1. Evolutionary pathways of seasonal influenza A and B viruses, 2011-2016 Xiyan Xu MD Deputy Director WHO Collaborating Center for Surveillance, Epidemiology and Control of Influenza Virus Reference Team Virology, Surveillance and Diagnosis Branch Influenza Division, NCIRD Centers for Disease Control and Prevention Atlanta, Georgia U.S.A. Xiyan Xu MD Deputy Director WHO Collaborating Center for Surveillance, Epidemiology and Control of Influenza Virus Reference Team Virology, Surveillance and Diagnosis Branch Influenza Division, NCIRD Centers for Disease Control and Prevention Atlanta, Georgia U.S.A.

2. 1918195719681977 1997 H2N2 “Asian” Pandemic H3N2 “Hong Kong” Pandemic 19331948 H1N1 “Spanish” Pandemic H1N1 “Russian” 2009 2014 H1N1pdm09 Pandemic 2016 of Influenza A Virus Periods of Observed Circulation in Humans

3. Phylogenetic Evolution of the HA Genes of Influenza A(H1N1) Viruses 2011-2016

4. Evolutionary Relationships Among Influenza A (H1N1) Hemagglutinin (HA) Genes, 2011 09/19/2011 Current Southern Hemisphere Vaccine Strain LR- Low Reactor to A/California/07/2009 (≥ 8 fold) # Egg Isolate @- Oseltamivir Resistant H275Y May 2011 June 2011 July 2011 August 2011 aus A/South Australia/4/2011 Jun aus A/Tasmania/14/2011 May $ aus A/Brisbane/190/2011 Jun A/Hong Kong/3976/2011 Jun nimr A/Hong Kong/3972/2011 Jun A/Brisbane/70/2011 Feb # $$ aus A/Brisbane/70/2011 IVR-162 Feb # aus A/Brisbane/500/2011 Jun aus A/Newcastle/1/2011 Apr niid A/Miyagi/32/2011 Feb $ A/Sapporo/163/2011 Mar C$$ LR niid A/Sapporo/163/2011 Mar C$$ A/St Petersburg/100/2011 Mar # FATAL $$ A/Heilongjiang-Xiangfang/191/2011 Jan # $ cnic A/Hunan-Yuhua/SWL173/2011 Feb # cnic A/Hunan-Jishou/SWL1124/2011 May cnic A/Shandong-Zhifu/SWL1200/2011 Apr $ A/Nonthaburi/78/2011 Jun $ aus A/Brisbane/151/2011 May aus A/Brisbane/183/2011 Jun A/Federated States Of Micronesia/6119/2011 May aus A/Tasmania/21/2011 Jun aus A/South Australia/2/2011 Jun cnic A/Fujian-Gulou/SWL1103/2011 Feb # cnic A/Heilongjiang-Xiangfang/SWL1528/2011 Mar # aus A/Philippines/1343/2011 Apr A/Hong Kong/3973/2011 Jun aus A/Newcastle/2/2011 May @ H1N1pdm 2011 HA Consensus 859 niid A/Chiba-C/16/2011 Mar niid A/Shimane/164/2011 Mar @ niid A/Yokohama/140/2011 Apr aus A/Brisbane/185/2011 Jun aus A/Brisbane/186/2011 Jun A/Brazil/5960/2011 Jun nimr A/Cape Town/60/2011 Jun # nimr A/Johannesburg/43/2011 Jun # aus A/Wellington/1/2011 May $ A/India/4947/2011 May A/Argentina/8836/2011 Aug nimr A/Mendoza/2672/11 Jun A/Santiago/14453/2011 Jul A/Valparaiso/17275/2011 Aug # A/Argentina/63/2011 May A/Santiago/7774/2011 Apr # nimr A/St. Petersburg/27/2011 Feb # $ A/New York/09/2011 Apr # $$ A/Bangladesh/9751/2011 Jul A/Panama/309335/2011 Jun A/Kenya/2994/2011 Mar LR A/Kenya/4494/2011 Jun A/Texas/10/2011 Jul aus A/Newcastle/58/2011 Jul A/Bangladesh/8324/2011 May A/Minnesota/03/2011 Feb FATAL F A/Minnesota/03/2011 Feb # FATAL $ A/Concepcion/16695/2011 Jul A/Santiago/15129/2011 Jul A/Santiago/18553/2011 Aug ORG A/Uganda/2707/2011 May aus A/Perth/29/2011 Mar @ nimr A/Johannesburg/32/2011 May # A/Argentina/656/2011 Aug LR A/Voronezh/1/2011 Mar # FATAL $$ A/Dominican Republic/5059/2011 Mar LR nimr A/Astrakhan/1/2011 Feb $ A/Brazil/8201/2011 Jul A/Chile/293/2011 May # A/Dominican Republic/5542/2011 Jul A/Trinidad/1648/2011 Jul A/Tanzania/412/2011 Jun A/St Petersburg/25/2011 Feb # A/Brisbane/10/2010 IVR158 # A/Brisbane/10/2010 Apr # F A/Christchurch/16/2010 Jul # A/Christchurch/16/2010 NIB-74 # A/Nigeria/4280/2011 Apr nimr A/Ghana/763/2011 May cnic A/Heilongjiang-Xiangyang/SWL196/2011 Mar A/Guangdong-Xiangzhou/1623/2011 Jul A/New Mexico/07/2011 Mar FATAL cnic A/Chongqing-Wanzhou/SWL53/2011 Feb A/Pakistan/680/2011 Jul nimr A/Umea/1/2011 May niid A/Ishikawa/70/2011 Mar @ nimr A/Hong Kong/3934/2011 Mar $ A/Pennsylvania/02/2011 Feb # FATAL F A/Maryland/04/2011 Feb @ # A/Alaska/14/2011 Mar LR A/Mexico/2208/2011 Mar # $ A/South Carolina/02/2010 Mar # F A/South Carolina/02/2010 X-205A # cnic A/Sichuan/1/2009 # $ NYMC X179 A/California/07/2009 # LR F A/California/07/2009 # $$ NYMC X179A A/California/07/2009 # F NYMC X181 A/California/07/2009 # $ 0.002 S143G A197T 7 K154E S190R V520A V234I N129T K154K/E G155E K154K/Q G155G/E G155E L191I D222G D97N S185T S451N H273Y I510T E235K A256V K153Q N156I N156D K153E 6 D97N R205K I216V V249L H138Q E356A G155E E374K N125D 4 5 A186T V272A N473D T474K V520A 1 K163T V199A P271S I295V S128P I372F E374K 8 N31D K146N 2 S162N ADD GLY A186T V272I A134T S183P A14 1S I295 V 3 G155E/G S83P Q223R K209T S203T I321V K154E G155E N156E /K

5. Evolutionary Relationships Among Influenza A (H1N1)pdm09 Hemagglutinin (HA) Genes, 2012 09/10/2012 Current Southern Hemisphere Vaccine Strain LR- Low Reactor to A/California/07/2009 (≥ 8 fold) # Egg Isolate @ - Oseltamivir Resistant H275Y H1 CDS Numbering April 2012 May 2012 June 2012 July 2012 August 2012 A/Idaho/15/2012 Apr A/Idaho/15/2012 Apr # A/Maryland/16/2012 May A/Wisconsin/16/2012 Jun A/Utah/16/2012 May A/Honduras/9720/2012 Jun A/Mexico/52/2011 Dec F A/Mexico/254/2012 Jan F A/Colorado/14/2012 Mar $ A215A/T A/Puerto Rico/06/2012 Jun A/Puerto Rico/06/2012 Jun # A/Washington/24/2012 Jun @ C$ A/Washington/24/2012 Jun @ # C$ A/Texas/34/2012 Mar @ A/El Salvador/530/2012 Apr A/El Salvador/530/2012 Apr # A/Georgia/08/2012 Mar LR F A9A/V G155E L191I A/New York/34/2012 Apr @ aus A/Brisbane/57/2012 May A/New York/10/2012 Mar @ H1N1pdm HA Consensus 2012 226 A/Honduras/9746/2012 Jun aus A/Victoria/514/2012 May p$ A/Belize/334/2012 A/Panama/310630/2012 Jun A/South Carolina/13/2012 Jun A/Maryland/12/2012 Mar @ aus A/Christchurch/3/2012 May A/Panama/310521/2012 Jun A/Panama/310657/2012 Jun nimr A/Ireland/12M17525/2012 Feb p$ aus A/Brisbane/70/2011 # A/St Petersburg/100/2011 Mar # F A/Nonthaburi/78/2011 Jun F aus A/Fiji/4/2012 Jul A/India/8942/2012 Apr LR A/India/8557/2012 May A/Bangladesh/9003/2012 Jun D472N ADD GLY A/India/7764/2012 Jul A/Hong Kong/7568/2012 Jun aus A/Singapore/12/2012 Jun aus A/Christchurch/11/2012 Jun aus A/South Auckland/5/2012 Jun A/Suriname/265/2012 May A/Ontario/RV117/2012 Jan LR F A/Illinois/03/2012 Apr @ A/Illinois/03/2012 Apr @ # A/Bangladesh/2033/2012 May LR G155G/E A215A/V A/Ethiopia/186/2012 Apr LR G155E K208E A/North Carolina/20/2012 Jul aus A/Singapore/11/2012 Jun A/Victoria/523/2012 Jun # $ cnic A/Gansu-Anding/SWL1188/2012 May A/Hong Kong/6293/2012 May LR G155G/E A215A/V G394G/D nimr A/Hong Kong/6609/2012 May A/Bangladesh/1027/2012 May LR G155G/E S190I A215A/V R403R/G A/Bangladesh/0002/2012 Apr aus A/Victoria/537/2012 Jun K119K/N ADD GLY A/Bangladesh/2014/2012 May LR S183S/P A/Ethiopia/205/2012 Jul aus A/Waikato/3/2012 Jun aus A/Wellington/23/2012 Jul cnic A/Xinjiang-Midong/SWL1132/2012 Mar p$ aus A/Victoria/637/2012 Jul A/Ethiopia/128/2012 May aus A/Sri Lanka/22/2012 aus A/Perth/16/2012 Mar @ A/Bangladesh/3341/2012 Jun LR G155G/E N156E/K A/Maryland/21/2012 Jul A/India/447/2012 Jun A/India/449/2012 Jun A/Nonthaburi/74/2012 Apr A/Washington/34/2012 Jul A/Argentina/42/2012 Jul A/Argentina/48/2012 Jul A/Iquique/44427/2012 Jun A/Valparaiso/17275/2011 Aug # F swe A/Boras/1/2012 Jul A/Maryland/13/2012 Apr $ A/Peru/234/2012 May nimr A/St Petersburg/27/2011 Feb # A/Minnesota/03/2011 Feb # F A/Minnesota/03/2011 Feb F A/Brazil/2320/2012 Jul LR G155E A/Brazil/9527/2012 May A/Paraguay/191/2012 Jun LR K153K/E S183P N496K A/Paraguay/20199/2012 Jun A/Paraguay/185/2012 Jun LR Y98H N156D S190S/R H352Q A/Paraguay/233/2012 Jun A/Brazil/7250/2012 May K119K/N ADD GLY A/Brazil/7250/2012 May # A/Natal/119715/2012 Jul A/Nebraska/10/2012 Aug nimr A/Ghana/ARI1181/2011 Oct A/Ethiopia/180/2012 Jun A/Ethiopia/198/2012 Jun A/Georgia/07/2012 Mar LR N156N/D A/Voronezh/1/2011 Mar # F A/Guyane/118/2012 Apr A/Florida/27/2011 Oct # F A/Minnesota/06/2012 Mar NYMC X181 A/California/07/2009 # NYMC X179A A/California/07/2009 # F NYMC X179 A/California/07/2009 # LR F A/California/07/2009 Apr # $ 0.002 S143G A197T D97N S185T S451N S69T N260D I216 T K54R K146 E V520A P271T E499 K I510T S162N ADD GLY S84N S84G H138R V249L V152I N26 0T N38D V173I V47I A186 T V272 A N47 3D T474 K V520 A L365 Q H138Q E356A K488 R D97N R205K I216V V249L E37 4K D127E K142R G155E S190R G202G/ E 7 6 5 8 V527 I K283R K311E S20 3T H138 Q G155E L191I I266F F330L T474M N38 D S45 1T V393I K283E E499K

