/2011 Feb # F afrims A/Thailand/KPPH-00066/2012 niid A/Laos/I650/2012 * namru2 A/Cambodia/FSS23932/2012 Dec A/Chiang Rai/312/2012 Oct $ nimr A/Netherlands/507/2012 cnic A/Jilin-Chaoyang/SWL1709/2012 Dec A/Bangladesh/2021/2012 Jul LR # F C$ A/Bangladesh/2021/2012 Jul LR F nimr A/Ukraine/3/2013 Jan A/Florida/02/2013 Jan A/Wisconsin/02/2013 Jan A/India/2192/2012 Dec # F A/India/2192/2012 Dec F $ A/India/2150/2012 Dec LR A H1pdm09 HA Consensus nimr A/Norway/35/2013 Jan nimr A/England/658/2012 Dec A/New York/01/2013 Jan A/Gansu-Ganzhou/33/2012 Nov # hk A/Hong Kong/62/2013 Jan A/Tanzania/340/2012 Dec # A/Utah/01/2013 Jan A/Cote DIvoire/1529/2012 Dec # A/Oman/412/2012 Dec usafsam A/NewYork/1428/2013 Jan A/Georgia/01/2013 Jan # cnic A/Beijing/SWLChaoyang-P031/2013 Jan LR usafsam A/Korea/1419/2013 Jan A/Japan/1419/2013 Jan A/Washington/24/2012 # F $ A/Washington/24/2012 F namru6 A/Peru/FPI03819/2012 nhrc A/SouthCarolina/x88/2012 usafsam A/SouthCarolina/22/2012 Oct A/Wyoming/31/2012 afrims A/Nepal/NPBH-00402/2012 afrims A/Bhutan/BTA-00098/2012 A/Tanzania/2085/2012 Dec # nimr A/Ghana/DILI-0902/2012 Oct cnic A/Beijing-Huairou/SWL11348/2012 Dec niid A/Yokohama/1/2013 Jan * A/Massachusetts/02/2013 Jan usafsam A/SouthDakota/1411/2013 Jan A/California/09/2013 Jan hk A/Hong Kong/9259/2012 Dec A/Ohio/02/2013 Jan Evolutionary Relationships Among Influenza A (H1N1)pdm09 Hemagglutinin (HA) Genes, /22/2013 Current Northern Hemisphere Vaccine Strain LR- Low Reactor to A/California/07/2009 Egg (≥ 8 fold) F - CDC Reference Antigen $- CDC Serology Antigen C$- Common Serology - Oseltamivir Resistant # Egg Isolate * – only HA1 region October 2012 November 2012 December 2012 January HA Genetic Groups Since September 2012 S185T S451N P83S S203T I321V E374K A197T S143G K163I V520A S84G D97N K283E E499K H138R V249L V234I H51N I295V R205K V249L I216V A186T V272A N473D T474K V520A N156S N125S K163Q A256T I116M R205K S69T N260D V520A K154K/E

Evolutionary Relationships Among Influenza A (H1N1)pdm09 Neuraminidase (NA) Genes, /22/2013 Current Northern Hemisphere Vaccine Strain LR- Low Reactor to A/California/07/2009 Egg (≥ 8 fold) F - CDC Reference Antigen $- CDC Serology Antigen C$- Common Serology - Oseltamivir Resistant H275Y # Egg Isolate HA Genetic Group Shown October 2012 November 2012 December 2012 January 2013 niid A/Yokohama/1/2013 Jan A/Ohio/02/2013 Jan A/California/09/2013 Jan A/Massachusetts/02/2013 Jan cnic A/Beijing-Huairou/SWL11348/2012 Dec nimr A/Ghana/DILI-0902/2012 Oct A/Tanzania/2085/2012 Dec # A/Georgia/01/2013 Jan # A/Cote DIvoire/1529/2012 Dec # nimr A/England/658/2012 Dec A/New York/01/2013 Jan nimr A/Norway/35/2013 Jan A/India/2150/2012 Dec LR A/Wisconsin/02/2013 Jan A/Utah/01/2013 Jan A/Tanzania/340/2012 Dec # A N1pdm09 NA Consensus A/Oman/412/2012 Dec A/India/2192/2012 Dec F $ A/India/2192/2012 Dec # F A/Florida/02/2013 Jan A/Gansu-Ganzhou/33/2012 Nov # A/Washington/24/2012 # F $ A/Washington/24/2012 F A/Wyoming/31/2012 A/Japan/1419/2013 Jan cnic A/Beijing/SWLChaoyang-P031/2013 Jan LR A/Minnesota/03/2011 Feb # F A/Minnesota/03/2011 Feb F A/Chiang Rai/312/2012 Oct $ niid A/Laos/I650/2012 nimr A/Netherlands/507/2012 cnic A/Jilin-Chaoyang/SWL1709/2012 Dec A/Minnesota/16/2012 Oct nimr A/Ukraine/3/2013 Jan A/Bangladesh/2021/2012 Jul LR # F C$ A/Bangladesh/2021/2012 Jul LR F A/Nigeria/7781/2012 Oct A/Cote DIvoire/1575/2013 Jan nimr A/Dakar/20/2012 Dec A/California/07/2009 Apr # F $ NYMC X179A A/California/07/2009 # F NYMC X181 A/California/07/2009 # G41R N44S ADD GLY L40V I106V N200S N248D V241I N369K D451G N222D N386S LOSS GLY N386K LOSS GLY V106I F74V N385T N44S ADD GLY

