( 12 ) United States Patent

US010137189B2 (12 ) United States Patent (10 ) Patent No. : US 10 , 137 , 189 B2 Garcia - Sastre et al. (45 ) Date of Patent : Nov . 27 , 2018

(54 ) INFLUENZA VIRUS VACCINES AND USES 5 ,589 , 174 A 12 / 1996 Okuno et al . THEREOF 5 ,625 , 126 A 4 / 1997 Lonberg et al . 5 ,631 ,350 A 5 / 1997 Okuno et al . 5 ,633 , 425 A 5 / 1997 Lonberg et al . ( 71 ) Applicant: ICAHN SCHOOL OF MEDICINE 5 ,661 , 016 A 8 / 1997 Lonberg et al. AT MOUNT SINAI, New York , NY 5 , 820 , 871 A 10 / 1998 Palese et al. (US ) 5 , 854 ,037 A 12 / 1998 Palese et al . 5 , 885 , 793 A 3 / 1999 Griffiths et al . 5 ,916 , 771 A 6 / 1999 Hori et al. ( 72 ) Inventors : Adolfo Garcia -Sastre , New York , NY 6 , 001, 634 A 12 / 1999 Palese et al . ( US ) ; Peter Palese, New York , NY 6 , 165 ,476 A 12 / 2000 Strom et al. (US ) ; Florian Krammer, New York , 6 ,337 ,070 B1 1/ 2002 Okuno et al . NY (US ) 6 ,720 , 409 B2 4 /2004 Okuno et al . 6 , 867, 293 B2 3 / 2005 Andrews et al . 6 , 887 ,699 B1 5 /2005 Palese et al . (73 ) Assignee : Icahn School of Medicine at Mount 6 , 942 , 861 B2 9 / 2005 McKee et al. Sinai , New York , NY (US ) 8 , 367, 077 B2 2 / 2013 Zurbriggen et al. 8 ,603 , 467 B2 12 /2013 Chen et al . ( * ) Notice : Subject to any disclaimer, the term of this 8 ,673 , 314 B2 3/ 2014 Garcia Sastre et al. patent is extended or adjusted under 35 8 , 828 ,406 B2 9 /2014 Garcia -Sastre et al. U .S .C . 154 (b ) by 102 days . 9 , 051 , 359 B2 6 / 2015 Garcia - Sastre et al. 9 , 175 ,069 B2 11 /2015 Garcia - Sastre et al. 9 ,371 , 366 B2 6 /2016 Garcia - Sastre et al. (21 ) Appl. No. : 15 / 158 ,785 9 . 452 ,211 B2 9 /2016 Meijberg et al. 9 ,701 , 723 B2 7 /2017 Garcia - Sastre et al. ( 22 ) Filed : May 19 , 2016 9 ,707 , 288 B2 7 / 2017 Schrader 9 , 708 , 373 B2 7 /2017 Garcia -Sastre et al. 2002 / 0164770 A1 11 / 2002 Hoffman (65 ) Prior Publication Data 2003/ 0134338 A1 7 / 2003 Makarocskiy US 2016 /0361408 A1 Dec. 15 , 2016 2004 / 0002061 Al 1 /2004 Kawaoka 2005 /0009008 A1 1 /2005 Robinson et al . Related U . S . Application Data 2005 / 0042229 Al 2 / 2005 Yang et al . 2005 /0048074 A1 3 / 2005 Cardineau et al. (62 ) Division of application No. 14 / 109, 358 , filed on Dec . 2005 /0064391 A1 3 / 2005 Segal et al. 2005 /0106178 A1 5 / 2005 O 'hagan et al. 17 , 2013 , now Pat. No . 9 ,371 , 366 . 2005 / 0201946 Al 9 / 2005 Friede et al. (60 ) Provisional application No . 61/ 738 ,672 , filed on Dec . 2006 /0008473 Al 1 /2006 Yana et al. 18 , 2012 , provisional application No . 61 / 840 ,899 , 2006 /0280754 Al 12 /2006 Garry et al . filed on Jun . 28 , 2013 . (Continued ) (51 ) Int. Ci. FOREIGN PATENT DOCUMENTS A61K 39 / 145 ( 2006 .01 ) CA 2121559 10 / 1994 C12N 7700 ( 2006 . 01) CA 2718923 9 /2009 CO7K 14 /005 ( 2006 .01 ) A61K 39 / 12 ( 2006 .01 ) (Continued ) A61K 39 /00 ( 2006 .01 ) (52 ) U .S . CI. OTHER PUBLICATIONS CPC ...... A61K 39 / 145 (2013 .01 ) ; A61K 39 / 12 Wang et al. (PNAS , 2010 , vol. 107 , p . 18979 - 18984 ). * ( 2013 .01 ) ; CO7K 14 / 005 ( 2013 .01 ) ; C12N 7700 Babai et al. , A novel liposomal influenza vaccine ( INFLUSOME ( 2013 .01 ) ; A61K 2039 /521 ( 2013 . 01 ); A61K VAC ) containing hemagglutinin - neuraminidase and IL - 2 or GM 2039 / 5252 ( 2013 .01 ); A61K 2039 / 54 CSF induces protective anti -neuraminidase antibodies cross ( 2013 .01 ) ; A61K 2039 /543 ( 2013 .01 ) ; A61K reacting with a wide spectrum of influenza A viral strains . Vaccine . 2039 / 545 ( 2013 .01 ) ; A61K 2039 /55 ( 2013 .01 ) ; 200 ; 20 (3 -4 ); 505 - 15 . A61K 2039 /70 ( 2013 .01 ); C12N 2760 / 16123 ( 2013 .01 ) ; C12N 2760 / 16134 ( 2013 .01 ) ; C12N (Continued ) 2760 / 16223 (2013 .01 ) ; C12N 2760 / 16234 (2013 .01 ) Primary Examiner - Agnieszka Boesen (58 ) Field of Classification Search None (74 ) Attorney, Agent, or Firm — Jones Day See application file for complete search history. ABSTRACT (56 ) References Cited (57 ) Provided herein are chimeric influenza hemagglutinin ( HA ) U .S . PATENT DOCUMENTS polypeptides, compositions comprising the same, vaccines 5 , 182 , 192 A 1/ 1993 Steplewski et al. comprising the same, and methods of their use . 5 , 413 , 923 A 5 / 1995 Kucherlapati et al . 5 , 545 , 806 A 8/ 1996 Lonberg et al. 5 , 569 , 825 A 10 / 1996 Lonberg et al. 5 , 571 ,709 A 11/ 1996 Devauchelle et al. 33 Claims, 56 Drawing Sheets 5 , 573, 916 A 11/ 1996 Cheronis et al. Specification includes a Sequence Listing . US 10 ,137 , 189 B2 Page 2

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( Mature residue 1 ) -- MKANLLVLLCALA - - - A4D ------ADTICIGYHANNSTDTVDTVLEKNVTVTHSVNL -- - - MAIIVLILLET - - AVR ------GDQICIGYHENNSTEKVDTILERNVTVTHAONI WR MKTIIALSYIFCLALGODL ZGNENSTATLCLGHHAVENGTLVKTITDDOIEVTNATEL MLSIVILFLLIAENS - - - 0 ONYTGNPVICMGHHAVANGOMVKTLADDOVEVVIAOEL - MERIVILLAIVS - - IVK ------SDOICIGYHANKSTKOVDTIMEKIVTVTHAODI