6. A/California/07/2009 Apr # F C$ PR NYMC X179A A/California/07/2009 # F w$ NYMC X181 A/California/07/2009 # A/Peru/108/2013 Apr nimr A/Dakar/20/2012 Dec nimr A/Ghana/DILI-0007/2013 Jan nimr A/Norway/120/2013 Jan A/Kenya/104/2013 Feb A/Washington/24/2012 Jun @ # F A/Washington/24/2012 Jun @ F A/Saipan/6197/2013 Feb # A/Saipan/6197/2013 Feb A/Zaporizza/417/2013 Mar FATAL $ PR niid A/Fukuoka-C/8/2013 May * A/Panama/313106/2013 Jun niid A/Saitama/131/2013 Jun * A/Panama/313202/2013 Jun A/Curico/47136/2013 Jul A/Bangladesh/2021/2012 Jul LR # F $ PR A/Bangladesh/2021/2012 Jul LR F PR A/Maryland/13/2012 Apr F PR A/Argentina/749/2013 Jun A/Utah/08/2013 Aug A/Mexico/2410/2013 Jul A/Brazil/791/2013 Jun A/Florida/16/2013 Jun A/Florida/16/2013 Jun # A/Bolivia/559/2013 Jun $ PR A/Bolivia/559/2013 Jun # $ PR A/Matagalpa/1076/2013 Jun A/Managua/3007401/2013 Jun A/Pennsylvania/05/2013 Apr # aus A/Perth/38/2013 Jun A/Florida/38/2013 Aug A/Indiana/20/2013 Jul A/Venezuela/19/2013 Jun FATAL nimr A/Stockholm/15/2013 Mar w$ A/California/24/2013 Aug nimr A/South Africa/3626/2013 Jun nimr A/South Africa/3626/2013 Jun # A/Venezuela/17/2013 Jun A/Wisconsin/12/2013 Aug A/Wisconsin/12/2013 Aug # A/Florida/19/2013 Jul @ aus A/South Australia/30/2013 Jul aus A/South Australia/17/2013 May # w$ A/Nevada/06/2013 Jul A/Nevada/06/2013 Jul # A/Brazil/5606/2013 Jul A/India/2213/2013 Apr A/Brazil/759/2013 Jun A/French Guiana/3078/2013 Jul A/Connecticut/02/2013 Jul A/Connecticut/02/2013 Jul # A/Uruguay/538/2013 Jul A/Santiago/43667/2013 Jul A/Texas/15/2013 Aug H1pdm HA Consensus since Feb 2013 n=706 niid A/Tokyo/32398/2013 Jun * cnic A/Sichuan-Gaoxin/SWL1172/2013 Jun # A/Indiana/22/2013 Aug A/Vietnam/3041/2013 Apr nimr A/Acores PT/139/2013 Apr w$ A/Linares/16708/2013 Mar # A/Haiti/1790/2013 Jun PR A/Suriname/133/2013 May A/India/2192/2012 Dec # F A/India/2192/2012 Dec F cnic A/Shanghai-Chongming/SWL1214/2013 May # cnic A/Jiangsu-Nanchang/SWL1264/2013 May # A/Guangxi-Longan/1167/2013 Apr LR cnic A/Guizhou-Qingzhen/SWL1251/2013 Jun w$ nimr A/Madagascar/02064/2013 May A/Florida/22/2013 May LR cnic A/Shanghai-Hongkou/SWL1415/2013 Jul cnic A/Fujian-Gulou/SWL1400/2013 May # cnic A/Fujian-Gulou/SWL1361/2013 May # cnic A/Shanghai-Putuo/SWL1203/2013 Apr # w$ cnic A/Jiangsu-Quanshan/SWL1495/2013 May # cnic A/Guangdong-Maonan/SWL1246/2013 Jun # cnic A/Guangdong-Yuexiu/SWL1651/2013 Jul # w$ cnic A/Jiangsu-Gaoyou/SWL1356/2013 Jun # A/Mar Del Plata/10091/2013 Jul A/Uruguay/279/2013 Jun A/Bolivia/1351/2013 Jul A/Argentina/911/2013 Jul A/Santiago/46965/2013 Jul A/Puerto Rico/01/2013 Jun PR A/Puerto Rico/03/2013 Jun A/Puerto Rico/05/2013 Jun LR A/Puerto Rico/01/2013 Jun # A/Puerto Rico/03/2013 Jun # A/Argentina/168/2013 Jun FATAL cnic A/Yunnan-Wenshan/SWL1162/2013 Jul A/Bangladesh/8207/2013 May A/Vietnam/3050/2013 Feb LR A/Peru/2001/2013 Jun A/Peru/155/2013 Jul LR A/Dominican Republic/7703/2013 Jun A/Dominican Republic/7293/2013 May $ PR A/Dominican Republic/7293/2013 May # A/Delaware/09/2013 Aug A/Peru/152/2013 Jun A/Haiti/2030/2013 Jun @ Current Southern Hemisphere Vaccine Strain LR- Low Reactor to A/California/07/2009 (≥ 8 fold) # Egg Isolate * – HA1 region only @ - Oseltamivir Resistant H275Y May 2013 June 2013 July 2013 August 2013 Evolutionary Relationships Among Influenza A (H1N1)pdm09 Hemagglutinin (HA) Genes, 2013 6B HA Genetic Groups Based on Total GISAID Sequences Collected Since February 2013 (n=706) 6C 7 8 9 6A K163Q A256T A73S K283E E499K H51N I295V V234I E99G T270A S71Y M257V A139D N156N/D K36N D97N I116M R205K K43R I286V P83S I321V E374K A186T V272A N473D T474K V520A K163I V520A S84G S143G A197T S69T N260D V520A S185T S203T S451N H138R N156S V249L 0.002 L32I D86E S128T T203S R259K S263A I460V V520A K163I N125S A48S K154E G155G/E A/Vietnam/3025/2013 Mar LR G155E N156K N156N/D HA Tree Includes 91 Sequences Collected Since February 2013 6

7. Evolutionary Relationships Among Influenza A (H1N1)pdm09 Hemagglutinin (HA) Genes, 2014 09/15/2014 Current Southern Hemisphere Vaccine Strain LR- Low Reactor to A/California/07/2009 (≥ 8 fold) # -Egg Isolate @ Oseltamivir Resistant-H275Y Marker * HA1 only April 2014 May 2014 June 2014 July 2014 August 2014 HA Genetic Groups Since February 1 st 2014 7 6A 6C 6B 4 A/New Zealand/0491/2014 Jun niid A/Nepal/0642/2014 Apr nimr A/La Reunion/2049/14 Jun nimr A/Norway/1916/2014 May A/Puerto Rico/16/2014 Jun A/Song Khla/139/2014 Mar A/Washington/07/2014 Feb LR A/French Guiana/1065/2014 Apr A/Hawaii/06/2014 Mar @ A/Hawaii/06/2014 Mar @ # nimr A/Saint-Petersburg/48/2014 Apr # A/St Petersburg/40/2014 Apr A/St Petersburg/40/2014 Apr # niid A/Hiroshima/58/2014 Apr @ nimr A/Krasnoyarsk/2/2014 Apr # A/Brazil/123/2014 Mar A/Hawaii/07/2014 May A/Bolivia/718/2014 Jun bra A/Mato Grosso Do Sul/66637/2014 Jul bra A/Mato Grosso/55656/2014 Jun A/North Carolina/04/2014 Feb @ A/North Carolina/04/2014 Feb @ # aus A/Perth/550/2014 Jun @ A/Bangladesh/8027/2014 Mar T278A LOSS GLY niid A/Nepal/0626/2014 Apr A/India/6427/2014 Mar FATAL A/Hong Kong/5008/2013 Sep F A/Aamazonas/129967-IEC/2014 May A/Guangdong-Zhongshan/1474/2014 May # A/Jiangsu-Tinghu/1363/2014 May # A/Jiangsu-Guangling/1711/2014 May # A/Guangdong-Luohu/1266/2014 Apr LR # A/Hong Kong/5958/2014 Jun A/Cambodia/0737/2014 Jun aus A/South Australia/38/2014 Jun A/Consensus/H1N1pdm/2014 HA A/South Australia/17/2013 May # wF nimr A/South Africa/3626/2013 Jun nimr A/South Africa/3626/2013 Jun # wF aus A/Sri Lanka/31/2014 May niid A/Wakayama/153/2013 Nov wF wSAg A/Minnesota/08/2014 Jun A/Minnesota/15/2014 Aug nimr A/Paris/1823/2014 Jun @ bra A/Distrito Federal/64451/2014 Jul A/Bangkok/1792/2014 Jul A/Bolivia/1115/2014 Jul nimr A/South Africa/4764/2014 Jun aus A/South Australia/1001/2014 Jun A/Hong Kong/5994/2014 Jun A/Hong Kong/5997/2014 Jun nimr A/South Africa/4042/2014 May wSAg A/Phuket/316/2014 Jul A/Bahrain/232/2014 Apr usafsam A/California/4018/2014 Jun A/Cambodia/0671/2014 Jun A/Puerto Rico/15/2014 Jun aus A/Suphanburi/234/2014 Apr @ A/New Zealand/0498/2014 May A/Panama/315031/2014 May A/Indiana/06/2014 Apr A/Brazil/9061/2014 Mar @ bra A/Sao Paulo/3-29343/2014 Jun A/India/5964/2014 May A/Michigan/04/2014 Mar A/Michigan/04/2014 Mar # aus A/Darwin/18/2014 Jun niid A/Hyogo/3030/2014 Mar wCSAg niid A/Niigata-C/56/2014 May aus A/Victoria/520/2014 Jul aus A/South Australia/1009/2014 Jul aus A/South Australia/77/2014 Jul aus A/Victoria/818/2014 Jun aus A/Canberra/24/2014 Jul aus A/Tasmania/24/2014 Jul A/Bolivia/882/2014 Jul A/Massachusetts/15/2013 Nov F A/Massachusetts/15/2013 Nov # F A/Wisconsin/08/2014 Apr bra A/Goias/42063/2014 May A/Maine/02/2014 Feb A/Maine/02/2014 Feb # A/Nevada/10/2014 Apr A/District Of Columbia/02/2014 May A/Virginia/06/2014 Mar @ A/Guatemala/58/2014 Jul nimr A/IIV-Moscow/138/2014 Mar # A/Kenya/103/2014 Mar A/Cambodia/0745/2014 Jun aus A/Nonthaburi/248/2014 May nimr A/Chita/25/2014 Apr # nimr A/Dakar/07/2014 Feb wSAg nimr A/Dakar/08/2014 Mar A/Shanghai-Putuo/1189/2014 Mar # nimr A/Ghana/Dili-0567/2014 Jun nimr A/Ghana/Dili-0618/2014 Jul A/Burkina Faso/291/2014 Mar A/Pennsylvania/07/2013 Oct F A/Vietnam/3050/2013 Feb # LR A/Vietnam/3050/2013 Feb LR A/Bangladesh/2021/2012 Jul LR # F A/Bangladesh/2021/2012 Jul LR F A/St Petersburg/100/2011 Mar # wF aus A/Brisbane/70/2011 Feb # wF A/Washington/24/2012 Jun @ # F A/Washington/24/2012 Jun @ F A/Christchurch/16/2010 Jul # wF NYMC X179A A/California/07/2009 # wF wSAg A/California/07/2009 Apr # F wSAg A/California/07/2009 Apr F 0.002 M257I E68G E491G T15I I460T N473D S84N R45K T474M K458Q T120A V321I V234I G155E N156K V520A H138R N156S V249L S143G A197T S69T N260D A141T P83S S203T I321V E374K D97N K283E E499K K163Q A256T S185T S451N S190R L524V D35E V30A I116M A186T M257V G155E N156K K153E S190R