Summary - 1 A(H1N1)pdm09 viruses co-circulated in varying proportions along with A(H3N2) and B viruses. Regional A(H1N1)pdm09 activity was reported by a few countries in Asia and Central America. An increase in activity was reported, with regional and widespread outbreaks in January in many countries in Europe. Widespread outbreaks were reported in Algeria in January. Localized and sporadic influenza activity were reported in many other countries in northern Africa, Asia and North America.

Most A(H1N1)pdm09 viruses were antigenically similar to the recommended vaccine virus A/California/7/2009. Most recent A(H1N1)pdm09 viruses belong to genetic Clades 6 and 7. The majority of A(H1N1)pdm09 viruses were sensitive to oseltamivir. Of the small number of viruses that were resistant to oseltamivir, all had the H275Y mutation. Summary - 2

A(H3N2) Viruses Sept 2012 – Jan 2013

Number of A(H3N2) Viruses Detected by GISRS Data source: FluNet, ( Global Influenza Surveillance and Response System (15 February 2013)

H3N2 Viruses Characterized During the Past 3 Years from September to January USAChinaJapanUKAustralia

H3 low reactors in HI assays by WHO CCs WHO CCA/Vic/361/11 (MDCK) Low (≥ 8 fold) CDC 761 (99%)5 (1%) CNIC 829 (100%) 0 (0%) NIID 88 (98%)2 (2%) NIMR 115 (95%)6 (5%) VIDRL 117 (100%) 0 (0%) Total1923 (97%) 13 (3%)

REFERENCE FERRET ANTISERA 3C EGGMDCKEGGMDCKHASEQDATE REFERENCE ANTIGENSVIC/361 TX/50 GROUPCHANGESCOLL.PASS. 1A/VICTORIA/361/ CH156Q, G186V,S219Y 1 10/24/11E3/E3 2A/VICTORIA/361/ C10/24/11C2/C3 3A/TEXAS/50/ C T128N, G186V, S198P, S219F 2 04/15/12E5 4A/TEXAS/50/ C T128N, S198P 2 04/15/12M1/C2 5A/TEXAS/50/2012 X C I226N 3 REASS 6A/TEXAS/50/2012 X-223A C I226N 3 REASS TEST ANTIGENS 4 7A/ARKANSAS/05/ A12/19/12C2 8A/VIRGINIA/03/ CT128A, R142G, N145S 2 01/04/13C2 9A/NEW HAMPSHIRE/21/ CT128A, R142G, N145S 2 12/14/12R1/C1 10A/SOUTH CAROLINA/16/ /07/12M1/C2 11A/KANSAS/16/ CT128A, R142G, N145S 2 12/12/12C1 12A/MASSACHUSETTS/15/ CT128A, R142G, N145S 2 12/18/12C1 13A/COTE D'IVOIRE/1331/ /07/12X/C1 14A/SAPPORO/125/ CN145S 3 11/01/12C1/C1 15A/HUBEI-HONGSHAN/1368/ CN145S 3 09/26/12C4/C2 16A/JIANGSU-XIUCHENG/1358/ CT128A, R142G, N145S 3 09/04/12C3/C2 17A/LAOS/717/ /17/12C2/C1 18A/LAOS/727/ /17/12C1/C1 HEMAGGLUTINATION INHIBITION REACTIONS OF INFLUENZA H3 VIRUSES (GUINEA PIG RED BLOOD CELLS) (01/24/13) 1. Egg-propagated A/Victoria/361/2011 differs from the cell-propagated A/Victoria/361/2011 at the 3 positions indicated. 2. Substitution in the HAs of the clade 3C viruses compared to cell-propagated A/Victoria/361/ Substitution in the HAs of the A/Texas/50/2012 reassortants compared to egg-propagated A/Texas/50/ All test viruses were cell-propagated.

Neutralization titer Post infection ferret sera VirusesA/StockholmA/AthensA/Vic Collection Passage18/11112/12361/11 Date History T/C F28/11T/C F16/12Egg F35/12T/C F14/12 Genetic group group 3Agroup 3Bgroup 3C REFERENCE VIRUSES A/Stockholm/18/20113A3/28/2011MDCK2/SIAT A/Athens/112/2012 3B 2/1/2012SIAT A/Victoria/361/2011 3C 10/24/2011E3/E A/Victoria/361/2011 3C 10/24/2011MDCK2/SIAT A/Texas/50/2012 3C 4/15/2012E5/E TEST VIRUSES A/England/565/20123B5/31/2012SIAT2/SIAT A/England/587/20123C (128, 142)10/31/2012SIAT1/SIAT A/England/586/20123C (128, 142)11/2/2012SIAT1/SIAT A/Austria/705367/ /6/2012SIAT1/SIAT A/England/593/20123C (128, 142)11/12/2012SIAT1/SIAT A/Thuringen/33/123C11/12/2012C2/SIAT A/Cairo/59/20123B12/6/2012C1/SIAT A/Norway/2496/20123C12/10/2012SIAT A/Austria/710638/ /11/2012SIAT1/SIAT A/Cairo/81/20133B12/11/2012C1/SIAT Antigenic Analysis of Influenza A(H3N2) Viruses - Plaque Reduction Neutralization (MDCK-SIAT)