??? 1 MIAIIVVAILAT - - AGR SDKICIGYEANNSITOIDTILEKNVIVIESVEL - - MNTILVFALVAVIPIN Tiiiií!- - ADKICLGHEAVSNGTKVNTLTERGVEVNATET co - - MEKFISIAT - LASINA - -- - YDRICIGVOSNNS 'IDTVNTLIXONVPVTOT 'MEL H9 -- METKAIIAALLMVTAAN ADKICIGYOSTNSTETVDTLTESNVPVTHTKEL H10 -- MYKVVVIIALLGAVKG - -- - LDRICLGHHAVANGTIVKTITNEOZEVTNATET H11 - MEKTILFAAIFL - - CVK 1 - ADEICIGYLSNNSTDKVDDIIENNVTVTSSVEL H32 - - - MEKFIILSTVLAASFA ------YDKICIGYOINNSTETINOISEONVPVTOVEEL H33 -- MALNVIA LTLIS - VCVH - - 1 - - ADRICVGYLSTNSSERVDOLLENGVPVTSSIDL H14 - - - MIALILVALALSHTAYSOIING "HGNPIICLGHHAVENGISVKPLIDNEVEVVSAKEL H15 - - MNTOIIVILVLGLSMVK ------SDKICLGHHAVANGTKVNFLTERGVEVVNATET H16 - - MMIKVLYFLIIVLGRYSK ------ADKICIGYLSNNSSDTVDTLTENGVPVTSSVDL H17 MELIVLLILLNPYT - - FVL ------GDRICIGYQANQNNQTVNTLLEQNVPVTGAQEI A Mature residue 1 ) ( Residue Ap ) (Residue Cp ) LEDSENGKLCRLKGIAPLOLGKCNIAGWLLGNPECDPLLPVRSNSVIVET PNSENGICYP LEKTENGKLCKLNGIPPLELGDCSIAGWLLGNPECDRLLTVPEWSYIMEKENPRNGLCYP VOSSSTGKICNN - PHRILDGIDCTLIDAI. LGDPHCDVFONET - WDIFVERSKAFS - NCYP HUAWN- ESCAPELCPE - PILL DUTCL : SALGEPGCGHLIGAE - DIFIEFRPILY - TCY ? LERTHNGKLCSLNGVKPIILRDCSVAGWILGNPMCDEFLNLPEWLVIVEKDNPINSLCYP LENOKEERFCKILKKAPLDLKGCTIEGWILGNPOCDLLLGDOSWSYIVERPTAONGICYP VERINIPKICSK - GKRTTDLGQCGILGTITGPPOCROFLEFS - ADLIIERREGND - VOYP VETEKEPAYONODLGAFLELRDCKIEAVIYGNPKODIHLKDOGWSYIVERESAPEGMCVP HG LHTEHNGMLCARDLGEPLILDICTIEGLIVGNPSCDILIGGKEWSYIVERSSAVNGMCYP H10 VESTNLNKLCMK - GRSYKDLGNCEFVGMLIGTPVCDPHLTGT - WDFLIERENAIA - ECVP H11 VETEHTGSFCSINGKOPISLGDCSFAGWILGNPMCDELIGKTSWSYIVEKPNPTNGICVP F12 VERGIDPILCGTELGSELVLDDCSLEGLILGNPKCDLYLNGREWSYIVEREKEMEGVCVP F13 IBINETGTVCSLNGVSPVELGDCSFEGWIVGNPACOSNFGIRENSYLIEDPAAPHGLCYP E14 VETNETDELCES - PLKLVDGODCHLINGALGSPGCDRLODIT - WDVEIERPTAVD - TCYP E15 VEIIGIDKVCTK - GKKAVDLGSCGILGTIIGPPOCDLHLEFK - ADISIERRNSSD - ICYP E16 VETNETGTVCSINGISPIELGDCSFEGWIVGNPSCATNINIREWSVLIEDPNAPNKFCYP H17 LETNHNGKLCSINGVPPIDLQSCTLAGWILGNPNCDSILEAEEWSVIKINESAPDDLCFP (Residue Ap ) Residue Cp ) A

GDFIDYEELREOLSSVSSFERFEIFPKESSWPNENINGVTAACSHE - GKSSFYRNLLWLT GSFNDYBELKHLLSSVIHFEKVKILPKORWIOHITIGG - SRACAVS - GNPSFERNMVWI: 1 YDVPDYASLRSIVASSGTIE - - FITEGETW - TGVTONGGSNACKRG - EGNGFFSRINWII FDVPEYOSLRSILANNGKFE - - FIAEEFOW - NTVKONGKSGACKRA - NVDDFFNRLNWIV GDFNDYEELKYLLSSTNHFEKIRIIPRSSWSNEDASSGVSSACPYI - GRSSFLRNVVWLI GVLNEVEELKALIGSGERVERFEMFPKSTWTGVDTSSGVTRACPYN - SGSSFYRNLLWII GKEVNEEALKOILRGSGGID - - KETMGFTY - SGIRINGOTSACRRS - G - SSFYAEMEWLL ES GSVENLERIRFVFSS24SYKRIRLFDYSRWNVIR. S -- -GISKACNA . STGGOSFYRSINWLT EO GNVENLERIRSIFSSAKSYKRIOIFPDKTWNVTYS - -GISRACSN ------SEYRSMRWIT H10 GATINEEALROKIMESGGIS - -- KMSTGFTYGSSITSAGTTKACMRN - GGDSFYAELKWLV H11 GTLESEEELRLKFSGVLEFNKFEVFTSNGWGAVNSGVGVTAACKFG - GSNSFFRNMVWLI H12 GSIENOESLRSLFSSIKKVERVKMFDFTKWNVTYT - - GISKACHNOSNOGSFYRSMRWIT K13 SRIELIPPTSWGEVLD - - GITSACRONTGONSFYRNLVWE ) K24 FDVPDYOSURSILASSGSLE - - FIAEOFTW - NGVKVOGSSSACLRG - GRNSFFSRLNWLT H15 GRFINERALROIIRESGGI ( ) -- - KESMGERY - SGIRIOGATSACKRA - V - SSFVSEMKWIS H16 GELDNNGELRHLFSGVNSFSRTELINPSKWGNVLD - - GVTASCLDR - GASSFYRNIVWIV H17 GNFENLODLLLEMSGVONFTKVKLFNPOSMTG - VTTNNVDOTCPFE -GKPSFYRNINWID