8. Evolutionary Relationships Among Influenza A(H1N1)pdm09 Hemagglutinin (HA) Genes Feb, 2016 Current Northern Hemisphere Vaccine Strain LR- Low Reactor to A/California/07/2009 (≥ 8 fold) # -Egg Isolate ORG – Original Clinical Specimen @ - Oseltamivir Resistant * HA1 only October 2015 November 2015 December 2015 January 2016 rus A/IIV-Moscow/195/2015 Dec rus A/Saint-Petersburg/RII639M/2016 Jan crick A/Ireland/2142/2016 Jan A/Alaska/263/2015 Nov # A/California/105/2015 Oct # A/Hong Kong/15587/2015 Oct # A/Colorado/20/2015 Nov A/California/102/2015 Nov # crick A/Iran/1337/20155 Nov crick A/Switzerland/16078014/2016 Jan A/Minnesota/45/2015 Oct F ger A/Mecklenburg-Vorpommern/1/2016 Jan ORG crick A/Poland/7474/2015 Dec crick A/Moscow/160/2015 Dec A/Ulaanbaatar/2871/2015 Nov ORG A/Pennsylvania/06/2016 Jan ORG crick A/Slovenia/2903/2015 Oct wF w$ A/Utah/01/2016 Jan ORG A/Nebraska/01/2016 Jan ORG usafsam A/Nevada/835/2015 Dec A/California/01/2016 Jan ORG A/Indiana/04/2016 Jan ORG A/Virginia/298/2015 Dec A/Michigan/72/2015 Dec A/Michigan/03/2016 Jan ORG A/New Hampshire/43/2015 Dec # A/New Hampshire/44/2015 Dec # crick A/Athens/12/2016 Jan 2016 A/H1N1pdm09 6B.1 HA Consensus A/Montana/03/2016 Jan ORG A/Michigan/65/2015 Oct @ niid A/Akita/5/2015 Nov swe A/Stockholm/66/2015 Nov ORG neth A/Netherlands/2916/2015 Nov ORG nor A/Norway/208/2016 Jan ORG HA1 A/Pakistan/380/2015 Nov ORG crick A/Saudi Arabia/4009/2015 Sep usafsam A/Cambodia/AD05917/2015 Nov rus A/Saint-Petersburg/10/2016 Jan rus A/Stavropol/07/2016 Jan crick A/Iran/116675/2015 Nov # A/Illinois/16/2015 Oct # A/Minnesota/45/2015 Oct # crick A/Latvia/11-044910/2015 Oct crick A/Ukraine/20/2016 Jan A/Kazakhstan/146/2015 Dec ORG A/Kazakhstan/140/2015 Dec ORG crick A/Cameroon/15v-9393/2015 Dec A/Bulgaria/758/2015 Dec ORG A/Bulgaria/010/2016 Jan ORG crick A/Czech Republic/3/2016 Jan A/Pakistan/394/2015 Dec ORG cnic A/Beijing-Xicheng/SWL13022/2015 Dec A/Costa Rica/0017/2016 Jan ORG aust A/Austria/896853/2016 Jan HA1 crick A/Norway/2846/2015 Dec A/Tennessee/22/2015 Dec ORG niid A/Kanagwa/75/2015 Dec A/St Petersburg/349/2015 Nov cnic A/Shanghai-Qingpu/SWL11063/2015 Dec cnic A/Shanghai-Huangpu/SWL11940/2015 Nov # A/Nepal/3431/2015 Sep crick A/Cameroon/15v-9415/2015 Dec A/Colorado/30/2015 Dec ORG @ A/Michigan/45/2015 Sep # F $ A/Michigan/45/2015 Sep F $ crick A/Iran/117007/2015 Nov # niid A/Fukushima/74/2015 Sep w$ usafsam A/South Korea/x2/2015 Oct crick A/Czech Republic/95/2015 Dec A/South Africa/4291/2015 Jul LR A/Pennsylvania/41/2015 Oct # A/Arkansas/10/2015 Nov # A/Bangladesh/3002/2015 May # F A/Bangladesh/3002/2015 May F niid A/Yokohama/90/2015 Oct w$ nor A/Norway/174/2016 Jan ORG HA1 A/Nepal/3421/2015 Sep A/North Carolina/04/2014 Feb # F @ A/Michigan/57/2015 Oct # aus A/Sydney/215/2015 Nov A/St Petersburg/61/2015 Feb # F w$ A/Florida/62/2014 Oct # F A/Florida/62/2014 Oct F A/South Australia/22/2015 Mar # wF A/Connecticut/05/2015 Oct # niid A/Yokohama/50/2015 Feb wF crick A/Georgia/1305/2015 Nov crick A/Antsirabe/5056/2015 Dec A/Maevatanana/4194/2015 Sep # chile A/Lautaro/72414/2015 Oct HA1 A/Costa Rica/0768/2016 Jan ORG A/Costa Rica/4060/2015 Nov ORG A/Costa Rica/0373/2015 Oct ORG A/Delaware/42/2015 Oct # A/Montana/07/2016 Jan ORG A/New York/01/2016 Jan ORG A/Colorado/01/2016 Jan ORG aus A/Tasmania/24/2014 Jul wF aus A/New Caledonia/58/2014 May wF A/Iowa/53/2015 Nov F A/Iowa/53/2015 Nov # F A/Shanghai-Putuo/1860/2015 Oct # C$ crick A/Hong Kong/88/2016 Jan 2016 A/H1N1pdm09 6B.2 HA Consensus cnic A/Beijing-Huairou/SWL120/2016 Jan cnic A/Yunnan-Mengzi/SWL11144/2015 Dec A/Shanghai-Putuo/1860/2015 Oct $ A/Massachusetts/01/2016 Jan ORG aus A/Perth/103/2015 Aug wF A/Minnesota/32/2015 Jul F crick A/Denmark/48/2015 Dec niid A/Fukuoka/15036/2015 Dec fra A/Paris/1906/2015 Sep crick A/Saudi Arabia/78085/2015 Sep aus A/Victoria/504/2015 Apr wF A/Florida/88/2015 Oct # A/Pakistan/370/2015 Nov ORG niid A/Wakayama/153/2013 Nov wF A/South Africa/3626/2013 Jun # F wF A/South Africa/3626/2013 X-243 # F A/South Australia/17/2013 May # wF A/Bolivia/559/2013 # F A/Vietnam/3050/2013 Feb # LR F A/Pennsylvania/07/2013 Oct F cnic A/Jiangsu-Sucheng/SWL1994/2015 Dec # A/Bangladesh/2021/2012 Jul LR # F crick A/Hong Kong/5659/2012 May wF aus A/Brisbane/70/2011 Feb # wF A/St Petersburg/100/2011 Mar # wF A/Christchurch/16/2010 Jul # wF w$ A/California/07/2009 Apr F $ A/California/07/2009 X-179A # F w$ A/California/07/2009 Apr # F $ 0.001 6B.1 6A 6C 6B.2 6B D127E M257I T310A I418V V199 A D222 G L191I S83P A141 T A215 G S162N ADD GLY I216T S84N K36M K311T L365Q N370S A48P S69P L365Q K163Q A256T K283E E499K D97N S185T S451N P83S S203T I321V E374K A261S V152T V173I D501E E491G L524V Q223R V234I D127E H138R V249L S143G A197T Q223R

9. Phylogenetic Evolution of the HA Genes of Influenza A(H3N2) Viruses 2011-2016

10. Evolutionary Relationships Among Influenza A (H3N2) Hemagglutinin (HA) Genes, 2011 09/19/2011 Current Southern Hemisphere Vaccine Strain LR- Low Reactor to A/Perth/162009 (≥ 8 fold) # Egg Isolate May 2011 June 2011 July 2011 August 2011 A/Argentina/566/2011 Aug A/Santiago/18454/2011 Aug ORG A/Georgia/01/2011 Feb F A/Paraguay/210/2011 Aug ORG nimr A/Ireland/11M27357/2011 Apr $ A/Santiago/14944/2011 Jul A/Iowa/19/2010 Dec F A/Texas/11/2011 Feb M$ A/Chile/72/2011 May M$ A/Florida/20/2011 Aug ORG A/Florida/21/2011 Aug A/Argentina/676/2011 Aug A/North Dakota/06/2011 Feb M$ A/Argentina/8823/2011 Jul A/Arizona/13/2010 Dec # F A/Arizona/13/2010 Dec F A/Iowa/19/2010 Dec # $$ aus A/South Auckland/7/2011 Jun A/Alaska/05/2010 Dec # aus A/Alaska/5/2010 IVR-161 # A/Florida/48/2010 Dec M$ A/Panama/307149/2010 Jun # F A/Pennsylvania/12/2011 Aug ORG A/Louisiana/06/2011 Aug A/Chile/64/2011 May M$ $ nimr A/Stockholm/17/2011 Feb $ nimr A/Santa Fe/1431/11 Jul A/Argentina/179/2011 Jun A/Maryland/17/2011 Jul A/Argentina/198/2011 Jul A/Argentina/215/2011 Jul A/Montana/05/2011 Mar # $$ A/Perth/10/2010 X-207A # F aus A/Perth/10/2010 May # nimr A/Serbia/1580/2011 Feb $ A/Peru/6311/2011 Jul A/Peru/7111/2011 Aug A/Ontario/RV0064/2011 Jan F niid A/Sakai/20/2011 Feb $ A/Hong Kong/3970/2011 May A/Missouri/06/2011 Mar M$ H3 2011 HA Consensus 513 A/Brazil/1151/2011 May M$ A/Brazil/5613/2011 Jul A/Brazil/6078/2011 Jul nimr A/La Reunion/1552/2011 Jun A/Bolivia/340/2011 Jun M$ A/Bolivia/401/2011 Jun A/Bolivia/405/2011 Jun A/Perth/10/2010 # F A/Perth/10/2010 X-207 # F cnic A/Hunan-Beihu/1143/2011 Mar # $ nimr A/Stockholm/15/2011 Jan $ A/Alabama/05/2010 Jul F aus A/Victoria/563/2010 Aug # aus A/Victoria/563/2010 IVR-160 # A/Tanzania/952/2011 May M$ nimr A/Johannesburg/107/2011 Jun nimr A/Johannesburg/153/2011 Jul A/Rhode Island/01/2010 Jan # F A/Rhode Island/01/2010 X-199 # A/Rhode Island/01/2010 Jan F A/Wyoming/09/2010 Dec F niid A/Yamagata/285/2011 Mar $ aus A/Victoria/8/2010 Aug # nimr A/Johannesburg/78/2011 Jun nimr A/Norway/1775/2011 Jul nimr A/Stockholm/18/2011 Feb $ nimr A/Ghana/731/2011 May $ nimr A/Ghana/Fs-11-1037/2011 Jun $ A/Taiwan/1328/2011 May nimr A/Hong Kong/3969/2011 May $ nimr A/Norway/1789/2011 Aug A/South Australia/03/2011 Jun $$ A/Hong Kong/3953/2011 Apr M$ aus A/Wellington/3/2011 Jun aus A/Newcastle/5/2011 Jun A/Iowa/06/2011 Aug A/Hong Kong/3974/2011 Jun A/Bangladesh/1539/2011 Jul A/Georgia/08/2011 Jul A/India/9912/2011 Jun A/Florida/22/2011 Aug ORG nimr A/Johannesburg/73/2011 Jun A/India/514/2011 Jul A/Bangladesh/5071/2011 May M$ $$ A/Hawaii/02/2011 Jul nimr A/Norway/1762/2011 Jul A/Victoria/208/2009 Jun # A/Alabama/03/2011 Apr A/Wisconsin/15/2009 Jun # F A/Perth/16/2009 # $$ A/Victoria/210/2009 Jun # $ A/Victoria/210/2009 X-187 # $ A/Taiwan/851/2010 # F cnic A/Shanghai-Luwan/188/2011 Feb # cnic A/Hunan-Yanfeng/165/2011 Apr $ niid A/Kumamoto-C/36/2011 Apr $ nimr A/Norway/1186/2011 Mar $ 0.002 2 E62K N144K- LOSE GLY K158N N189K K173Q I361R 1 I260M R261Q P162S E50K K62E K158N N189K T212A D53N Y94H I230V E280A T48A K92R N312S V223I A198S N312S S45N ADD GLY T48I N144D – LOSE GLY N145S D487N N145S D487N S45N ADD GLY D53N T128A S262N L427F D489N 3 4 5 6 I192T S199A S45N ADD GLY I522T H156Q G186V S219F E280T ADD GLY A138S R142G 2KE N8D G186V S219F G5E E280T ADD GLY G5E H156Q G186V S219F R208K