Passage< 4-fold>8 foldtotal tested n%n%n VIC/361C2/C344699%31%449 VIC/361E3/E38519%36481%449 VIC/361 IVR-165EX/E200%10100%10 TX/50M1/C %00%449 TX/50E537283%7717%449 HI/22C3448>99%1<1%449 HI/22E422951%21047%449 Summary of fold differences between reference viruses and test antigens in HI assays performed by CDC since January 2013

Sept 2012 to Feb 2013 – Gold, Aug 2011 to Aug 2012 – Blue, Earlier – Grey A/Victoria/361/2011-cell A/Victoria/361/2011-egg Antigenic Cartography of A(H3N2) Viruses A/Perth/16/2009

H3N2 Hemagglutinin changes compared to A/Victoria/361/2011-cell Victoria/361/2011 cell grown $ Receptor binding site Glycosylation site Antigenic site B Antigenic site D Antigenic site C Antigenic site E Antigenic site A G186V H156Q S219Y Victoria/361/2011 egg grown 3C

Texas/50/2012 cell grown $^ T128N 180° rotation Q33R N278K S198P ¥ N126 Texas/50/2012 egg grown S219F G186V H3N2 Hemagglutinin changes compared to A/Victoria/361/2011-cell

G186V I226S

A/Texas/50/2012 Apr # F $ A/Perth/16/2009 # F A/Jiangsu-Danyang/1647/2012 Oct # A/Jiangsu-Donghai/57/2012 Sep # A/Puerto Rico/36/2012 Jun # F A/Virginia/16/2012 Dec # A/Brisbane/299/2011 Aug # F usafsam A/Florida/1378/2013 Jan nimr A/Austria/710638/2012 Dec A/Delaware/23/2012 Dec # A/South Carolina/16/2012 Nov $ A/Florida/01/2013 Jan usafsam A/Texas/1406/2013 Jan A/Tanzania/303/2012 Nov A/Arkansas/05/2012 Dec A/Alaska/24/2012 Oct # A/Ohio/02/2012 Mar F A/Ohio/02/2012 Mar # F A/Ohio/02/2012 X-221 # F namru2 A/Cambodia/FSS23444/2012 Nov nimr A/Ukraine/551/2012 Dec nimr A/Cairo/136/2012 Dec A/Victoria/361/2011 Oct F $ A/Victoria/361/2011 IVR-165 # F A/Victoria/361/2011 Oct # F $ A/Hawaii/22/2012 Jul F $ A/Hawaii/22/2012 Jul # F A/Texas/50/2012 Apr F $ A/Texas/50/2012 X-223A # F A/Texas/50/2012 X-223 # F A H3 HA Consensus A/Seoul/3531/2012 Dec A/Delaware/01/2013 Jan LR A/Delaware/15/2012 Nov F $ niid A/Yokohama/164/2012 Dec * A/Arizona/09/2012 Oct # F A/California/04/2013 Jan usafsam A/Washington/1531/2013 Jan namru2 A/Cambodia/FSS22141/2013 Nov A/North Carolina/02/2013 Jan A/Ontario/RV2944/2012 Nov cnic A/Heilongjiang-Xiangfang/11272/2012 Dec * nimr A/Sachsen/2/2013 Jan usafsam A/Florida/1324/2013 Jan usafsam A/Guam/1490/2012 Dec lrmc A/Italy/x178/2013 Jan A/Illinois/01/2013 Jan usafsam A/DistrictofColombia/1414/2013 Jan nhrc A/Illinois/NHRC367623/2012 Dec * A/Ohio/01/2013 Jan A/South Dakota/12/2012 Oct # usafsam A/Virginia/1373/2013 Jan A/New York/03/2013 Jan A/North Dakota/08/2012 Dec nimr A/England/676/2012 Dec A/Montana/01/2013 Jan usafsam A/SouthDakota/1410/2013 Jan usafsam A/Alabama/1197/2013 Jan A/Colorado/27/2012 Dec A/Oregon/15/2012 Dec A/Nebraska/02/2013 Jan cnic A/Beijing-Huairou/128/2013 Jan * A/Virginia/03/2013 Jan nimr A/Athens GR/14/2013 Jan A/Rhode Island/02/2013 Jan A/Yamaguchi/30/2012 Oct LR usafsam A/NewYork/1365/2013 Jan A/New York/39/2012 Oct # A/West Virginia/01/2013 Jan lrmc A/Qatar/x119/2013 Jan A/Beijing-Xicheng/12423/2012 Oct $ usafsam A/Georgia/1407/2013 Jan A/Oklahoma/03/2013 Jan A/North Carolina/01/2013 Jan Evolutionary Relationships Among Influenza A (H3N2) Hemagglutinin (HA) Genes, C.1 3B 6 3A 5 A/Perth/16/09- like 1 3C.2 3C.3 3C K62E K144N ADD GLY T212A P162S I260M R261Q D53N Y94H I230V E280A S199A K2E N8D LOSS GLY N144D LOSS GLY N145S D487N L3I D53N N145S D487N N144K LOSS GLY V223I A198S N312S S45N ADD GLY T48I Q33R N278K N145S T128A LOSS GLY R142G D489N R33Q H156Q G186V S219Y T128N LOSS GLY A198P G186V S219F I226N HA Genetic Groups Since September 2012