E - K - EGSYPKI KNSYVNKKGKEVLVLWGI EHPPNSKEÇONLYONENAYVSVVISNYNRRE K - K - GSNYPIAKGSYNNISGEOMLIIAGVEHENDETEORTLYONVGIYVSIGISTLNKRS 1.LIILIO KS - - GS ' I ' Y PVLNVTMPNNDNEDKLYIWGVEHESTNOBOTSLYVORSGRVIVSIRRSOOSI KSD - GNAYPLONLTKINNGDYARLYIWGVEHESTSTEOFNLYKNNZGRVTVSIKTSOTSV K - K - NNTYPTIKRSYNNTNOEDLLILWGIFHPNDAAEOTKLYONPTTYVSVGTSTLNORS KIK - SAAYSVIKGAYNNTGNOPILYFWGVHHPPDTNEONTLYGSGDRYVRMGTESMNFAK H7OGA SNTONASEDOMKSYKINTRKESALIVWGIRUSGSTEOTKIVGSGNKLITVG HE ENEGAYVNNEDGDIIELWGIHAPPOTKECTILYKNANTISSVTINTI NRSE HG PFONAEYTÄNNERENILEMWGIRUPPIDTECTDLVKNADTITSVITEDI NRTF H10 SKTKGONF POTINTYRNTDTAEELIIWGIHAPSSTOEKNDLYGTQSLSISVESSTVONNF F11 H - O - SGTYPVIKRTFNNTKGRDVLIVNGIEHPATLSEHODLYKKESSYVAVGSETYNRRF H12 LK - - SGOFPVOIDEYKNTRDSDIVFTWAIFHPPTSDEOVKLYKNEDTLSSVITVSINRSF E13 K - K - NTRYPVISKTYNNTIGRDVLVLWGI EHPVSVDETKTLYVINSDEYILVSIKSWSEKY E14 KAT - NGNYGPINVTKENTGSYVRLYL GVEHESSDNBORDLYKVATGRVIVSIRSDOISI E15 SSMNNOVFPOLNOTYRNIRKEPALIVNGVENSSSI. DEONKLYGIGNKLITVGSSKYOOSF H16 K - K - DEKY ? VIKGDYNNTIGRDVLVLWGIFHEDTETTATNLYVNKNPYTLVSTKEWSKRY H17 G - - - - NSGLPENIEIKNPTSNPLLLLWGIANTKDAAQCRNLYGNDYSYTIFNFGEKSEEF FIG . 1A atent Nov . 27 , 2018 Sheet 2 of 56 US 10 , 137 , 189 B2

DPCIERPXR0AORMNYYKILIKPGITTIREAMRI: IAPMYAPALOXOPO . . .. . IRVIAINRINGOSORMORSKTILDIKOTINERSTOKLIAPETGFRISSROS ------YPODIGORDVRGOCORYSPYKTIVE . GOIVXUDIOMEPAGBYXNX. - . - • - - - * 208IXARRAVIORORIDYYNSILKPGEOINVESMONL IAPWYAPAFVOTSNK - - - VPSVIRPOINOOSOR DOWLIIDENCIVIPORNOAFIAPNHASELE ------DENIZPRPIVROUCKMD YWGIUKR :36TLKIRINGNI : IAPRFGXLINGESY - * KVIGORPIVNGONORIUYYKOVEEDOMKIRSMGXLRDWYGHVLIGESH - .. .. . H10 VPVVGARPOVNOSERIDFAKTI YOPGONITBODNOCLIRPSKVORI: T - - - - - TIH TYBINIRPRONOWGRMTRYKKIVIPORAITRESNGARLAPA YABBIVSVGN C1X KPNIGPRDIVE GOXOGRMOYVAEVONPOOIVKIVINGNINPROHLI10 - ...... ETH KIBIGRPGYNGOR SWIXSLIBROSMITIENGGELARRXOYII22 VOX ------3 VINIGSRPSVRNOSORIA12710W , 911ENSIONI HAPROHYKISXST - - .. . * PPSAKPKNOOGARIDHBWMLOOP VITEZGAFIREDRATKORSNDRIEINOK * €ISIRIG - DCOROWANYWELMIPGERIMENIGL: LAPRYOITIENZGT- ...... HI , PPEICORDEVKRHODRIDEXKGSLEN STIRIES TOKI: IAPBYGFYYKRKBOX ------

SCIITS - NASIHECHTKEQIILGAINSSLPYONIHPVTICECEPTYROREDRIUTOLAN S IMKT - EGELUNCUTKOOTPLGOINITIPPUNVAPITIORCPKYXSSALVIATOURNV SIMSSDAPID0 - CISKITONGSIENOKPPONVNKITIGKOPKY KOUTKANOMROV STILIAIRIOS - OVSKRIONSLITIKPPONIEKIROXORY KOG : DAGMANI SAIMKS - GLAXONDIYXIVGEINSSMPFHMIHEUTIGEOPKYVKSORDVLAICURNY OXYPES - YLEISNODRTOOTVAUVLKINIPONSELWIGSOPKYVKSASLLATOLEN SMOOSEVOVAM86N5339G730381. PRONIOSKIVOKORNYVKX811STOWN GRI IOWEDDIGNOIKOTYAGRINGSKPPONASPHEMORCEKIVEKÄS0887GERNE GRILKT- OINNONVOCOTEKJOLNITLPPANIAKYAFUMCPKYYQVISLX : PYCUNIV DWIOSKAL I DISCESKOPVROOSINDPOWI. SPRIVOXONYMORSLIAOMROV 11 GXLR3 - EINR3CSTKO5IGGINNKS HUVUXENTIGXPXYWNY BLAGA ANV H12 GRILAN NEM VIEDOLNEGOMBOKPRONISKIVIGNOPKYIPSCILICIAN 413 GRIPOS - RIKMSKONTKQTAYOQININKTRONI DINDIGOOPKZIKSGOLXLANGLANV STVINSOXAIGA - ISPODKOSI OAO PRONSEILONOPKVKX08144 TORPN . SIGID& OIDES SUR FYSGGT3: NBOLHKONIDSKAVGKRRYVKOSSIBIALOMONV inim SRIRE . OVEMBROIKOT9LOGINTIKTFONIERXALODCEUTYGODNIATCON H . GOLMX3 KURISKSIKOGALNS . WONHOOTIONC PRYNAISL4 . ANGLEN

- - - - SIOSRALPOAICOFIXGWIOMIDOWYGYMHONBOSQIRXOXSONDINGIIN 2 . . . OYEURIGAIGOTZOGKRMIDGWYSYHDENDXGSGAAXSOOK INGIIN pc . . KERGELTRIAGE GWOGMIDGIGERHOORONGORONATAIDOT - - - - AKASROLDATZOFIEMOWOCL IDOWYORPHOUDEGTOMADLASTOARIDIK - - - DIRTROLIGDIAGR9XGNIOMIDGYGYMANSORYADK93T XAVDOI IN 27 - - * - SVEPROLEGIAGRICUWSCMIDGWGBHSNSEGIGMAXOXSTBAIDKIIN P . - - . AVSSROOFOAIZOFIXOWPOIVROWER OVIKOMONOSTOKIOMIS P . - - - R AGAISJF TENGWEGMVD3WX3ERBU80GIGOGATYNSTQANLI OITO ITM - * - * ISSROUBODIAQFISGOWPGLING YOPCHRDSSTIAADKESTQADITS ZIM W . VOORGLEGATAUFISMOPOLVAGYOM HOVASCULARDAOSTOLAIDMMON

: L . . . MISNROLKODIAQR19 QKPOL INGWYGPHONEOGIGAOKESTOVAIDOTT - - -- OXOGKGLYGSIXTENGWG0 DXOVYGEXIONADOGTA01: 30 AION: ,;? - - - - SIGEROUPOXICOPIEGOWDOLINOWYCTOBONBONORMATXINRITO LY p . .. OMEOK NG GAIGGFIXOGWOMIDWYGYHENOX6SOYADIATOKOVSIIN