11. Evolutionary Relationships Among Influenza A (H3N2) Hemagglutinin (HA) Genes, 2012 09/11/2012 Current Southern Hemisphere Vaccine Strain LR- Low Reactor to A/Perth/16/2009 (≥ 8 fold) # Egg Isolate * – only HA1 region April 2012 May 2012 June 2012 July 2012 August 2012 spn A/CastillaLaMancha/126/2012 Aug* A/Curico/51369/2012 Jul A/Santiago/45700/2012 Jun A/Kentucky/05/2011 Nov $ A/West Virginia/17/2012 Aug LR A/Brisbane/299/2011 Aug # F namru6 A/Peru/IRFc0001/2012 May A/Santiago/35234/2012 May p$ A/Puerto Rico/08/2012 Jun LR A/Nevada/25/2012 Jul A/Perth/10/2010 # F aus A/Wellington/19/2012 Jul aus A/Fiji/8/2012 Jun aus A/Canberra/1001/2012 Jul namru6 A/Peru/IRP0096/2012 May A/Paraguay/32/2012 Jul LR A/Brazil/8751/2012 Jun A/Wisconsin/25/2012 Aug A/Indiana/158/2012 Aug LR A/Minnesota/10/2012 May A/Kenya/120/2012 Apr A/Rhode Island/01/2010 Jan # F aus A/Victoria/873/2012 Aug aus A/Tasmania/26/2012 Jun A/Utah/17/2012 Jun LR A/Ethiopia/141/2012 May LR aus A/Victoria/342/2012 Jul A/Astrakhan/06/2012 May LR aus A/South Australia/30/2012 May p$ A/South Australia/30/2012 May # $ nimr A/Ghana/FS-12-758/2012 Jun A/Ohio/02/2012 Mar $ A/Ohio/02/2012 Mar # C$ A/Nevada/20/2012 Apr LR # A/Nevada/20/2012 Apr LR A/Maryland/02/2012 Jan # p$ A/Utah/23/2012 Jul LR aus A/Cambodia/10/2012 Jul A/Alaska/16/2012 Jul LR aus A/Wellington/21/2012 Jul A/Rhode Island/01/2012 Jan LR F A/Bangladesh/5071/2011 May F namru6 A/Peru/IRPc0102/2012 May usafsam A/Guam/2452/2012 May* niid A/Yokohama/148/2012 Jul A/Suriname/295/2012 May LR nimr A/Madagascar/03619/2012 Jun namru6 A/Peru/IREc0012/2012 Jun aus A/Sri Lanka/12/2012 A/Pennsylvania/16/2012 Aug A/Colorado/16/2012 May LR A/Victoria/361/2011 Oct # $ A/Victoria/361/2011 IVR-165 # p$ A/Victoria/361/2011 Oct $ aus A/Victoria/1002/2012 Jul A/South Carolina/14/2012 Aug LR aus A/Victoria/448/2012 Aug aus A/Tasmania/22/2012 Jul A/Micronesia/6310/2012 Jul A/Micronesia/6307/2012 Jul A/Ontario/RV2818/2012 Jul A/Alaska/21/2012 Aug nimr A/Hong Kong/8152/2012 Jun p$ A/Washington/33/2012 Aug LR A/California/35/2012 Jul LR A/North Carolina/21/2012 Aug LR A/Hong Kong/8118/2012 Jun LR aus A/Philippines/26/2012 Jul aus A/Wellington/36/2012 Jul A/Hong Kong/8116/2012 Jun nimr A/Hong Kong/8117/2012 Jun p$ aus A/Singapore/25/2012 Jun A/Idaho/22/2012 Jul LR A/Kentucky/12/2012 Aug LR niid A/Kumamoto-C/14/2012 Jun A/Idaho/20/2012 Jun LR $ niid A/Kawasaki/86/2012 Jun* A/Hawaii/16/2012 Aug aus A/Christchurch/516/2012 Jul A/St Lucia/2073/2012 May LR aus A/Darwin/1001/2012 Jul A/Ohio/73/2012 Aug A/Washington/43/2012 Aug aus A/Canberra/33/2012 Jul aus A/Cambodia/5/2012 Jul A/British Columbia/RV2820/2012 Jun nimr A/Glasgow/407664/2012 Apr # A/Texas/50/2012 Apr # A/Texas/50/2012 Apr A/New Hampshire/10/2012 May # A/New Hampshire/10/2012 May nimr A/Madagascar/03536/2012 Jun A/Berlin/93/2011 Dec NC# p$ A/Punta Arenas/52090/2012 Jul H3N2 HA Consensus 2012 797 A/Vina Del Mar/49586/2012 Jul LR A/Linares/52087/2012 Jul A/Puerto Montt/51699/2012 Jul A/Shanghai-Chongming/1205/2012 Jun niid A/Taiwan/426/2012 Apr #* niid A/Taiwan/285/2012 Mar #* nimr A/Brisbane/1/2012 Jan # niid A/Taiwan/613/2012 May #* niid A/Yokohama/152/2012 Jul aust A/Austria/111/2012 Jul* A/Puerto Rico/23/2012 Jun LR aus A/Victoria/84/2012 Jul aus A/South Australia/108/2012 Jul A/Victoria/208/2009 Jun # WF A/Alabama/03/2011 Apr A/Perth/16/2009 # $ A/Wisconsin/15/2009 Jun # F A/Taiwan/851/2010 # F A/Chungbuk/644/2011 Nov A/Jiangsu-Xinpu/1205/2012 May # cnic A/Jiangsu-Xinpu/1179/2012 Apr* 0.002 5 7 6 3C 3A 3B 4 A/Perth/16/09-like 1 2 E62K N144K LOSS GLY E50K P162S I260M R261Q S279Y T212A D53N Y94H I230V E280A S199A N8D LOSS GLY N31S S45G N121K K2E R142G S45N ADD GLY L3I N144D LOSS GLY N145S D487N V223I A198S N312S N145S D487N I140M D53N T128S I140M S45N ADD GLY T48I N278K Q33R R142G T128A LOSS GLY K452R I25M I140L L3I N145S D489N S45T T128N LOSS GLY 3

12. A/Perth/16/2009 # F A/Wisconsin/15/2009 Jun # F cnic A/Shanghai-Fengxian/115/2013 Jan # * A/Victoria/208/2009 Jun # A/Montana/05/2011 Mar # F A/French Guiana/1118/2013 May usafsam A/Florida/4088/2013 Jun A/Alaska/02/2013 Feb PR A/Puerto Rico/36/2012 Jun # F PR A/Rhode Island/01/2010 Jan # F A/Indonesia/Nihrd-Drs490/2012 Jan LA A/Ohio/02/2012 Mar F A/Ohio/02/2012 Mar # F A/Victoria/361/2011 Oct F $ MN# PR A/Victoria/361/2011 IVR-165 # F A/Victoria/361/2011 Oct # F $ MN$ PR aus A/Victoria/361/2011 NIB 79 # A/Texas/50/2012 Apr F $ MN$ PR A/Texas/50/2012 Apr # F C$ MN$ PR A/Texas/50/2012 X-223A # F A/Texas/50/2012 X-223 # F w$ A/Hawaii/22/2012 Jul F A/Hawaii/22/2012 Jul # F cnic A/Shanghai-Changning/1507/2012 Aug # w$ * aus A/Singapore/22/2012 Jun nimr A/Ghana/DARI-0098/2013 Jul A/Vietnam/3055/2013 May A/Kamphaengphet/175/2013 May A/India/1477/2013 Mar A/American Samoa/4786/2013 Feb $ MN$ A/American Samoa/8097/2013 May A/American Samoa/4786/2013 Feb # w$ A/Bangladesh/9269/2013 May A/Minnesota/05/2013 Jul A/Vietnam/3064/2013 May A/Alaska/04/2013 Apr PR A/Bolivia/902/2013 May A/Argentina/555/2013 Jun A/Brazil/265/2013 Apr A/Venezuela/05/2013 Jun A/Peru/140/2013 May aus A/Auckland/502/2013 Jun A/Valparaiso/34097/2013 May A/Uruguay/396/2013 Jul A/Georgia/03/2013 Jul A/Georgia/03/2013 Jul # A/Phuket/186/2013 Jun A/Nonthaburi/174/2013 May aus A/Victoria/504/2013 Jun # w$ aus A/Brisbane/1/2013 Feb # w$ A/Missouri/04/2013 Mar A/Missouri/04/2013 Mar # A/Santiago/47142/2013 Jul A/Santiago/36541/2013 Jun niid A/Chiba-C/39/2013 Apr w$ * nimr A/South Africa/3941/2013 Jun A/Delaware/15/2012 Nov F PR niid A/Osaka/32/2013 May w$ * A/Alaska/05/2013 Apr PR A/Arizona/09/2012 Oct F A/Arizona/09/2012 Oct # F niid A/Taiwan/692/2013 Jun * niid A/Osaka/35/2013 Jun * A/Victoria/505/2013 Jun # $ MN$ H3 HA Consensus since Feb 2013 n=522 aus A/Christchurch/507/2013 May A/Brazil/3873/2013 Jul A/Massachusetts/12/2013 Jul A/Utah/07/2013 Jul A/Texas/14/2013 Aug A/Santiago/35652/2013 May nimr A/Ghana/Dili-0443/2013 Jun A/Guatemala/287/2013 Jul A/Argentina/433/2013 Jun nimr A/Bulgaria/270/2013 Feb w$ A/Massachusetts/07/2013 Apr @ nimr A/Plzen/17/2013 Jan w$ A/New York/39/2012 Oct F $ A/New York/39/2012 Oct # F $ MN$ PR nimr A/Samara/73/2013 Mar w$ A/Massachusetts/11/2013 Jul nimr A/South Africa/4671/2013 Jun A/Bangladesh/9334/2013 May A/Bangladesh/9334/2013 May # A/Florida/21/2013 Jul nimr A/Ghana/DILI-518/2013 Jul niid A/Yokohama/153/2013 Apr w$ * niid A/Yamaguchi/30/2012 Oct LR * A/Maryland/04/2013 Mar LR $ MN$ niid A/Kanagawa/141/2013 May * A/Uruguay/322/2013 Jun cnic A/Beijing-Xicheng/11536/2013 Jul * aus A/Auckland/500/2013 May cnic A/Fujian-Yanping/2294/2013 Jun * cnic A/Jiangxi-Yushui/1220/2013 Apr * w$ A/Panama/313131/2013 Jun A/Ecuador/440/2013 Apr A/Arkansas/07/2013 Jul A/Arkansas/13/2013 Aug A/Managua/1083/2013 Jun A/El Salvador/433/2013 Mar PR cnic A/Hunan-Lusong/1532/2013 Jun * w$ A/West Virginia/11/2013 Jul niid A/Taiwan/741/2013 Jun * cnic A/Jiangsu-Tinghu/1269/2013 May * aus A/South Australia/29/2013 Jun * cnic A/Jiangxi-Xinzhou/1300/2013 Jun * cnic A/Jiangsu-Gusu/1625/2013 Jun * A/Missouri/05/2013 Aug Evolutionary Relationships Among Influenza A(H3N2) Hemagglutinin (HA) Genes, 2013 Current Southern Hemisphere Vaccine Strain LR- Low Reactor to A/Victoria/361/2011 (≥ 8 fold) # Egg Isolate * HA1 region only LA – Low Avid @ Oseltamivir Resistant E119V May 2013 June 2013 July 2013 August 2013 3C.3 HA Genetic Groups Based on Total GISAID Sequences Collected Since February 2013 (n=522) 3C.2 3C.1 4 1 3A 3B 6 5 G186V S219F 0.002 V223I I140M N145S D487N D53N Y94H I230V E280A K62E K144N ADD GLY T212A N144D N145S D487N LOSS GLY S199A N144D LOSS GLY A198S N312S T128N LOSS GLY S198P L157S V347M Q33R N278K S45N ADD GLY T48I N145S G186V N246S LOSS GLY D489N V347M T128A LOSS GLY R142G I226N L157S M347V D7E N144K H156Q G186S G186V N246N/T S145N G186V S219F I140K L194L/P