Evolutionary Relationships Among Influenza A (H3N2) Neuraminidase (NA) Genes, A/New York/39/2012 Oct # A/West Virginia/01/2013 Jan A/Rhode Island/02/2013 Jan A/Virginia/03/2013 Jan A/North Carolina/01/2013 Jan A/Oklahoma/03/2013 Jan nimr A/England/676/2012 Dec nimr A/Sachsen/2/2013 Jan A/Ontario/RV2944/2012 Nov cnic A/Beijing-Huairou/128/2013 Jan cnic A/Heilongjiang-Xiangfang/11272/2012 Dec A/North Dakota/08/2012 Dec A/Ohio/01/2013 Jan A/Illinois/01/2013 Jan A/Yamaguchi/30/2012 Oct LR A/Delaware/15/2012 Nov F $ niid A/Yokohama/164/2012 Dec A N2 Consensus A/Delaware/01/2013 Jan LR A/Seoul/3531/2012 Dec cnic A/Beijing-Xicheng/12423/2012 Oct $ A/Oregon/15/2012 Dec A/Montana/01/2013 Jan A/Nebraska/02/2013 Jan A/Hawaii/22/2012 Jul # F A/Hawaii/22/2012 Jul F $ A/North Carolina/02/2013 Jan A/Texas/50/2012 Apr # F $ A/Texas/50/2012 X-223A # F A/Texas/50/2012 Apr F $ A/Texas/50/2012 X-223 # F A/Victoria/361/2011 IVR-165 # F A/Victoria/361/2011 Oct # F $ A/Victoria/361/2011 Oct F $ A/Ohio/02/2012 Mar # F A/Ohio/02/2012 Mar F $ nimr A/Cairo/136/2012 Dec nimr A/Ukraine/551/2012 Dec A/South Carolina/22/2012 Nov A/Virginia/16/2012 Dec # A/Puerto Rico/36/2012 Jun # F nimr A/Austria/710638/2012 Dec A/Delaware/23/2012 Dec # A/Florida/01/2013 Jan A/South Carolina/16/2012 Nov $ A/Brisbane/299/2011 Aug # F A/Tanzania/303/2012 Nov A/Alaska/24/2012 Oct # A/Arkansas/05/2012 Dec A/Jiangsu-Danyang/1647/2012 Oct # A/Jiangsu-Donghai/57/2012 Sep # A/Perth/16/2009 # F D93G S315R T148T/I/K (I/K LOSS GLY) D151/D/N/V/G/S/A (N ADD GLY) S367N ADD GLY K369T I464L D127N E258K I307M L338F N342D E381G N402D LOSS GLY R430S E221D T238A V143M L81P N402D LOSS GLY M24T V143M S416N H336N E258K N329T LOSS GLY R150H D251V D304N N43D 3B 3A 5/6 3C A/Perth/16/09- like 1

Summary Influenza A(H3N2) viruses caused widespread outbreaks in North America and were the predominant circulating viruses globally. H3N2 viruses also caused regional or widespread activity in some Asian and European countries. The majority of recent A(H3N2) viruses tested were antigenically similar to the cell-propagated A/Victoria/361/2011 reference virus and egg and cell- propagated A/Texas/50/2012 viruses. Post-infection ferret antisera raised against the egg-propagated A/Victoria/361/2011 virus had HI and neutralization titers that were at least 8-fold lower compared to the homologous titer. The HA genes of most recent A(H3N2) viruses fell into phylogenetic clade 3C while a smaller proportion had HA genes that fell into other phylogenetic clades such as 3A, 3B, 5 and 6. These genetic clades were antigenically indistinguishable. All tested H3N2 viruses remained susceptible to neuraminidase inhibitors.

Influenza B Viruses Sept 2012 – Jan 2013 Influenza B Viruses Sept 2012 – Jan 2013

Introduction In recent years both B/Victoria lineage and B/Yamagata lineage viruses have co-circulated. During the 2012/13 Northern Hemisphere season, the proportion of B/Yamagata lineage viruses increased and this lineage predominated in many countries.