KYYTY IKKENZOFIAVOKBANTERANANLÖKKVI OPLOIWOYNBLOVILENSKTGOE KYNSVIKWBOXESVOKRESNANROONI MKEO ? GOVIY VIRRI, ISKINDKHOIRKEPROVECRIODLINYVSOTKIDLWA UNAELLVOLENOHTIDU KUNST IDKMUTRPEAVOKSENNLERRVSNLNKKMODOPLDVHTUMVELLVLENEATLIE KOVNSTIOXIBIOBAVDKERSNI ZKRITIKAMSOGEDUNDYNAEOLVLLEMORTLIT. KNOLIEKIOPEDIDNEYTEVEKOTONL IMKOTKOCITRUKSYNAEOTVAMENDATIOL KVINVOKMNRAPEVINKAFAVEURTIMIKOKIDUCIBULKA NBELLVILENOX TLDE HS KYNTIOXANKOYOTIDAENEASAALM1XNXIR10DIWYDRAULVLONORTLDE H ) :) KIXALIXKINK831888 & SET930NYINYIKOS IDIWIYNDBILVANEN : 33M 711 XVIIVAMNINYEOVOX878878SXINOLSKROOSVIRAUN11: 20 SNEKOLIU DININIOXMINIYYNKSPREVESRONMINSKIDOOITDISASIJAELIV1ZENOK0 1 : 8 KINNI IONMINDAIRGRINOVEK : IKMLADRIDOAVIDINS UNAKOIVUXENDKWIN KAD TEKINEKYBOIENZEROVEO ODLZKYVEDTY DLWYNBELL VALENOHTIDY H15 KARLIEKINKORSLIONEFTEVE0QONVINTROSLTS INSYNDELLVANENOHTIDI His KIVIIKKMNGN :SINGREDOVEKAILOR VIVIDIWSYNOXLOVILONORTLOL K NIDOAMNSORESNIKOSHUIRI : DRZWISDKVWS04 :DIWSYNIKI : I: VOINETO

posse atent Nov . 27 , 2018 Sheet 3 of 56 US 10 , 137 , 189 B2

HDSNVKNI, YEKVKSOLKNNAKEIGNGCEEFYEKCDNECMESVENGTYDYPKYSEESKINE HDSNVENLYDRVRMOLRDNAKELGNGCFEFYHKCDDECMNSVENGTYDYPKYEEESKLNR ??( TDSEMNKLFEKTRROLRENALDMGNGCFKIYHKCDNACIESIRNGTYDHDVYRDEALNNR H4 TDSEMNKLFERVRROLRENABDKGNGCFEIFHKCDNNCIESIRNGTYDHDIYRDEAINNR 55 HDSNVNNIVDKVRLOLKDNARELGNGCFEFYHKCONECMESVRNGIYDYPOVSEEARINR E6 HDANVKNIVERVKSOLRDNAMILGNGCFEFWAKCDDECMESVKNGIYDYPKYODESKINR E ? ADSEMNRIVERVRKOLRENAEEDGIGCFEIFHKCDDDCMASIRINTYDHSKYREEAMONR H8 HDSNVKNLFDEVKRRLSANAIDAGNGCFDILHKODNECMETIKNGTYDHKEYEEZAKLER H9 HDAVVNNL VNKVKRALGSNAVEDGNGCFELYHKODDOCMETIRNGTYDROKVOEESRIER H10 ADSEMLNLVERVRKOLRONAEEDGKGCFEIYHTCDDSCMESIRANDYDHSOYREEALLNR H1 HDSNVENLEEKVRRMLKDNAKDEGNGCEOE' YEKCDNKCIERVENGOYDEKEFEEESKINK K32 HDANVRNLEDRVRRVLRENAIDTGDGCFEI LEKCDNNCMOTIENGØYNEKEYEEESKIER H13 HDANVKNLFEOVRRELKONBIDEGNGCEELLEKCNDSOMETIK H14 TDSEMNKIFERVRROLRENAEDOGNGCFEIFHOCDNNCIESIENGTYDHNIYRDEAINNR H15 ADSEMNKLYERVRROLRENAEEDGTGCFEIFHRCDDOCMESIRNNTYNETEYROBALONR H16 HDANVRNLHDOVKRALKSNAIDEGDGCFNLLHKCNDSCMETIRNGTYNHEDYREESOLKR H17 HDANVKNIFEKVKAOLKDNAIDEGNGCFLLLHKCNNSCMDDIKNGTYKYMDYREISFIEK

ET EKVIGVKLESMG - IVOILAIVSTVASSIVLIVSLGAISFWMCSNGSLOCRICI H2 NEI KGVKLSNMG - VYOILAIYATVAGSLSLAIMIAGISLWMCSNGSLOCRICI H3 FQIKGVELKSGY - -- KDWILWISFAISCFLLCVVLLGFIMWACORGNIRCNICI FOIOGVKLPOGY - - KDIILWISFSISCFLLVALLLAFILWACONGNIRCOICI H5 FEISGVKLESMG - VYQILSIYSTVASSLALAIMIAGLSEKMCSNGSLOCRICI H6 OEIESVKIESI. G - VYOILAIYSIVSSSIVLVGLIIAVGIWMCSNGSMOCRICI H7 IOIDEVKISSGY - - KDVILWFSFGASCELLLAIAMGLVFICVKNGNMRCTICI H8 SKINGVKLEENT - TYKILSIYSTVAASLCLAILIAGGLILGMONGSCRCMFCI E9 OKIEGVKLESEG - TYKILTIYSTVASSLVLAMGFAAFLFWAMSNGSCRCNICI FIO LNINPVKLSSGY - - KDIILWFSFGESCFVLLAVVMGLVFFCLKNGNMRCTICI F11 OEIEGVKIDSSGNVYKILSIYSCIASSIVLAALIMGFMFWACSNGSCRCTICI E12 OKVNGVKLEENS - TVKILSIVSSVASSLVLLI:MI IGGEIFGCONGNVRCIFCI E13 OBIOGIKLKSEDNVVKALSIVSCIASSVVLVGLILSFIMWACSSGNCRENVCI H14 IKINPVTLTMGV - - - KDIILWISFSMSCFVFVALILGFVLWACONGNIRCOICI H15 IMINPVKLSSGY - - KDVILWFSFGASCVILLAIAMGLIFMCVKNGNLRCTICI H16 OEIEGIKLKTEDNVYKVLSIYSCIASSIVLVGLILAFIMWACSNGSCRFNVCI HJ ? OKIDGVKLODYS - RYYIMILYSTIASSVVLGSLIIAAFLKGCOKGSIOCKICI

FIG . 10 atent Nov . 27 , 2018 Sheet 4 of 56 US 10 , 137 , 189 B2

M2 globular head

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Para estaX8 oor atent Nov . 27 , 2018 Sheet 5 of 56 US 10 , 137 , 189 B2 rrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrr'

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conelencom atent Nov . 27 , 2018 Sheet 6 of 56 US 10 , 137 , 189 B2