13. Current Northern Hemisphere Vaccine Strain LR- Low Reactor to A/Texas/50/2012 Cell (≥ 8 fold) F - CDC Reference Antigen # -Egg Isolate April 2014 May 2014 June 2014 July 2014 August 2014 Evolutionary Relationships Among Influenza A(H3N2) Hemagglutinin (HA) Genes, 2014 aus A/Victoria/503/2014 May # aus A/Newcastle/25/2014 May # aus A/Newcastle/22/2014 Jun # A/Santiago/45290/2014 Jul niid A/Sapporo/116/2014 Mar A/Bolivia/871/2014 Jul A/New Mexico/09/2014 Apr # A/Nevada/09/2014 Apr # A/New Jersey/21/2014 Jul ORG A/Argentina/120/2014 Jul A/Washington/18/2013 Nov # F A/Consensus/H3/2014 HA aus A/South Australia/1005/2014 Jul cnic A/Shanghai-Xuhui/1370/2014 Apr cnic A/Anhui-Luyang/1286/2014 Apr LR A/Argentina/155/2014 Jul nimr A/South Africa/4655/2013 Jun cl118-76 # wF A/New York/39/2012 Oct # F A/India/7752/2014 Jun LR nimr A/Glasgow/4165/2014 Jun A/New Zealand/0193/2014 Jun LR A/Cambodia/715/2014 Jun ORG LR A/California/02/2014 Jan LR F cnic A/Hubei-Wujiagang/1702/2014 Aug aus A/Sydney/85/2014 Jun A/Alaska/29/2014 Jul LR A/North Carolina/13/2014 Apr # A/Switzerland/9715293/2013 # LR F aus A/Victoria/27/2014 Jun cnic A/Hunan-Furong/1531/2014 Jul cnic A/Tianjin-Hexi/1329/2014 Jul A/Burkina Faso/323/2014 May ORG LR cnic A/Jiangxi-Zhushan/1614/2014 Aug nimr A/Ghana/Dili-0659/2014 Jul aus A/Sri Lanka/29/2014 May nimr A/Dakar/12/2014 Jul nimr A/Stockholm/6/2014 # wF A/New York/05/2014 Jan LR # F aus A/Tasmania/11/2014 Mar # wF nimr A/Norway/466/2014 Feb cl58 # wF aus A/South Australia/55/2014 Jun # nimr A/Finland/440/2014 Apr cl55 # wF A/Palau/6775/2014 Mar LR # A/Palau/6720/2014 Apr # A/Palau/6759/2014 Mar # F A/Argentina/177/2014 Jul aus A/Sydney/92/2014 Jun niid A/Tokyo/34059/2014 May nimr A/Hong Kong/146/2013 Jan cl21 # wF A/Louisiana/39/2013 Dec F nimr A/Hong Kong/5738/2014 Apr cl121 # wF A/Alaska/18/2014 Jun LR A/Bangladesh/4008/2014 Jun A/Wisconsin/17/2014 Jul ORG LR A/Minnesota/18/2014 Jul ORG niid A/Kanagawa/159/2014 Jun A/Texas/50/2012 Apr # F A/Texas/50/2012 Apr F 0.001 3C.3 3C.2 3C.2b 3C.2a 3C.1 3C.3b 3C.3a L157S V347M N122D LOSS GLY E62K K83R R261Q M347K V347K F159Y A138S F159S N225D K326R R326K A19S T128A LOSS GLY R142G N145S D489N D225G G186V L3I N144S LOSS GLY K160T ADD GLY N225D Q311H F159Y T128N LOSS GLY S198P I140I/K D225D/N I140R S219S/F H156R N246H LOSS GLY H183F G186V D225N N246T LOSS GLY G186D D190G G186E S145N

14. Current Southern Hemisphere Vaccine Strain LR - Low Reactor to A/Switzerland/9715293/2013 Cell (≥ 8 fold) ITT – Insufficient HA Titer for HI Testing VNR-Virus Not Recovered (no HA) # Egg Isolate *HA1 region only May 2015 June 2015 July 2015 August 2015 Evolutionary Relationships Among Influenza A(H3N2) Hemagglutinin (HA) Genes 2015 A/Florida/63/2015 Aug ORG nimr A/Hong Kong/11713/2015 Jun A/Peru/37/2015 May ITT A/Colombia/5614/2015 Jul ORG ITT A/Washington/31/2015 Mar LR A/Texas/65/2015 Aug ORG A/Alaska/139/2015 Aug ORG ITT A/Colombia/5615/2015 Jul ORG VNR A/Brazil/187/2015 May FRA A/Panama/316634/2015 Jul ORG ITT aus A/Tasmania/25/2015 Jun A/Ecuador/1673/2015 Aug ORG FRA aus A/South Australia/21/2015 Mar w$ A/Victoria/503/2015 Mar # A/Brisbane/47/2015 Mar # A/Hawaii/44/2015 Jul ORG ITT FRA A/Alaska/138/2015 Aug ORG ITT A/Ohio/22/2015 Jul ORG ITT A/Washington/39/2015 Jul ORG A/Michigan/37/2015 Jun A/Iowa/36/2015 Jul ORG ITT A/Alaska/36/2015 Jun ORG ITT FRA A/Alaska/35/2015 Jun ORG ITT FRA bra A/Sao Paulo/60985/2015 Jul A/Santiago/44139/2015 Jun nimr A/South Africa/R3776/2015 Jun aus A/Canberra/20/2015 Jun A/Florida/50/2015 Jun FRA A/Hong Kong/11741/2015 Jun ITT A/Alaska/22/2015 Jun ITT FRA cnic A/Anhui-Luyang/1465/2015 Jun cnic A/Jiangxi-Yushui/1477/2015 Jun A/Texas/09/2015 Feb LR nimr A/Hong Kong/7127/2014 Jul A/Hong Kong/7127/2014 # F $ aus A/Victoria/673/2014 Sep # A/Singapore/KK943/2014 Oct # cnic A/Guangdong-Huicheng/1443/2015 Jun aus A/Christchurch/500/2015 Jun cnic A/Shanghai-Pudongxin/1901/2015 Jun A/Alaska/144/2015 Aug ORG ITT A/New Jersey/51/2015 Aug ORG VNR niid A/Hyogo/1041/2015 Jul A/Santiago/42575/2015 Jun nimr A/South Africa/R3944/2015 Jul A/Argentina/196/2015 Jul ITT A/Ecuador/1668/2015 Jun ORG ITT FRA A/Bangladesh/3400/2015 May ITT A/Tennessee/07/2015 Feb LR A/Wisconsin/20/2015 Feb F $ A/Guatemala/142/2015 Jun ORG aus A/Brisbane/82/2015 Apr w$ A/Hawaii/46/2015 Jul ORG ITT A/Alaska/143/2015 Aug ORG ITT A/Mexico/1783/2015 Jul ITT niid A/Gifu/46/2014 Sep wF w$ A/Maine/17/2015 Mar LR A/Santiago/40992/2015 Jun A/Indiana/09/2015 Mar LR aus A/South Australia/1004/2015 Jul A/Ecuador/1670/2015 Feb ORG ITT FRA 2015 H3 HA 3C2a Consensus 1368 A/Florida/59/2015 Aug ORG A/South Carolina/07/2015 Feb LR bra A/Sao Paulo/61282/2015 Jul swe A/Stockholm/40/2015 Aug aus A/New Caledonia/71/2014 Aug wF w$ A/Michigan/15/2014 Sep F $ aus A/New Caledonia/104/2014 Sep wF w$ A/New Caledonia/71/2014 Aug # LR F $ A/Canberra/82/2014 Jul # F A/Fiji/02/2015 Mar # niid A/Sakai/72/2014 Mar wF A/Brazil/8004/2015 Feb LR FRA A/Nebraska/04/2014 Mar F M$ A/Brazil/56/2015 Mar LR niid A/Hyogo/4001/2014 Dec w$ A/Hong Kong/4801/2014 M$ niid A/Hyogo/3054/2014 Nov wF A/Hong Kong/4801/2014 # F wF $ M$ A/Hong Kong/5738/2014 # F wF A/Louisiana/39/2013 Dec F A/Pennsylvania/28/2014 Apr aus A/Tasmania/24/2015 Jun aus A/Victoria/511/2015 May w$ A/New Hampshire/16/2015 Mar LR A/Pennsylvania/09/2015 Jan F M$ bra A/Distrito Federal/58900/2015 May aus A/Newcastle/54/2014 Aug wF 2015 H3 HA 3C3b Consensus A/Khmelnitsky/460/2015 Apr FRA nimr A/Netherlands/525/2014 Dec wF cnic A/Yunnan-Gucheng/11744/2015 May A/Hawaii/38/2015 May ITT aus A/Newcastle/11/2015 May 2015 H3 HA 3C3 Consensus A/Dominica/672/2015 Mar ORG ITT aus A/Victoria/814/2015 Jul A/New York/39/2012 Oct # F wF A/New York/39/2012 Oct F wF A/Guatemala/9704/2015 May ORG A/Guatemala/9922/2015 Jun ORG A/Santiago/39170/2015 Jun niid A/Niigata-C/44/2015 May bra A/Sao Paulo/10-22878/2015 Jul bra A/Sao Paulo/3-35046/2015 Jun A/Stockholm/06/2014 Jun # F wF A/Stockholm/06/2014 Jun F wF A/Peru/27/2015 Apr FRA A/Peru/39/2015 May FRA A/Ecuador/2384/2015 Jun ORG FRA A/Ecuador/2369/2015 Apr ORG FRA A/Argentina/229/2015 Jul A/Argentina/255/2015 Aug A/Panama/316597/2015 Jun ORG VNR A/Mexico/1714/2015 Jun A/Mexico/1797/2015 Jul 2015 H3 HA 3C3a Consensus A/Switzerland/9715293/2013 Dec F wF $ M$ niid A/Osaka-C/2003/2014 Jan wF A/Laos/122/2015 Feb FRA cnic A/Qinghai-Chengdong/1314/2015 Apr cnic A/Jiangsu-Qingpu/1660/2015 Apr # A/California/02/2014 Jan F A/South Australia/55/2014 Jun # F w$ A/South Australia/55/2014 Jun F cnic A/Yunnan-Wuhua/1281/2015 May A/North Carolina/13/2014 Apr F A/North Carolina/13/2014 Apr # F A/Switzerland/9715293/2013 Dec # F wF $ M$ A/Switzerland/9715293/2013 NIB-88 # F wF w$ cnic A/Guangxi-Changzhou/316/2015 May A/Texas/50/2012 # F A/Texas/50/2012 F 0.002 3C.2a 3C.3 3C.3a 3C.1 3C.3b 3C.2b A138S F159S N225D T128A LOSS GLY R142G N145S P198S L3I N144S LOSS GLY K160T ADD GLY N225D Q311H D489N F159Y L157S V347K G5E N31S E62K N122D LOSS GLY Q197H K83R R261Q K326R Y94H S124N LOSS GLY S198P E62G D489N I140M K207R I25M K2N D53N S198P Y94H Q197R R142K L532V Q197K V347M S114T N171K I406V G484E R261L R142G

15. B Victoria-lineage Yamagata-lineage of Influenza B Virus Periods of Observed Circulation in Humans Dominant Influenza B viruses in the U.S. B/Sichuan/379/99 B/Hong Kong/330/2001 B/Shanghai/361/2002 B/Malaysia/2506/2004 B/Florida/4/2006 B/Brisbane/60/2008 B/Phuket/3073/2013 B/Wisconsin/01/2010 B/Massachusetts/02/2012 B/Brisbane/60/2008 1940 1987 1990 2001 2002200320042005200620072008200920102011 20122013 2014 2015 2016.