Influenza B viruses were 23% of total Data source: FluNet, ( Global Influenza Surveillance and Response System (15 February 2013)

Influenza B viruses analyzed by WHO CCs September 2012 to January 2013

Influenza B activity Data source: FluNet, ( Global Influenza Surveillance and Response Systemwww.who.int/flunet

Number of B Viruses Detected by GISRS Data source: FluNet, ( Global Influenza Surveillance and Response System (15 February 2013)

B viruses characterized during the past 3 NH seasons (Sept to Jan)

B low reactors in HI assays in WHO CCs WHO CCVictoria (Bris/60/2008) Yamagata (Wisc/1/2010) CDC Low Reactors 119 (80%) 29 (20%) 312 (100%) 0 (0%) CNIC Low Reactors 108 (94%) 7 (6%) 25 (100%) 0 (0%) NIID Low Reactors 19 (100%) 0 (0%) 6 (100%) 0 (0%) NIMR* Low Reactors 26 (97%) 1 (3%) 39 (58%) 28 (42%) (B/Stockholm/12/2011)* VIDRL Low Reactors 163 (93%) 12 (7%) 15 (54%) 13 (46%) Total Low Reactors 435 (90%) 49 (10%) 397 (91%) 41 (9%)

B/Victoria Lineage Viruses

REFERENCE FERRET ANTISERA Y2Y3V1 MDCKEGGMDCKEGGMDCKEGG MDCKEGGMDCKHADATE REFERENCE ANTIGENSEST/55669MA/02 WI/1W1/1 TX/06BRI/60 NV/03NJ/1GROUPCOLL.PASS. 1B/ESTONIA/55669/ Y-203/14/11C2C2/C2 2B/MASSACHUSETTS/02/ Y-203/13/12E3 3B/MASSACHUSETTS/02/ Y-203/13/12M1/C2 4B/MASSACHUSETTS/02/2012 BX-51B REASSE3E7 5B/MASSACHUSETTS/02/2012 BX-51C REASSE3E7 6B/WISCONSIN/01/ Y-302/20/10E4 7B/WISCONSIN/01/ Y-302/20/10C1/C2 8B/TEXAS/06/ Y-302/16/11E4 9B/BRISBANE/60/2008* V-1A08/04/08E4/E4 10B/BRISBANE/60/ V-1A04/08/08CX,C4/C1 11B/NEVADA/03/ V-1A02/02/11E3 12B/NEW JERSEY/1/ V-1A04/26/12C2 TEST ANTIGENS 13B/WISCONSIN/15/ /26/12C1 14B/ARKANSAS/03/ Y-212/26/12C1 15B/GEORGIA/01/ /01/13C1 16B/GEORGIA/02/ Y-201/04/13C1 17B/NEW MEXICO/04/ Y-211/26/12M1/C2 18B/NEW YORK/01/ /10/13C1 19B/OREGON/04/ Y-212/31/12M1/C1 20B/TEXAS/24/ Y-211/27/12E3 21B/WYOMING/01/ /02/13C1 22B/TEXAS/38/ /20/12M1/C1 23B/BANGLADESH/3009/ /20/12C2 24B/INDIA/2178/ /20/12C1 25B/INDIA/2239/ /27/12C1 26B/INDIA/2242/ /28/12C1 27B/TEXAS/37/ /24/12C1 28B/UTAH/17/ V-1A12/25/12C1 29B/NEBRASKA/13/ V-1A12/30/12C1 30B/INDIA/2024/ V-1A11/26/12C1 HEMAGGLUTINATION INHIBITION REACTIONS OF INFLUENZA TYPE B VIRUSES (01/25/13)

B/Victoria Antigenic Cartography Recent B/Victoria lineage viruses are antigenically similar to B/Brisbane/60/2008 B/Brisbane/60/2008-cell Sept 2012 to Feb 2013 – Gold, Aug 2011 to Aug 2012 – Blue, Earlier – Grey