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4443 Swwwwayo Fig.4A atent Nov . 27 , 2018 Sheet 7 of 56 US 10 , 137 , 189 B2

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000000000 atent Nov . 27 , 2018 Sheet 8 of 56 US 10 , 137 , 189 B2

AHK / 1 /68 (H3 ) ODLPGNONS TAPECLGHHAVENGEL* * * * * * * * * KIITOPOIRVINATELVOSSSTGKT* * + APerth / 16 /09 (H3 ) OKLPCNDNS TACLCLCHHAVENGTI STEINDOIEVINA TEL: VOS STORE APR / 8 / 34 (H1 ) -- - - PTICIGYHANNSTD TWD TVI EKNVTVTHSTALLEDSANGKA A / Cai/ 4 /09 ( H1 ) - - - - DILCIGYHANINSPO TVDOVLAKNVTV THS VNLLEDKHNICKER ANN / 1203 /04 (H5 ) Almallard Aberta /24 / 01 (H7 ) ------DECLCHHAVANCIK DICIGYHANNSTE VUTT VOTESEKNVTVTHAODT TEKETEVVNATETVETVNIEKIS ARKKINCK AHK /1 / 68 (H3 ) APerth / 6 /09 (H3 ) A /PR /8 : 34 (H1 ) Globular head domain A /Cal / 4 /09 (H1 ) ANN1203/ 04 (H5 ) Almallard /Aberta /24 /01 (H7 ) AHK / 168 (H3 ) SISECI TRNCS LENDKEFONVINULTYGACEKAV KONTEK ZATOMRNVPEK- CHAGLIGA 334 A /Perth / 16 /09 (H3 ) VSECITRAGSTENDKEFON MARITYSACPRIVKONDTA LATEMRNVPEK - CERCEFGA ?234 A /PR / 8 /34 (411 ) NIK COTEL GATKSSLPYON THENTICE CEKYVRSAKLRMYTGERNTESTO - SROZEGA 331 A / Cal/ 4 /09 (H1 ) NOTCONEKGAINASLPEONTHETTIEKCPKYVKST KERETGERNIPSIQ - SRELEGA 332 ANN / 1203 /04 (15 ) NIKCODE - CAINSSTPPANTHET RICE CPKEVKSNREVLÅTELENSPORE - TROLERA ??331 Almallard /Aberta / 24 /01 (H7 ) GDEF HACE TIMSSEREONINEROVOKOPAYVKOT SE L LATGHRNVEEN KERSLIGA 326 A /HK / 1 /65 (H3 ) TAGETEKSHEEKIDEHY GERHONS ECICAADEKSTO ARTDOINGKENRVIEKTMEKEHOTE KEF SEVG 404

APerth /16 /09 (H3 ) LAGE LENSWEGMUDGEVEERHONSECRGMAADLKSTO+ NATDOR. CEL. NROEGEINEKEHORS KETERMES 404 APR /8 /34 ( 1 ) LACE LEGGWPMIDGWYGSCHHONE OGSGYAAN QKSTORA INGUINKVDIV IEKMINTOS TAVCKEFL?KLEK 401 A /Cal / 4 / 09 (HI ) LAGE LEGEN TERVDGWYGYHHONEOGSGYAADLKSTONA IDEE TNKYNSVIEKMINTOF DAVGKETNHLEK 402 ANN / 1203/ 04 (H5 ) LAGFIECOW. COMWDGWYGYHKONECGSGYAADKESTO KALDGVINKYNS TIDKMNIORE AVEREENISEER 401 Almallard /Aberta / 24 /01 (H7 ) LACH TENGWECILEDGWYGERHONANCE GRAADMKSIO SATROL TGKLNRLEDKTNOOFEZIONEFSEIEO 396 A /HK / 1/ 68 (43 ) RIODEKYVEDIKIDLASYNAELEVALENOHT. IDE DOSEMNKBOEKIRROLRENAEDMGNCCEKTYHKED 474

A /Perth ( 16 /09 (43 ) RBOLESKYVEDIKIDLApos SYNAELLVALENOHT:TDI TOSEMNKLEDEKTKKOLRENAEDMGNGCHIYHKCD 474 APR /8 /34 (Hi ) BENUNKKVDOGDADIKUNAELLVILLE NERTILDI HD SNVKNL YEKVIKSORE KIVYAKE IGNGCHEE YHKOB 171 A /Cal / 4 /09 (H1 ) RIENI NK KVODGELDIMTYNAELLYLLEKERTLINDSUVKNLYEKVESELKONNAKE LENGCHEFYHKCL 472

ANN1203/ 04 (H5 ) BIENENKKMEDGE; L : D VWTYNAELLVILAVE BERILDI99 HDSNVIONLYOKURLOLRDINAKELGNCCHEE YHKCL 471iN Arallard/ Albertat24/ 01 ( 47 ) CIENT INTROSTEVE NATIVA VENCHTTDANCE MANAGENTO RENATEGOTEPHECE 16 A /HK / 1 /68 (H3 ) MAGICSIRKGTYDHUVIRDEAPAORU TREQIKGVERKSGYKDYWILNISFAEU :33 13 IC -CPLE WHENWEL GEIMSORGN LA 543Tr S A /Perth /16 /09 (43 ) NA @ TCSIRNGTYDHD VYROBATEN INREOIKGVERKSGYKLILWISFAIS - CELE VALIGE IMACOKEN 0549 NA A /PR /8 /34 (H1 ) SE QUE SVRNCTEDYRE 20VESEESKUNREKVIEGVKLESMCEYOTLARYSTVÅSSL VB ,VISIGAISMASSNAS 54114 STEMESVKNGTYD YEKISELAKENRES I DGVKLE STRDIQILALYSTVASSE VILMSI CAISTRACSNGS 1547 . ANN120304 (HS ) LESMESVRNGIYDYBOESELARLINEDISGVKLES IGI YOTE SEXSTVASSZAL AIMVACE STAUCENCS 54101-

0 Ajmallard /Abenta /24 / 01 (47 ) DOOMESIRANTYDHTOERTESHONRTOIDFVKESSGERD TTLWISE GAS- CETILAIAMGLVDICIKONGN 535; AHK / 1 /68 (H3 ) 550 A /Perth 16 /09 (43 ) TROUECH 550 APR / 8 /34 (61 ) LOOR LCD 548 ACal/ 4 /09 (11 ) LQERIORE 549 ANN1203 /04 (H5 ) LOERICI 549 Almallard / Alberta /24 / 01 (H7 ) MROTICI 542

Bogor atent Nov . 27 , 2018 Sheet 9 of 56 US 10 , 137, 189 B2

Fig.7A Fig.7B atent Nov . 27 , 2018 Sheet 10 of 56 US 10 , 13713 , 189 B2

PR8-CH5 47.8% 10

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* * * * * * * * * atent Nov . 27 , 2018 Sheet 11 of 56 US 10 , 137, 189 B2

Perth-CH7Negative

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(0607 Wine ) nja atent Nov . 27 , 2018 Sheet 12 of 56 US 10 , 137, 189 B2

2000

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...... FifiFFFFFF . warmy #444444444444444444444444444444444444444444444444444444444444444.44A-4A+*44444444444444444444444444444444444444444444444444444: *FFFFFFAAAFFFFFAFAFFAFFFFFRFFFFFAF1AFFFFFAF-FFFFFFFWFFFFFFFFFFF+MFARFAFFFFFFFAFFFFFFFFFFFFFFFFFFAFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFFRFPFAF#/ wwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwww vw PR8A $ +

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+ mo wanan + ???????????????????? intentati F HAO NP GAPDH U . S . Patent Nov . 27 , 2018 Sheet 13 of 56 US 10 ,137 , 189 B2

H5HAwww a-Cal/09HA C-H1HA O-PR8HA C-H3HA ?FANP - a-H7 Mock

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III PR8-CH1CH5 HDOT

WHO PR8 atent Nov . 27 , 2018 Sheet 14 of 56 US 10 , 137, 189 B2

. .. . .