16. Evolutionary Relationships Among Influenza B Hemagglutinin (HA1) Genes, 1985-2010 B/Florida/4/2006 B/Shanghai/361/2002 B/Beijing/184/93 B/Sichuan/379/99 B/Yamagata/16/88 B/Victoria/02/1987 B/Hong Kong/330/2001 B/Shandong/7/97 B/Malaysia/2506/2004 B/Brisbane/60/2008 0.01 Yamagata Lineage Victoria Lineage 1.77 x 10 -3 nt/site/year (n=1699) 1.8 x 10 -3 nt/site/year (n=1794)

17. Phylogenetic Evolution of the HA Genes of Influenza B/Yamagata-lineage Viruses 2011-2016

18. Evolutionary Relationships Among Influenza B Yamagata Lineage Hemagglutinin (HA) Genes, 2011 09/19/2011 LR- Low Reactor to B/Florida/4/2006 (≥ 8 fold ) # Egg Isolate May 2011 June 2011 July 2011 August 2011 cnic B/Shanghai-Songjiang/190/2011 Feb # niid B/Ibaraki/6/2011 Feb cnic B/Shanghai-Songjiang/1100/2011 Feb # cnic B/Shanghai-Zhangning/1143/2011 Mar cnic B/Shanghai-Zhangning/1133/2011 Feb # cnic B/Jiangsu-Beitang/1135/2011 Apr B/Hong Kong/598/2011 Apr cnic B/Hunan-Yuhu/134/2011 Mar cnic B/Sichuan-Anyue/139/2011 Mar # $ cnic B/Gansu-Chengguan/572/2011 Mar cnic B/Shanghai-Luwan/1188/2011 Apr cnic B/Chongqing-Wanzhou/1152/2011 Mar cnic B/Jiangsu-Xinpu/192/2011 Mar cnic B/Hunan-Beihu/1300/2011 May cnic B/Hubei-Wuchang/1108/2011 Apr cnic B/Shanghai-Songjiang/1108/2011 Mar niid B/Taiwan/289/2011 Mar nimr B/Hong Kong/765/2011 Jun B/Washington/01/2010 Nov # FATAL cnic B/Tianjin-Binhaixin/1125/2011 Apr cnic B/Shanghai-Luwan/187/2011 Feb cnic B/Tianjin-Hexi/156/2011 Feb # cnic B/Tianjin-Hexi/180/2011 Feb # B YAM 2011 HA Consensus 118 cnic B/Beijing-Xicheng/1962/2011 May B/Hong Kong/781/2011 Jun niid B/Saitama/18/2011 Mar niid B/Hyogo/1053/2011 Apr niid B/Hyogo/1051/2011 Apr cnic B/Anhui-Huashan/1216/2011 May nimr B/Hong Kong/568/2011 Apr cnic B/Shanghai-Pudongxin/1238/2011 May cnic B/Beijing-Xicheng/1677/2011 Apr cnic B/Jiangsu-Quanshan/1329/2011 Apr cnic B/Tianjin-Hedong/1174/2011 May cnic B/Shanghai-Luwan/1217/2011 May # $ cnic B/Shanghai-Songhui/1104/2011 Mar # B/Shanghai-Baoshan/197/2011 Mar niid B/Taiwan/288/2011 Apr B/Shanghai-Zhangning/1725/2010 Dec B/Wisconsin/01/2010 Feb # C$$ B/Wisconsin/01/2010 BX-41A # B/Wisconsin/01/2010 BX-41 # B/Hong Kong/2060/2010 Sep # B/Shanghai-Fengxian/1271/2011 Jul B/Hubei-Wujiagang/158/2009 BX-39A # B/Hubei-Wujiagang/158/2009 BX-39 # B/Hubei-Wujiagang/158/2009 # F niid B/Saitama/63/2011 Apr niid B/Saitama/65/2011 May B/Indiana/06/2011 Mar B/North Carolina/09/2011 Feb B/Colorado/04/2011 Mar B/North Carolina/19/2011 Feb B/Texas/06/2011 Feb # F B/Texas/06/2011 Feb F B/Louisiana/08/2011 Feb B/Illinois/03/2011 Mar B/Florida/06/2011 Mar B/North Carolina/24/2011 Feb B/Pennsylvania/13/2010 Sep # aus B/Victoria/500/2011 Jan # B/Michigan/03/2011 Feb aus B/Surat Thani/29/2011 Feb niid B/Yokohama/54/2011 Apr swe B/Stockholm/12/2011 Feb $ B/Wisconsin/04/2011 Apr B/Bangladesh/1994/2010 Jan # F B/Indiana/10/2011 Aug nimr B/Hong Kong/602/2011 Apr nimr B/Latvia/2-70/2011 Feb $ B/New Mexico/05/2011 May aus B/Townsville/2/2011 Feb nimr B/Serbia/1894/2011 Mar $ nimr B/Serbia/2095/2011 Mar $ B/British Columbia/RV0028/2011 B/Washington/02/2010 Oct # LR niid B/Sapporo/34/2011 Mar nimr B/Lyon/1179/2011 Mar B/Bangladesh/3333/2007 Aug # F B/Brisbane/03/2007 Mar # B/Chongqing/Yongchuan18/2007 Jan # niid B/Taiwan/344/2011 Apr niid B/Taiwan/381/2011 May nimr B/Hong Kong/748/2011 Jun B/Finland/61/2011 Feb swe B/Stockholm/17/2011 Feb B/Finland/39/2010 Dec # F cnic B/Fujian-Xiangcheng/2150/2011 May nimr B/Estonia/55669/11 Mar $ nimr B/Estonia/55763/11 Mar $ B/Florida/04/2006 Nov # F B/Pennsylvania/07/2007 Mar # 0.002 R48K P108A S230G S150I N166Y S230D T182A E479D N116K T182K N203S V87I G141R T199N M252V G184E V29A L173Q V87I T222A T182A K254R 1 2 3

19. B/Florida/04/2006 Nov # F B/Hubei-Wujiagang/158/2009 Mar # F B/Wisconsin/01/2010 BX-41A # B/Wisconsin/01/2010 BX-41 # B/Wisconsin/01/2010 Feb # F $ B/Wisconsin/01/2010 Feb F cnic B/Jiangsu-Hailing/1949/2012 Nov # * cnic B/Yunnan-Wuhua/1143/2013 May cnic B/Yunnan-Dali/1135/2013 Apr cnic B/Guangxi-Xixiangtang/1311/2013 Jun w$ cnic B/Guangdong-Chikan/33/2013 Jun niid B/Shizuoka/121/2013 May * cnic B/Sichuan-Dongqu/1418/2013 May cnic B/Sichuan-Dongqu/1333/2013 May nimr B/Antananarivo/1226/2013 Apr nimr B/Mahajanga/697/2013 Mar B/New York/04/2013 May B/Dominican Republic/7672/2013 Jul B/Bahrain/115/2013 Feb B/Bahrain/18/2013 Jan B/Texas/06/2011 Feb F B/Texas/06/2011 Feb # F B/Bolivia/211/2013 Mar B/Khmelnitsky/524/2013 May $ B/Ukraine/484/2013 Apr B/Castro/50476/2013 Jul aus B/Christchurch/502/2013 May cnic B/Fujian-Licheng/1181/2013 May B/Brazil/325/2013 May B/Brisbane/36/2012 Jun # F w$ B/Estonia/55669/2011 Mar F B/Finland/39/2010 Dec # F B/Massachusetts/02/2012 Mar F $ B/Massachusetts/02/2012 BX-51C # F B/Massachusetts/02/2012 Mar # F C$ B/Massachusetts/02/2012 BX-51B # F w$ B/Laos/198/2013 Mar aus B/South Auckland/13/2013 Jun aus B/Tauranga/2/2013 Jun niid B/Saitama/15/2013 Jun * B/Omsk/19/2013 Mar nimr B/Vaslui/139688/2013 Apr aus B/Christchurch/2/2013 Jun aus B/Christchurch/503/2013 May nimr B/Ukraine/5941/2013 Apr w$ aus B/Auckland/503/2013 Jun nimr B/Jordan/30332/2013 May B/Kenya/111/2013 May B/Bahrain/146/2013 Feb B/Nevada/08/2013 May cnic B/Fujian-Gulou/1272/2013 Apr B/Kenya/112/2013 Apr B/Santiago/23499/2013 Apr B Yam HA Consensus since Feb 2013 n=633 aus B/Victoria/522/2013 Jul aus B/Victoria/504/2013 May aus B/Victoria/502/2013 May # w$ cnic B/Qinghai-Chengzhong/2154/2013 Apr aus B/Victoria/526/2013 Jul hk B/Hong Kong/75/2013 Apr * niid B/Fukui/28/2013 Jun * niid B/Fukui/24/2013 May w$ * niid B/Oita/5/2013 Jun * niid B/Sakai/15/2013 May * hk B/Hong Kong/44/2013 Mar * nimr B/South Africa/2800/2013 May cnic B/Shanghai-Putuo/120/2013 Jan w$ niid B/Sapporo/21/2013 May w$ * B/Hawaii/04/2013 May B/Alabama/02/2013 May aus B/Wellington/1/2013 May B/Alaska/04/2013 Apr aus B/Canberra/5/2013 Jun nimr B/South Africa/3786/2013 Jun nimr B/England/580/2012 Oct w$ aus B/South Australia/16/2013 May nimr B/Madagascar/01481/2013 Apr cnic B/Chongqing-Yuzhong/1361/2013 Apr # B/Santiago/7221/2013 Jan # LR B/Chiang Rai/169/2013 Apr nimr B/Iceland/63/2013 May aus B/Auckland/500/2013 May nimr B/Jordan/30314/2013 May B/Nong Khai/172/2013 May cnic B/Shanghai-Huangpu/1491/2013 May # B/Santiago/17411/2013 Mar B/Guatemala/260/2013 Jul B/Hawaii/01/2013 May $ B/Illinois/01/2013 Jan B/Illinois/01/2013 Jan # B/Brazil/374/2013 May B/Song Khla/1598/2013 Jun B/Arizona/06/2013 May nimr B/South Africa/4437/2013 Jun aus B/Victoria/3/2013 Jun B/French Guiana/8161/2013 Jun aus B/Perth/37/2013 Jun B/District Of Columbia/01/2013 Mar deletion N165 B/Florida/05/2013 May 2 HA Genetic Groups Based on Total GISAID Sequences Collected Since February 2013 (n=633) 0.0005 R48K P108A T182A S230G T189A T121S V267I Current Southern Hemisphere Vaccine Strain LR- Low Reactor to B/Wisconsin/01/2010 (8 ≥ fold) # Egg Isolate * - HA1 region only May 2013 June 2013 July 2013 August 2013 Evolutionary Relationships Among Influenza B Yamagata Lineage Hemagglutinin (HA) Genes, 2013 S150I N166Y S230D E479D N203S K299E E313K N116K T182K G184E T37A K299E E313K Q122K R279K 3 Reassortant HA-Y3/NA-V1A Reassortan ts HA-Y3/NA- V4 A182T T75I