B/Ohio/01/2005 Feb # LR F B/Hiroshima/09/2010 Sep # LR F cnic A/Jiangsu-Runzhou/1697/2012 Nov # * niid B/Laos/I772/2012 Oct * cnic A/Jiangxi-Xunyang/52/2012 Dec * afrims B/Thailand/KRCH-00010/2012 afrims B/Thailand/PMKA1934/2012 B/Montana/06/2012 Oct LR B/Montana/05/2012 Oct # LR F B/Brisbane/60/2008 Aug F B/Brisbane/60/2008 Aug # F $ B/Michigan/09/2011 Sep # F nimr B/Denmark/23/2012 Nov namru6 B/Peru/IRPc00144/2012 * B/Jiangsu-Hailing/1740/2012 Sep # cnic A/Jiangsu-Qingpu/11269/2012 Oct * B/Nevada/03/2011 Feb # F B/Nevada/03/2011 Feb F B/Uganda/2851/2012 afrims B/Bhutan/BTF-00088/2012 B Victoria HA Consensus usafsam B/Nebraska/1075/2012 Dec usafsam B/Nebraska/908/2012 Dec B/Nebraska/05/2012 Nov cnic A/Jiangsu-Pingjiang/1494/2012 Dec * namru6 B/Nicaragua/INI00520/2012 Nov * afrims B/Philippines/AFPA-00187/2012 B/Louisiana/01/2012 Dec B/Honduras/648/2012 Nov cnic A/Jiangsu-Tianning/1676/2012 Dec # * B/Tanzania/335/2012 Dec LR nimr B/Bayern/1/2013 Jan usafsam B/Florida/1189/2012 Dec usafsam B/Texas/770/2012 Dec B/Peru/1634/2012 Oct namru6 B/Pampagrande/FPT01070/2012 Dec * namru6 B/Piura/FPP01690/2012 Dec * B/Utah/17/2012 Dec usafsam B/Nevada/847/2012 Dec nimr B/Lyon/2760/2012 Dec nimr B/Jordan/30014/2012 Dec afrims B/Thailand/KPPH-00092/2012 B/Bangkok/282/2012 Oct B/Wisconsin/01/2013 Jan LR B/Wyoming/10/2012 Dec B/India/2024/2012 Nov LR cnic A/Fujian-Yanping/2322/2012 Dec * B/Bangladesh/3249/2012 Oct aus B/Victoria/824/2012 Oct usamruk B/Kenya/244/2012 afrims B/Philippines/AFPA-00149/2012 B/Wisconsin/16/2012 Dec LR B/Texas/02/2013 Jan B/Virginia/05/2012 Dec LR B/New Jersey/02/2013 Jan LR Evolutionary Relationships Among Influenza B Victoria Lineage Hemagglutinin (HA) Genes, /22/2013 LR- Low Reactor to B/Brisbane/60/2008 Egg (≥ 8 fold) F - CDC Reference Antigen $ - CDC Serology Antigen # Egg Isolate * - HA1 region only ____ 165N October 2012 November 2012 December 2012 January A 1B Intra-clade Reassortants HA-1A/NA-3 Intra-clade Reassortants HA-1B/NA-4 N75K N165K S172P L58P V87I N129S N171D P58S H122L V15I V146I N218D A169E N129D G184E A154T K209N HA Genetic Groups Since September 2012

Evolutionary Relationships Among Influenza B Victoria Lineage Neuraminidase (NA) Genes, /22/2013 LR- Low Reactor to B/Brisbane/60/2008 Egg (≥ 8 fold) F - CDC Reference Antigen $ - CDC Serology Antigen # Egg Isolate HA Genetic Group Shown October 2012 November 2012 December 2012 January 2013 B/Texas/02/2013 Jan B/Wisconsin/16/2012 Dec LR B/Virginia/05/2012 Dec LR B/New Jersey/02/2013 Jan LR B/Honduras/648/2012 Nov B/Louisiana/01/2012 Dec insert L76 B/Nebraska/05/2012 Nov cnic A/Jiangsu-Pingjiang/1494/2012 Dec cnic A/Jiangsu-Tianning/1676/2012 Dec # nimr B/Lyon/2760/2012 Dec B/Montana/05/2012 Oct # LR F B/Montana/06/2012 Oct LR B/Tanzania/335/2012 Dec LR B/Wisconsin/01/2013 Jan LR B/Wyoming/10/2012 Dec B/Peru/1634/2012 Oct B/Utah/17/2012 Dec nimr B/Bayern/1/2013 Jan B Victoria NA Consensus nimr B/Jordan/30014/2012 Dec B/Bangkok/282/2012 Oct aus B/Victoria/824/2012 Oct B/India/2024/2012 Nov LR B/Bangladesh/3249/2012 Oct cnic A/Fujian-Yanping/2322/2012 Dec B/Uganda/2851/2012 B/Nevada/03/2011 Feb # F B/Nevada/03/2011 Feb F B/Brisbane/60/2008 Aug # F $ B/Brisbane/60/2008 Aug F B/Jiangsu-Hailing/1740/2012 Sep # cnic A/Jiangsu-Qingpu/11269/2012 Oct B/Hiroshima/09/2010 Sep # LR F cnic A/Jiangsu-Runzhou/1697/2012 Nov # B/Ohio/01/2005 Feb # F B/Michigan/09/2011 Sep # F nimr B/Denmark/23/2012 Nov cnic A/Jiangxi-Xunyang/52/2012 Dec S41P P42S N125K V271I K272Q D320K D329E D340N D342G D384N A395V K404E D463N A465T ADD GLY T8M L73F A389T S397R N340D D329N I204V N220K A358E H61Q K375M S295R D35G N59D R65S I348V A395T P51S L73F N199D V63M K343E L73F N198S S345N 1A 1B Intra-clade Reassortants HA-1A/NA-3 3 Intra-clade Reassortants HA-1B/NA-4 4

B/Yamagata Lineage Viruses WHO information meeting on influenza vaccine composition for southern hemisphere September 2012 Beijing

Antigenic analysis of B/Yamagata viruses (1)

Antigenic analysis of B/Yamagata viruses (2)