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m manandamamlanana

meny U . S . Patent Nov . 27 , 2018 Sheet 15 of 56 US 10 , 137 , 189 B2

PY102(1ug/n) Fig.110 D

C179(1ug/ml)

PR8DNAonly Calo9splitvaccine U . S . Patent Nov . 27 , 2018 Sheet 16 of 56 US 10 , 137, 189 B2

NC99/cH9N1 PR8inactivated #NC99 CHON1 + + +

5.0 Dayspostchallenge 2.5

110 100 90 survival Percent atent Nov . 27 , 2018 Sheet 17 of 56 US 10 , 137, 189 B2

os (

anti-H1sera99 C179umhe netnegative 100

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* * ug/mlantibodyconcentration

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FIG . 36 US 10 , 137 , 189 B2 INFLUENZA VIRUS VACCINES AND USES In addition to annual epidemics , influenza viruses are the THEREOF cause of infrequent pandemics . For example , influenza A viruses can cause pandemics such as those that occurred in This application is a divisional of U . S . patent application 1918 , 1957 , 1968, and 2009 . Due to the lack of pre - formed Ser. No . 14 / 109 ,358 ( issued as U . S . Pat . No. 9 , 371, 366 ) , 5 immunity against the major viral antigen , hemagglutinin filed Dec . 17 , 2013 , which claims priority to U . S . Provi- (HA ) , pandemic influenza can affect greater than 50 % of the sional Patent Application No . 61 / 738 ,672 , filed Dec . 18 , population in a single year and often causes more severe 2012 , and U .S . Provisional Patent Application No . 61/ 840 , disease than epidemic influenza . A stark example is the 899 , filed Jun . 28 . 2013 , the disclosure of each of which is pandemic of 1918 , in which an estimated 50 - 100 million 10 people were killed ( Johnson and Mueller ( 2002 ) Updating incorporated herein by reference in its entirety . the Accounts : Global Mortality of the 1918 - 1920 “ Spanish ” This invention was made with government support under Influenza Pandemic Bulletin of the History of Medicine 76 : Grant Nos . A1070469 , A1086061 and 105 - 115 ) . Since the emergence of the highly pathogenic HHSN266200700010C awarded by the National Institutes avian H5N1 influenza virus in the late 1990s (Claas et al. of Health . The government has certain rights in the invenH 15 ( 1998) Human influenza A H5N1 virus related to a highly tion . pathogenic avian influenza virus . Lancet 351: 472 - 7 ) , there have been concerns that it may be the next pandemic virus . 1 . INTRODUCTION Further, H7 and H9 strains are candidates for new pandemics since these strains infect humans on occasion . Provided herein are chimeric influenza virus hemagglu - 20 An effective way to protect against influenza virus infec tinin polypeptides and compositions comprising the same, tion is through vaccination ; however, current vaccination vaccines comprising the same, and methods of their use. approaches rely on achieving a good match between circu lating strains and the isolates included in the vaccine . Such 2 . BACKGROUND a match is often difficult to attain due to a combination of 25 factors . First , influenza viruses are constantly undergoing Influenza viruses are enveloped RNA viruses that belong change : every 3 - 5 years the predominant strain of influenza to the family of Orthomyxoviridae ( Palese and Shaw ( 2007 ) A virus is replaced by a variant that has undergone sufficient Orthomyxoviridae : The Viruses and Their Replication , 5th antigenic drift to evade existing antibody responses . Isolates ed . Fields' Virology , edited by B . N . Fields, D . M . Knipe and to be included in vaccine preparations must therefore be P . M . Howley . Wolters Kluwer Health /Lippincott Williams 30 selected each year based on the intensive surveillance efforts & Wilkins , Philadelphia , USA , p1647 - 1689 ). The natural of the World Health Organization (WHO ) collaborating host of influenza A viruses are mainly avians, but influenza centers . Second , to allow sufficient time for vaccine manu A viruses ( including those of avian origin ) also can infect facture and distribution , strains must be selected approxi and cause illness in humans and other animal hosts ( bats , mately six months prior to the initiation of the influenza canines, pigs, horses , sea mammals , and mustelids ) . For 35 season . Often , the predictions of the vaccine strain selection example , the H5N1 avian influenza A virus circulating in committee are inaccurate , resulting in a substantial drop in Asia has been found in pigs in China and Indonesia and has the efficacy of vaccination . also expanded its host range to include cats , leopards , and The possibility of a novel subtype of influenza A virus tigers , which generally have not been considered susceptible entering the human population also presents a significant to influenza A (CIDRAP - Avian Influenza : Agricultural and 40 challenge to current vaccination strategies. Since it is impos Wildlife Considerations) . The occurrence of influenza virus sible to predict what subtype and strain of influenza virus infections in animals could potentially give rise to human will cause the next pandemic , current, strain -specific pandemic influenza strains. approaches cannot be used to prepare a pandemic influenza Influenza A and B viruses are major human pathogens, vaccine . causing a respiratory disease that ranges in severity from 45 sub - clinical infection to primary viral pneumonia which can 3 . SUMMARY result in death . The clinical effects of infection vary with the virulence of the influenza strain and the exposure , history, In one aspect , provided herein are chimeric influenza age , and immune status of the host . The cumulative mor - hemagglutinin (HA ) polypeptides that induce a cross -pro bidity and mortality caused by seasonal influenza is sub - 50 tective immune response against the conserved HA stem stantial due to the relatively high attack rate . In a normal domain of influenza viruses . The chimeric influenza HA season , influenza can cause between 3 - 5 million cases of polypeptides provided herein comprise a stable ( e . g . , prop severe illness and up to 500 ,000 deaths worldwide ( World erly formed ) HA stem domain and a globular HA head Health Organization ( 2003 ) Influenza : Overview ; March domain that is heterologous to the stem domain ( i . e . the head 2003 ) . In the United States , influenza viruses infect an 55 and stem domains are derived from different strains and / or estimated 10 - 15 % of the population (Glezen and Couch RB subtypes of influenza virus ) . ( 1978 ) Interpandemic influenza in the Houston area , 1974 