20. B/Chanthaburi/315/2015 Jul ORG B/Santiago/37246/2015 Jun B/Alaska/27/2015 Jun B/French Guiana/7165/2015 May ORG B/Florida/67/2015 Jul aus B/South Australia/50/2015 Jun B/Alaska/31/2015 Jun B/Florida/51/2015 May # LR B/Antofagasta/42514/2015 Jun B/Puerto Montt/42299/2015 Jun # B/Maine/17/2015 Jun B/New Zealand/79/2015 May B/Puerto Rico/01/2015 Aug ORG B/Brazil/4926/2015 Jul B/New Zealand/328/2015 Jun B/New Zealand/478/2015 Jul B/New Zealand/426/2015 Jun B/New Zealand/515/2015 Jul aus B/Newcastle/1003/2015 Jun B/Bangkok/42/2015 Jun aus B/Christchurch/502/2015 Jul aus B/Canberra/28/2015 Jul B/Hong Kong/1326/2015 Jun B/Paraguay/4726/2015 Jun cnic B/Beijing-Chaoyang/1486/2015 Mar #* niid B/Yamagata/78/2015 Jun cnic B/Fujian-Cangshan/33/2015 May #* cnic B/Hubei-Shashi/840/2015 May #* B/Maryland/12/2015 Mar # LR niid B/Sapporo/2/2015 Feb w$ cnic B/Guangxi-Gangbei/1503/2015 Jun* nimr B/Hong Kong/1325/2015 Jun B/Hong Kong/1324/2015 Jun B/Hong Kong/1328/2015 Jun cnic B/Jiangxi-Zhanggong/1437/2015 Jun* cnic B/Guangdong-Futian/1372/2015 May #* cnic B/Sichuan-Dongqu/1592/2015 Jun* cnic B/Shanghai-Qingpu/1378/2015 May #* niid B/Taiwan/227/2015 Jun B/New Zealand/229/2015 Jun B/Iowa/05/2015 Mar B/Iowa/23/2015 Apr LR B/Nebraska/05/2015 Mar LR B/Alaska/44/2015 Jun bra B/Sao Paulo/2-16361/2015 Jul B/California/12/2015 Feb # $ B/California/12/2015 Feb $ aus B/Sydney/1013/2015 Jun B/New Zealand/443/2015 Jun nimr B/Hong Kong/1323/2015 Jun aus B/Brisbane/118/2015 Jun nimr B/Hong Kong/1327/2015 Jun aus B/Victoria/519/2015 Jul B/Mexico/1447/2015 Apr B/New Zealand/558/2015 Jul B/New Zealand/444/2015 Jun B/New Zealand/746/2015 Jun B/New Zealand/950/2015 Jul B/New Zealand/955/2015 Jul B/Florida/63/2015 Jun # B/Indiana/20/2015 Apr # B/Florida/65/2015 Jun niid B/Kagoshima/3052/2015 Jun nor B/Norway/2538/2015 Jun B/Concepcion/32003/2015 May B/Concepcion/32003/2015 May # bra B/Sao Paulo/3-35674/2015 Jul B/Acre/135657-IEC/2015 May ORG bra B/Sao Paulo/53930/2015 Jun B/Paraguay/950/2015 May B/Santiago/40993/2015 Jun B/Mexico/1274/2015 Mar nor B/Norway/2558/2015 Jul* aus B/Victoria/32/2015 Jul B/Martinique/2105/2015 Mar ORG B/Hawaii/21/2015 Jul ORG B/Hawaii/23/2015 Jul ORG aus B/Victoria/503/2015 Apr w$ B/Victoria/503/2015 Apr # C$ usafsam B/Nevada/6172/2015 Jun B/Hyogo/3210/2015 niid B/Hyogo/3210/2015 Feb w$ aus B/Victoria/532/2015 Jul nimr B/Hong Kong/3417/2014 Jun wF aus B/Canberra/13/2015 Jun aus B/Tasmania/4/2015 Jun 2015 B Yam HA Consensus 1197 B/Alaska/46/2015 Jul ORG B/Peru/25/2015 May B/Ecuador/12015/2015 Jun ORG B/Brazil/7643/2015 Jul bra B/Rondonia/58053/2015 Jul bra B/Mato Grosso/57643/2015 Jul B/Para/135112-IEC/2015 May bra B/Sao Paulo/60268/2015 Jul B/Pernambuco/135315-IEC/2015 Apr ORG usafsam B/Colorado/6018/2015 May B/New Zealand/597/2015 Jul bra B/Sao Paulo/10-19744/2015 May B/South Carolina/05/2015 Feb # B/Arkansas/10/2015 Mar # B/Concepcion/45743/2015 Jun B/Mexico/1460/2015 Apr B/New Zealand/1050/2015 Jul B/Santiago/34853/2015 May B/Brisbane/09/2014 Mar # F B/Utah/09/2014 May # F $ B/Phuket/3073/2013 Nov # F wF $ B/Phuket/3073/2013 Nov F wF $ B/New Hampshire/02/2015 Jan den B/Denmark/06/2015 Mar aus B/Malaysia/1388/2015 nimr B/Dakar/09/2015 May nimr B/Ghana/DILI-15-0311/2015 Apr nimr B/South Africa/R3192/2015 Jun nimr B/South Africa/R3762/2015 Jun aus B/Tasmania/1/2015 Jun nimr B/South Africa/R3183/2015 Jun B/Guangdong-Liwan/1133/2014 Feb # F B/Shanghai-Hongkou/1286/2014 Apr # B/Shanghai-Chongming/1364/2014 Apr # cnic B/Guangdong-Maonan/1338/2015 Apr #* niid B/Sakai/36/2011 Nov wF B/Wisconsin/01/2010 Feb # F wF aus B/Sydney/39/2014 Dec wF spn B/Catalonia/NSVH110112773/2015 Jan* spn B/Navarra/215/2015 Jan* B/Brisbane/36/2012 Jun # F wF B/Massachusetts/02/2012 Mar # F wF B/Massachusetts/02/2012 Mar F wF cnic B/Shanghai-Putuo/1147/2015 Feb # @* niid B/Yamaguchi/3/2015 Feb aus B/Brisbane/50/2015 Apr niid B/Taiwan/24/2015 Feb B/Laos/110/2015 Feb LR nimr B/Tsaralalana/1283/2015 Mar B/Laos/187/2015 Feb LR B/Laos/317/2015 May niid B/Laos/O306/2015 May B/Laos/100/2015 Feb LR B/Laos/94/2015 Feb LR B/Laos/99/2015 Feb LR $ 0.005 Evolutionary Relationships Among Influenza B Yamagata Lineage Hemagglutinin (HA) Genes 2015 Current Southern Hemisphere Vaccine Strain LR- Low Reactor to B/Phuket/3073/2013 (≥ 8 fold) # -Egg Isolate *HA1 only May 2015 June 2015 July 2015 August 2015 Y3 Y2 Y3V1A Y3V4 M252V R48K P108 T182A S150I N166Y S230D T37A Q122K T182K K212R K299E E313K T235R N203S N218 D K299E E313K N116K L173Q I125 L D233N ADD GLY N505D M252V M252I D459E R48K K397Q G184E K488R I246L K212R T199I HA Genetic Groups Since February 1st 2015

21. Phylogenetic Evolution of the HA Genes of Influenza B/Victoria-lineage Viruses 2011-2016

22. Evolutionary Relationships Among Influenza B Victoria Lineage Hemagglutinin (HA) Genes, 2011 aus B/South Australia/18/2011 Jun aus B/Victoria/1003/2011 Jul niid B/Niigata/785/2011 Jun B/Georgia/07/2010 Nov F niid B/Taiwan/371/2011 May # B/Texas/09/2011 Jun aus B/South Australia/10/2011 Jun B/Nevada/14/2011 May B/Santiago/14210/2011 Jul B/Minnesota/03/2011 May aus B/South Australia/6/2011 Jun aus B/Victoria/503/2011 May B/Bolivia/812/2011 Aug ORG B/Georgia/07/2010 Nov # F B/New Brunswick/1214/2011 May B/Massachusetts/03/2011 Apr B/Honduras/8060/2011 Jul B/Santiago/14666/2011 Jul B/Arizona/02/2011 Aug FATAL B/Arizona/03/2011 Aug FATAL B/Dominican Republic/5486/2011 Jul # B/Dominican Republic/5508/2011 Jul B/Indiana/09/2011 Aug B/California/02/2011 Jan # B/Santiago/6025/2011 Mar # $$ B/Santiago/18086/2011 Aug nimr B/Ghana/FS-11-244/2011 Feb $ nimr B/Ghana/516/2011 Apr $ B/Brisbane/60/2008 Aug # $$ B/Brisbane/60/2008 BX-31B # B/Brisbane/60/2008 BX-35 # B/Uganda/2719/2011 Jun B VIC 2011 HA Consensus 462 cnic B/Hunan-Yuhua/1316/2011 Jun niid B/Fukushima/43/2011 Jun cnic B/Shanghai-Luwan/1216/2011 May # $ niid B/Aichi/64/2011 Apr $ B/Tanzania/85/2011 Jun B/Nevada/16/2011 Aug B/Wisconsin/02/2011 Jan # nimr B/Hong Kong/767/2011 Jun B/Bangladesh/5549/2011 May $ nimr B/Ghana/735/2011 May $ swe B/Stockholm/18/2011 Jul aus B/Waikato/1/2011 Jun B/Bangladesh/8322/2011 Aug B/Bangladesh/9234/2011 Aug cnic B/Chongqing-Wanzhou/1294/2011 Jun aus B/Victoria/1001/2011 Jul B/Nevada/03/2011 Feb # $ B/Nevada/03/2011 Feb F swe B/Stockholm/3/2011 Jan $ B/India/2229/2011 Jul B/India/4969/2011 May B/Ontario/1256/2011 May cnic B/Beijing-Xicheng/1875/2011 May swe B/Stockholm/4/2011 Mar $ aus B/Tasmania/2/2011 Jun niid B/Aomori/37/2011 Jun B/Brazil/9442/2011 Jun niid B/Shizuoka/57/2011 Mar $ B/Shanghai-Jingan/1392/2011 Apr # LR C$$ cnic B/Shanghai-Songjiang/1204/2011 May # cnic B/Hunan-Hengnan/35/2011 Jun cnic B/Sichuan-Wenjiang/279/2011 May cnic B/Chongqing-Yuzhong/1384/2010 $ cnic B/Shanghai-Songjiang/176/2011 Feb # nimr B/Hong Kong/591/2011 Apr $ B/Hiroshima/09/2010 Sep # LR F cnic B/Jiangsu-Chongchuan/11150/2011 Jun B/Chanthaburi/74/2011 May B/Brazil/4331/2011 May B/Peru/2097/2011 Jun niid B/Shimane/41/2011 Jun cnic B/Anhui-Luyang/1142/2011 May niid B/Niigata/666/2011 May niid B/Yokohama/64/2011 May $ niid B/Tochigi/19/2011 Jun aus B/Brisbane/23/2011 Jun niid B/Fukushima/25/2011 May niid B/Kobe/98/2011 Jun B/Hong Kong/259/2010 Mar # aus B/Wellington/4/2011 Jun aus B/Victoria/506/2011 Jun B/St Petersburg/05/2011 Feb # nimr B/St. Petersburg/5/2011 Feb # $ aus B/Victoria/304/2006 # B/Fujian/Gulou1272/2008 Mar # F B/Hunan-Yuhu/311/2009 Mar F B/Bolivia/1526/2010 # LR $$ B/Peru/8510/2010 Oct LR B/Malaysia/2506/2004 # B/Uruguay/12/2008 Jun # LR B/Laos/833/2010 Sep LR niid B/Taiwan/318/2011 Apr # aus B/Cambodia/30/2011 Jan # $ aus B/Darwin/19/2011 Jan niid B/Chiba/17/2011 Mar B/Laos/89/2011 Feb LR F B/Ohio/1/2005 # F 0.002 09/19/2011 Current Southern Hemisphere Vaccine Strain LR- Low Reactor to B/Brisbane/60/2008 (≥ 8 fold) # Egg Isolate ____ 165N May 2011 June 2011 July 2011 August 2011 1 N75K N165K S172P L58P K167R T182K T37I N165K 6 5 3 2 4 V15I V146I V225I I228V G528E H122N R80G N129S N171D