REFERENCE FERRET ANTISERA Y1Y2Y3 EGGMDCKEGGMDCKEGGMDCKHADATE FL/4EST/55669MA/02 WI/1W1/1 TX/06 GROUPCOLL.PASS. 1B/FLORIDA/04/ Y-111/01/06E3 2B/ESTONIA/55669/ Y-203/14/11C2C2/C2 3B/MASSACHUSETTS/02/ Y-203/13/12E3 4B/MASSACHUSETTS/02/ Y-203/13/12M1/C2 5B/MASSACHUSETTS/02/2012 BX-51B REASSE3E7 6B/MASSACHUSETTS/02/2012 BX-51C REASSE3E7 7B/WISCONSIN/01/ Y-302/20/10E4 8B/WISCONSIN/01/ Y-302/20/10C1/C2 9B/TEXAS/06/ Y-302/16/11E4 10B/TEXAS/06/ Y-302/16/11M1/C2 TEST ANTIGENS 11B/WISCONSIN/15/ /26/12C1 12B/ARKANSAS/03/ Y-212/26/12C1 13B/GEORGIA/01/ /01/13C1 14B/GEORGIA/02/ Y-201/04/13C1 15B/NEW MEXICO/04/ Y-211/26/12M1/C2 16B/NEW YORK/01/ /10/13C1 17B/OREGON/04/ Y-212/31/12M1/C1 18B/TEXAS/24/ Y-211/27/12E3 19B/WYOMING/01/ /02/13C1 20B/TEXAS/38/ /20/12M1/C1 21B/BANGLADESH/3009/ /20/12C2 22B/INDIA/2178/ /20/12C1 23B/INDIA/2239/ /27/12C1 24B/INDIA/2242/ /28/12C1 HEMAGGLUTINATION INHIBITION REACTIONS OF INFLUENZA B/YAMAGATA-LINEAGE VIRUSES (01/25/13)

B/Yamagata Antigenic Cartography Clade 2 and 3 viruses were antigenically distinguishable by many sera B/Wisconsin/1/2010-egg Sept 2012 to Feb 2013 – Gold, Aug 2011 to Aug 2012 – Blue, Earlier – Grey B/Massachusetts/2/2012-egg

B/Florida/04/2006 Nov # F B/Wisconsin/01/2010 Feb F $ B/Wisconsin/01/2010 Feb # F $ B/Bangladesh/7005/2012 Oct B/Hawaii/13/2012 Nov cnic B/Heilongjiang-Jiguan/1409/2012 Dec * B/Nong Khai/322/2012 Oct B/Hubei-Wujiagang/158/2009 Mar # F B/Vermont/07/2012 Dec nimr B/Rheinland-Pfalz/4/2013 Jan usafsam B/Nevada/845/2012 Dec B/Texas/06/2011 Feb F B/Texas/06/2011 Feb # F B/Cote DIvoire/1507/2012 Dec nimr B/Ghana/DILI-0859/2012 Oct B/Quebec/RV2958/2012 Nov B/Dominican Republic/6986/2012 Dec aus B/Brisbane/36/2012 Jun B/Estonia/55669/2011 Mar F afrims B/Thailand/KPPH-00148/2012 B/Massachusetts/02/2012 Mar F $ aus B/Wellington/3/2012 Jul B/Nevada/17/2012 Dec B/Massachusetts/02/2012 BX-51C # F B/Massachusetts/02/2012 Mar # F $ B/Massachusetts/02/2012 BX-51B F B/Alabama/01/2013 Jan B/Chanthaburi/318/2012 Oct niid B/Yokohama/82/2012 Dec * B/Texas/24/2012 Nov # usafsam A/Oklahoma/1557/2013 Jan afrims B/Bhutan/BTG-00006/2012 usafsam B/Texas/1322/2013 Jan usafsam B/Colorado/1468/2013 Jan lrmc B/Germany/x170/2013 Jan B/North Carolina/05/2012 Dec B/New Mexico/04/2012 Nov $ nimr B/Lyon/2771/2012 Dec B/India/2127/2012 Dec B/Kansas/02/2012 Dec B/Missouri/01/2013 Jan usafsam B/Alaska/1351/2012 Dec usafsam B/Illinois/704/2012 Dec B/Oman/14/2013 Jan usafsam B/SouthCarolina/1462/2013 Jan B Yamagata HA Consensus usafsam B/NewYork/1201/2013 Jan B/India/2152/2012 Dec lrmc B/Belgium/x54/2012 B/Texas/01/2013 Jan usafsam B/Florida/1376/2013 Jan B/Ohio/01/2013 Jan usafsam B/Maryland/583/2012 Dec B/Georgia/02/2013 Jan B/Georgia/04/2013 Jan Evolutionary Relationships Among Influenza B Yamagata Lineage Hemagglutinin (HA) Genes, Y2 Y3 HA Genetic Groups Since September 2012 K88R E479D R48K P108A T182A S230G S150I N166Y S230D T182K N203S M252V V29A L173Q K299E E313K T37A K299E E313K N116K T189A N197D LOSS GLY