In certain embodiments , a chimeric influenza hemagglu 76 . N Engl JMed 298 : 587 -592 ; Fox et al. ( 1982 ) Influenza tinin (HA ) polypeptide provided herein comprises (i ) the virus infections in Seattle families, 1975 - 1979 . II . Pattern of stem domain of the hemagglutinin from an influenza virus of infection in invaded households and relation of age and prior 60 the H1 subtype and ( ii) the globular head domain of the antibody to occurrence of infection and related illness. Am hemagglutinin from an influenza virus of the H5 subtype J Epidemiol 116 : 228 -242 ) and are associated with approxi (sometimes referred to herein as a “ cH5/ 1 chimeric influenza mately 30 , 000 deaths each year ( Thompson W W et al. hemagglutinin polypeptide” ) . In a specific embodiment, the ( 2003 ) Mortality Associated with Influenza and Respiratory stem domain of a cH5 / 1 chimeric influenza hemagglutinin Syncytial Virus in the United States. JAMA 289 : 179 - 186 ; 65 polypeptide is the stem domain of A / California / 4 / 2009 Belshe ( 2007 ) Translational research on vaccines : influenza (H1N1 ) HA (or the stem domain of an A / California / 4 / 2009 as an example . Clin Pharmacol Ther 82 : 745 - 749 ). like influenza virus HA ). In another specific embodiment, US 10 , 137 , 189 B2 the stem domain of a cH5/ 1 chimeric influenza hemagglu - In certain embodiments , a chimeric influenza hemagglu tinin polypeptide is the stem domain of A / California / 4 / 2009 t inin (HA ) polypeptide provided herein comprises (i ) the (H1N1 ) HA ( or the stem domain of an A /California / 4 /2009 stem domain of the hemagglutinin from an influenza virus of like influenza virus HA ) and the globular head domain of the the H3 subtype and (ii ) the globular head domain of the cH5 / 1 chimeric influenza hemagglutinin polypeptide is the 5 hemagglutinin from an influenza virus of the H5 subtype globular head domain of A /Vietnam / 1203 / 2004 (H5 ) HA (or ( sometimes referred to herein as a “ cH5 / 3 chimeric influenza the globular head domain of an A / Vietnam / 1203 /2004 (H5 ) hemagglutinin polypeptide ” ) . In a specific embodiment, the stem domain of a cH5 / 3 chimeric influenza hemagglutinin like influenza virus HA ) . In another specific embodiment, polypeptide is the stem domain of A /Victoria / 361 / 2011 the stem domain of a cH5/ 1 chimeric influenza hemaggluYo10 (H3N2 ) HA ( or the stem domain of an A /Victoria / 361/ 2011 tinin polypeptide is the stem domain of A /California /4 / 2009 (H3N2 ) - like influenza virus HA ) . In another specific (H1N1 ) HA (or the stem domain of an A /California / 4 / 2009 embodiment, the stem domain of a cH5 / 3 chimeric influenza like influenza virus HA ) and the globular head domain of the hemagglutinin polypeptide is the stem domain of A /Victoria / CH5 / 1 chimeric influenza hemagglutinin polypeptide is the 361/ 2011 (H3N2 ) HA (or the stem domain of an A / Victoria / globular head domain of Allndonesia / 5 /2005 (H5 ) HA (or 15 361 /2011 (H3N2 ) -like influenza virus HA ) and the globular the globular head domain of an A / Indonesia / 5 /2005 ( H5 ) head domain of the cH5/ 3 chimeric influenza hemagglutinin like influenza virus HA ). In another specific embodiment, polypeptide is the globular head domain of A / Vietnam / 1203 / the stem domain of a cH5 / 1 chimeric influenza hemagglu - 2004 (H5 ) HA (or the globular head domain of an A / Viet tinin polypeptide is the stem domain of A / California / 4 / 2009 nam // 12031203 // 2004 2004 (15H5 )) _ - like ininfluenza virus HA ) . In another (H1N1 ) HA (or the stem domain of an A / California / 4 /2009 - 20 specific embodiment, the stem domain of a cH5/ 3 chimeric like influenza virus HA ) and the globular head domain of the influenza hemagglutinin polypeptide is the stem domain of cH5/ 1 chimeric influenza hemagglutinin polypeptide is the A /Victoria /361 / 2011 (H3N2 ) (or the stem domain of an globular head domain of A / Anhui/ 1 /2005 (H5 ) HA (or the A /Victoria /361 / 2011 (H3N2 ) - like influenza virus HA ) HA globular head domain of an A / Anhui/ 1 / 2005 (H5 ) -like influ and the globular head domain of the cH5 / 3 chimeric influ enza virus HA ) . In another specific embodiment, the stem 25 enza hemagglutinin polypeptide is the globular head domain domain of a cH5/ 1 chimeric influenza hemagglutinin poly - of A / Indonesia / 5 /2005 (H5 ) HA (or the globular head peptide is the stem domain of A /California / 4 /2009 (H1N1 ) domain of an A / Indonesia / 5 / 2005 (H5 ) - like influenza virus HA (or the stem domain of an A /California /4 / 2009- like HA ). In another specific embodiment, the stem domain of a influenza virus HA ) and the globular head domain of the cH5 / 3 chimeric influenza hemagglutinin polypeptide is the cH5 / 1 chimeric influenza hemagglutinin polypeptide is the 30 stem domain of A /Victoria / 361/ 2011 (H3N2 ) HA ( or the globular head domain of A /Bar headed goose / Quinghai/ 1A / stem domain of an A / Victoria / 361/ 2011 ( H3N2) - like influ 2005 (H5 ) HA ( or the globular head domain of an A /Bar enza virus HA ) and the globular head domain of the cH5 / 3 headed goose / Quinghai/ 1A / 2005 (H5 ) - like influenza virus chimeric influenza hemagglutinin polypeptide is the globu HA ) . In another specific embodiment, the stem domain of a lar head domain of A / Anhui/ 1 / 2005 (H5 ) HA (or the globu cH5 / 1 chimeric influenza hemagglutinin polypeptide is the 35 lar head domain of an A /Anhui / 1 / 2005 (H5 ) - like influenza stem domain of A /California / 4 / 2009 (H1N1 ) HA ( or the virus HA ) . In another specific embodiment, the stem domain stem domain of an A / California / 4 / 2009 - like influenza virus of a cH5/ 3 chimeric influenza hemagglutinin polypeptide is HA ) and the globular head domain of the cH5 / 1 chimeric the stem domain of A /Victoria / 361/ 2011 (H3N2 ) HA (or the influenza hemagglutinin polypeptide is the globular head stem domain of an A / Victoria / 361/ 2011 (H3N2 ) - like influ domain of A / turkey / Turkey / 1 /2005 (H5 ) HA ( or the globular 40 enza virus HA ) and the globular head domain of the cH5 / 3 head domain of an A /turkey / Turkey / 1 / 2005 (H5 ) - like influ - chimeric influenza hemagglutinin polypeptide is the globu enza virus HA ) . In another specific embodiment, the stem lar head domain of A /Bar headed goose / Quinghai /1A / 2005 domain of a cH5 / 1 chimeric influenza hemagglutinin poly (H5 ) HA (or the globular head domain of an A /Bar headed peptide is the stem domain of A / California / 4 / 2009 (H1N1 ) goose / Quinghai / 1A / 2005 (H5 ) - like influenza virus HA ) . In HA (or the stem domain of an A / California / 4 / 2009- like 45 another specific embodiment, the stem domain of a cH5 / 3 influenza virus HA ) and the globular head domain of the chimeric influenza hemagglutinin polypeptide is the stem cH5 / 1 chimeric influenza hemagglutinin polypeptide is the domain of A /Victoria / 361/ 2011 (H3N2 ) HA (or the stem globular head domain of A /Whooperswan /Mongolia / 244 / domain of an A / Victoria /361 /2011 (H3N2 ) - like influenza 2005 (H5 ) HA ( or the globular head domain of an A /Whoop virus HA ) and the globular head domain of the cH5 / 3 erswan /Mongolia / 244 /2005 (H5 ) - like influenza virus HA ) . 