23. B/Ohio/01/2005 Feb # LR F B/Cambodia/1412/2011 Oct # LR F B/Malaysia/2506/2004 Dec # B/Hunan-Yuhu/311/2009 Mar F cnic B/Liaoning-Zhenxing/1281/2012 Nov * B/Fujian Gulou/1272/2008 Mar # F B/Uruguay/12/2008 Jun # LR B/Bolivia/1526/2010 # LR F aus B/Victoria/304/2006 # * B/Laos/011/2013 Jan cnic B/Gansu-Qilihe/188/2013 Mar * cnic B/Jiangxi-Xunyang/510/2013 Jan * B/Montana/05/2012 Oct LR F B/Montana/05/2012 Oct # LR F B/Hiroshima/09/2010 Sep # LR F B/Michigan/09/2011 Sep # F nimr B/Ghana/Fs-718/2013 Jul cnic B/Guangdong-Yuncheng/1198/2013 Mar * B/Brisbane/60/2008 Aug F B/Brisbane/60/2008 Aug # F C$ B/Phuket/151/2013 Mar B/Nevada/03/2011 Feb # F B/Nevada/03/2011 Feb F B/Nevada/03/2011 BX-47A # F B/Nevada/03/2011 BX-47 # F nimr B/Tehran/1236/2012 Dec # cnic B/Guangdong-Duanzhou/1160/2013 May * cnic B/Jiangsu-Tianning/1676/2012 Dec # * cnic B/Jiangsu-Danyang/1718/2012 Nov # * cnic B/Jiangsu-Chongchuan/11052/2013 Jun # w$ * B/Vietnam/3072/2013 Apr B/Vietnam/3071/2013 May niid B/Fukui/26/2013 May * niid B/Chiba-C/46/2013 Jun * niid B/Taiwan/12/2013 Apr * B/Hong Kong/74/2013 Apr cnic B/Shanghai-Huangpu/1347/2013 Apr w$ * cnic B/Beijing-Haidian/1386/2013 May # * B/Indonesia/Nihrd-Buas704/2013 Mar cnic B/Fujian-Licheng/1114/2013 Apr * cnic B/Jiangsu-Qingpu/1256/2013 Mar # w$ * B/Brazil/368/2013 Apr B/Santiago/49517/2013 Jul B/Indiana/04/2013 Apr cnic B/Henan-Zhongyuan/1147/2013 Mar * aus B/Victoria/802/2013 May niid B/Sapporo/24/2013 May * aus B/South Auckland/9/2013 May aus B/Canberra/2/2013 May aus B/South Australia/81/2012 Nov # w$ B/New Jersey/01/2012 Apr F B/New Jersey/01/2012 Apr # F B/Nevada/10/2013 May nimr B/Estonia/77361/2013 Apr B/Beijing-Chaoyang/1943/2012 Apr LR F B/Rhode Island/01/2013 Apr nimr B/Portalegre PT/233/2013 Mar w$ B/Utah/08/2012 Oct F B/Utah/08/2012 Oct # F B/French Guiana/1021/2013 May B/Brazil/390/2013 May B/Brazil/7795/2013 Jul B/California/05/2013 Apr B/New Jersey/04/2013 Apr B/Georgia/07/2013 Apr nimr B/Jordan/30330/2013 May B/Brazil/260/2013 May B/Brazil/389/2013 May B/Valparaiso/1032/2013 Jan # B/Santiago/36883/2013 Jun B/Uruguay/177/2013 Jun B/Colorado/05/2013 Apr B/Nevada/09/2013 May nimr B/Norway/2090/2013 Apr usafsam B/Florida/3957/2013 May B/Texas/02/2013 Jan F w$ B/Alaska/06/2013 May B/Pennsylvania/03/2013 Apr B/Peru/7084/2013 Jun B/Texas/02/2013 Jan # F $ B/Virginia/05/2013 Apr FATAL B/New Jersey/07/2013 May B/Vermont/02/2013 Apr B/Natal/124182/2013 Jun B Vic HA Consensus since Feb 2013 n=231 niid B/Tokyo/30018/2013 May * niid B/Aichi/55/2013 May * niid B/Ehime/6/2013 May * usafsam B/Guam/3822/2013 Apr niid B/Nagano/2313/2013 May * niid B/Tokyo/13134/2013 Jun * niid B/Tochigi/5/2013 May * niid B/Kumamoto/24/2013 May * B/North Carolina/10/2013 Apr FATAL B/Japan/3942/2013 Apr aus B/South Australia/36/2012 Sep # w$ B/Massachusetts/03/2013 Mar LR B/Massachusetts/04/2013 Apr B/Brazil/6004/2013 Jun 1A Evolutionary Relationships Among Influenza B Victoria Lineage Hemagglutinin (HA) Genes, 2013 LR- Low Reactor to B/Brisbane/60/2008 (≥ 8 fold) # Egg Isolate * - HA1 region only ____ 165N May 2013 June 2013 July 2013 August 2013 1B N129D A169E K209 N G184E T12 1A V90I A154 E S277R D526E N75K N165K S172P V146I L58P N171D N129K I7V 0.002 V17 7I N43 S V15I V87I H122L N129S K167R 4

24. Evolutionary Relationships Among Influenza B Victoria Hemagglutinin (HA) Genes 2015 Current Southern Hemisphere Quadrivalent Vaccine Strain LR- Low Reactor to B/Brisbane/60/2008 (≥ 8 fold) # -Egg Isolate * HA1 only May 2015 June 2015 July 2015 August 2015 V1B V1A niid B/Nagasaki/68/2015 May niid B/Yokohama/27/2015 Jun B/Florida/58/2015 Jun aus B/Wellington/3/2015 May B/Idaho/25/2015 Jun 2015 B Vic HA Consensus 354 niid B/Tokyo/50143/2015 Apr B/Indiana/25/2015 Apr aus B/Victoria/525/2015 Jul aus B/Victoria/557/2015 Jun B/French Guiana/8123/2015 Jul B/Nevada/27/2015 Jun B/Nevada/23/2015 Jun B/Wyoming/24/2015 Apr $ B/Mexico/1434/2015 Apr niid B/Mie/3/2015 Feb w$ aus B/Sydney/11/2015 Jun B/Indiana/25/2015 Apr # B/Santiago/34852/2015 May # B/Idaho/21/2015 May # B/Idaho/21/2015 May B/Alaska/40/2015 Jun B/New Zealand/427/2015 Jun aus B/Tasmania/2/2015 Jun aus B/Tasmania/5/2015 Jun nimr B/Hong Kong/1183/2015 May B/Washington/63/2015 Jul cnic B/Beijing-Xicheng/11261/2015 May* B/New Zealand/537/2015 Jul aus B/South Australia/49/2015 Jun aus B/Brisbane/136/2015 Jun aus B/Brisbane/46/2015 Apr w$ aus B/South Australia/1015/2015 Jul B/Utah/41/2015 Jul ORG B/Texas/94/2015 Jun nimr B/South Africa/R1588/2015 Apr B/Hawaii/14/2015 Jun B/Hawaii/14/2015 Jun # B/Hawaii/22/2015 Jul ORG niid B/Fukushima/34/2015 Jun B/Missouri/01/2015 Feb B/Missouri/01/2015 Feb # B/Florida/54/2015 Jun B/Indiana/27/2015 May B/Texas/11/2015 Feb LR cnic B/Liaoning-Zhenxin/1319/2015 Jun* B/Mexico/1259/2015 Mar B/Wisconsin/45/2015 Apr B/Paraguay/5133/2015 Jun B/Texas/02/2013 BX-53B # F B/Texas/02/2013 BX-53C # F B/Texas/02/2013 BX-53A # F B/Texas/02/2013 Jan # F $ B/Florida/33/2014 Sep LR B/Florida/33/2014 Sep NC1 B/Florida/33/2014 Sep NC3 B/Texas/02/2013 Jan F w$ B/Florida/55/2015 Jun B/Maryland/14/2015 Mar B/Maryland/14/2015 Mar # B/Paraguay/1131/2015 May aus B/South Australia/11/2012 May wF nimr B/South Australia/81/2012 Nov # wF cnic B/Beijing-Xicheng/11151/2015 May* cnic B/Jiangxi-Yuanzhou/1721/2015 May* cnic B/Fujian-Cangshan/1374/2015 May #* cnic B/Fujian-Cangshan/1456/2015 Jun #* cnic B/Fujian-Gulou/1298/2015 Feb #* nor B/Norway/2288/2015 May* B/Brazil/2786/2015 Mar B/Hong Kong/1198/2015 May niid B/Taiwan/113/2015 Apr cnic B/Guangdong-Luohu/1422/2015 May #* cnic B/Hunan-Yuhua/1917/2015 Jun* aus B/Brisbane/18/2013 Jun wF aus B/South Australia/48/2015 May nimr B/Johannesburg/3964/2012 Aug # wF B/Utah/08/2012 Oct # F B/Utah/08/2012 Oct F nimr B/Formosa/V2367/2012 Aug wF niid B/Taiwan/197/2015 May usafsam B/Thailand/PMKA3985/2015 Feb aus B/Bankgok/22/2015 Apr niid B/Osaka/11/2015 Mar niid B/Aichi/62/2013 Oct wF cnic B/Yunnan-Chuxiong/1807/2015 May* cnic B/Yunnan-Chuxiong/1913/2015 Jun* nimr B/Finland/530/2015 Apr aus B/New Caledonia/6/2014 Nov # B/Hong Kong/1372/2015 Jun nimr B/Hong Kong/1337/2015 Jun B/Indiana/22/2015 Apr aus B/New Caledonia/6/2014 Nov aus B/Canberra/30/2015 Jul aus B/Darwin/17/2015 Jul aus B/Newcastle/1005/2015 Jun B/Nevada/03/2011 Feb # F B/Brisbane/60/2008 Aug # F $ B/Brisbane/60/2008 Aug F $ cnic B/Guangxi-Changzhou/31/2015 Jan B/Hiroshima/09/2010 Sep # LR F B/Montana/05/2012 Oct # LR F cnic B/Jiangxi-Yushui/11102/2014 Dec B/Fujian Gulou/1272/2008 Mar # F B/Hunan-Yuhu/311/2009 Mar F B/Ohio/01/2005 Feb # LR F 0.002 N75K N165K S172P N148S L58P K56N V124A D526E V146I K209N I97M A154E T258A N129S N171D I553V G230D V87I V90I A154E V177I N393D V15I G184E A169E V146I N129D V248I I318V I117V I424L A506V G256R V252M T35A G184E

25. Geographic Distribution of Influenza B HA Genetic Groups Based on HA Sequences Availability

26. Conclusions Seasonal influenza viruses evolve rapidly, responsible for annual influenza epidemics. Closely monitoring of genetic and antigenic evolution of influenza viruses are important in selection of appropriate vaccine viruses. Improving global influenza surveillance is essential for achieving a match between circulating viruses and vaccine strains.

27. Questions? Thank you !

28. Bedford, et al., Global circulation patterns of seasonal influenza viruses vary with antigenic drift Nature14460 523:217-225