Evolutionary Relationships Among Influenza B Yamagata Lineage Neuraminidase (NA) Genes, B/New Mexico/04/2012 Nov $ B/Ohio/01/2013 Jan B/Texas/01/2013 Jan B/Georgia/02/2013 Jan B/Georgia/04/2013 Jan B/Kansas/02/2012 Dec B Yamagata NA Consensus B/India/2127/2012 Dec niid B/Yokohama/82/2012 Dec nimr B/Lyon/2771/2012 Dec B/India/2152/2012 Dec B/Chanthaburi/318/2012 Oct B/North Carolina/05/2012 Dec B/Oman/14/2013 Jan B/Estonia/55669/2011 Mar F aus B/Wellington/3/2012 Jul B/Nevada/17/2012 Dec B/Massachusetts/02/2012 BX-51B F B/Massachusetts/02/2012 BX-51C F B/Massachusetts/02/2012 Mar # F $ B/Massachusetts/02/2012 Mar F $ aus B/Brisbane/36/2012 Jun B/Cote DIvoire/1507/2012 Dec nimr B/Ghana/DILI-0859/2012 Oct B/Quebec/RV2958/2012 Nov B/Dominican Republic/6986/2012 Dec B/Texas/06/2011 Feb # F B/Texas/06/2011 Feb F B/Vermont/07/2012 Dec nimr B/Rheinland-Pfalz/4/2013 Jan B/Hubei-Wujiagang/158/2009 Mar # F B/Wisconsin/01/2010 Feb # F $ B/Wisconsin/01/2010 Feb F $ B/Hawaii/13/2012 Nov B/Bangladesh/7005/2012 Oct B/Nong Khai/322/2012 Oct cnic B/Heilongjiang-Jiguan/1409/2012 Dec B/Florida/04/2006 Nov # F Y2 Y3 D463N A465T ADD GLY Q42R A68T T125K K186R D340N T106I I248V S295R A55T R65H L73P K343E

Summary B/Victoria and B/Yamagata lineage viruses co-circulated. The proportion of B/Yamagata viruses has increased in many countries, while B/Victoria viruses predominated in some countries. B/Victoria lineage viruses –Antigenically and genetically remain similar to the previously used vaccine virus, B/Brisbane/60/2008. B/Yamagata lineage viruses – HA genes of the viruses were in clade 2 or 3. –Clade 3 viruses were antigenically and genetically closely related to the 2012/13 NH vaccine virus, B/Wisconsin/1/2010. –Some ferret antisera are able to detect antigenic differences between recent clade 2 and 3 viruses. –Clade 2 viruses have circulated widely in recent months.

Summary of A(H1N1)pdm09 viruses A(H1N1)pdm09 viruses Continued to circulate at relatively low levels Increase observed in some parts of Europe in January Viruses are antigenically similar to A/California/7/2009 vaccine virus HA genes are in clades 6 and 7 but these clades are antigentically indistinguishable.

Summary of influenza A(H3N2) Predominant viruses globally and especially in Canada and the U.S. Some other countries in the Northern Hemisphere reported regional and widespread outbreaks. Most recent viruses have HAs that: –Genetically fall into clade 3C; remainder fall into clades 3A, 3B, 5 and 6 –Antigenically indistinguishable –Antigenically similar to cell-propagated A/Victoria/361/2011, egg- and cell- propagated A/Texas/50/2012 viruses –Showed at least 8-fold reduction in HI and NT using antisera against egg- propagated A/Victoria/361/2011

Summary of influenza B (1) Influenza B viruses circulated and caused outbreaks in many countries. Both B/Victoria/2/87 and B/Yamagata/16/88 lineages co-circulated. –B-Vic viruses prevalent in some countries (e.g., China) –B-Yam viruses continued to increase in proportion and becoming dominant in many countries The majority of recent B/Victoria/2/87 lineage viruses were antigenically and genetically closely related to B/Brisbane/60/2008. Most recent B/Yamagata/16/88 lineage viruses –HA genes fall into clades 2 or 3, with the proportion of clade 2 viruses increasing significantly in Europe and North America –Many clade 2 vs. clade 3 viruses are antigenically distinguishable in HI tests especially in laboratories in Melbourne and London

Publications Vaccine composition recommendation report and summary report on H5/H9 vaccine viruses: –WHO GlSRS website: –WHO Weekly Epidemiological Record: Candidate vaccine viruses and reagents – WHO Global Influenza Surveillance and Response System (GISRS):

Acknowledgements WHO Collaborating Centers in Beijing, London, Melbourne and Tokyo for seasonal influenza data National Influenza Centers (over 20 submitted written reports in addition to data provided through FluNet) Essential Regulatory Laboratories for human serology data Many staff from CDC’s Influenza Division, including Alexander (Sasha) Klimov, Xiyan Xu, Rebecca Garten, Julie Villanueva, Angie Foust, Wendy Sessions, Elizabeth Blanchard, Thomas Rowe, Jan Mabry, Jackie Katz, Vic Vegilla and many others