50 chimeric influenza hemagglutinin polypeptide is the globu In specific embodiments, the stem domain of the hemagglu - lar head domain of A /turkey / Turkey / 1 / 2005 (H5 ) HA (or the tinin from an influenza virus of the H1 subtype of a cH5 / 1 globular head domain of an A / turkey / Turkey / 1 / 2005 (H5 ) chimeric influenza hemagglutinin polypeptide provided like influenza virus HA ) . In another specific embodiment, herein is from an H1 subtype that the majority of the the stem domain of a cH5 / 3 chimeric influenza hemagglu population is naive to . In certain embodiments, the stem 55 tinin polypeptide is the stem domain of A /Victoria / 361 /2011 domain of the hemagglutinin from an influenza virus of the (H3N2 ) HA ( or the stem domain of an A /Victoria / 361/ 2011 H1 subtype of a cH5 / 1 chimeric influenza hemagglutinin (H3N2 ) - like influenza virus HA ) and the globular head polypeptide provided herein is from an upcoming H1N1 domain of the cH5 / 3 chimeric influenza hemagglutinin vaccine strain , e . g . , the H1N1 vaccine strain in use in the polypeptide is the globular head domain of A /Whooper year 2013 , 2014 , 2015 , 2016 , 2017 , 2018 , 2019 , 2020 , 2021 , 60 swan /Mongolia /244 / 2005 (H5 ) HA ( or the globular head 2022 , 2023 , 2024 , 2025 , 2026 , 2027 , 2028 , 2029 , 2030 , domain of an A /Whooperswan /Mongolia / 244 /2005 (H5 ) 2031 , 2032, 2032 , 2033 , 2034 , or 2035 . like influenza virus HA ) . In a specific embodiment, a cH5/ 1 chimeric influenza In another specific embodiment, the stem domain of a hemagglutinin polypeptide does not comprise the stem c H5/ 3 chimeric influenza hemagglutinin polypeptide is the domain of A /Puerto Rico / 8 /34 (“ PR8” ) HA and does not 65 stem domain of A /harbor seal/ Massachusetts / 1 /2011 comprise the globular head domain of A /Vietnam / 1203 / (H3N8 ) HA (or the stem domain of an A /harbor seal/ 2004 (H5 ) HA . Massachusetts/ 1 / 2011 (H3N8 ) - like influenza virus HA ). In US 10 , 137 , 189 B2 another specific embodiment, the stem domain of a cH5/ 3 influenza virus HA ). In another specific embodiment, the chimeric influenza hemagglutinin polypeptide is the stem stem domain of a cH5 /3 chimeric influenza hemagglutinin domain of A /harbor seal/ Massachusetts / 1 / 2011 (H3N8 ) HA polypeptide is the stem domain of A /Indiana / 10 / 2011 ( or the stem domain of an A / harbor seal /Massachusetts / 1 / (H3N2 ) HA ( or the stem domain of an A /Indiana / 10 / 2011 2011 (H3N8 ) - like influenza virus HA ) and the globular head 5 (H3N2 ) - like influenza virus HA ) and the globular head domain of the cH5 / 3 chimeric influenza hemagglutinin domain of the cH5 / 3 chimeric influenza hemagglutinin polypeptide is the globular head domain of A /Vietnam / 1203 / polypeptide is the globular head domain of A /Indonesia / 5 / 2004 (H5 ) HA (or the globular head domain of an A / Viet - 2005 (H5 ) HA (or the globular head domain of an A / Indo nam / 1203 / 2004 (H5 ) - like influenza virus HA ) . In another nesia / 5 /2005 (H5 ) - like influenza virus HA ) . In another spe specific embodiment, the stem domain of a cH5 / 3 chimeric 10 cific embodiment, the stem domain of a cH5 / 3 chimeric influenza hemagglutinin polypeptide is the stem domain of influenza hemagglutinin polypeptide is the stem domain of A /harbor seal/ Massachusetts / 1 /2011 (H3N8 ) HA (or the A / Indiana/ 10 /2011 (H3N2 ) ( or the stem domain of an A / In stem domain of an A /harbor seal/ Massachusetts / 1 / 2011 diana / 10 /2011 (H3N2 ) - like influenza virus HA ) HA and the (H3N8 ) - like influenza virus HA ) and the globular head globular head domain of the cH5 / 3 chimeric influenza domain of the cH5 / 3 chimeric influenza hemagglutinin 15 hemagglutinin polypeptide is the globular head domain of polypeptide is the globular head domain of A / Indonesia / 5 / A / Anhui/ 1 / 2005 (H5 ) HA ( or the globular head domain of 2005 (H5 ) HA ( or the globular head domain of an A / Indo - an A / Anhui/ 1 / 2005 (H5 ) - like influenza virus HA ) . In nesia / 5 /2005 (H5 )- like influenza virus HA ). In another spe - another specific embodiment, the stem domain of a cH5/ 3 cific embodiment, the stem domain of a cH5 / 3 chimeric chimeric influenza hemagglutinin polypeptide is the stem influenza hemagglutinin polypeptide is the stem domain of 20 domain of A / Indiana / 10 /2011 (H3N2 ) HA (or the stem A /harbor seal/ Massachusetts / 1 /2011 (H3N8 ) HA (or the domain of an A / Indiana /10 / 2011 (H3N2 ) - like influenza stem domain of an A /harbor seal/ Massachusetts / 1 / 2011 virus HA ) and the globular head domain of the cH5 / 3 (H3N8 ) - like influenza virus HA ) and the globular head chimeric influenza hemagglutinin polypeptide is the globu domain of the cH5 / 3 chimeric influenza hemagglutinin lar head domain of A /Bar headed goose / Quinghai/ 1A / 2005 polypeptide is the globular head domain of A / Anhui/ 1 / 2005 25 (H5 ) HA (or the globular head domain of an A /Bar headed (H5 ) HA ( or the globular head domain of an A / Anhui/ 1 / 2005 goose / Quinghai/ 1A / 2005 (H5 ) - like influenza virus HA ). In (H5 ) - like influenza virus HA ) . In another specific embodi - another specific embodiment , the stem domain of a cH5 / 3 ment , the stem domain of a cH5/ 3 chimeric influenza chimeric influenza hemagglutinin polypeptide is the stem hemagglutinin polypeptide is the stem domain of A / harbor domain of A / Indiana / 10 / 2011 (H3N2 ) HA ( or the stem seal/ Massachusetts / 1 /2011 (H3N8 ) HA (or the stem domain 30 domain of an A / Indiana / 10 /2011 (H3N2 ) - like influenza of an A /harbor seal/Massachusetts / 1 /2011 (H3N8 ) - like virus HA ) and the globular head domain of the cH5 / 3 influenza virus HA ) and the globular head domain of the chimeric influenza hemagglutinin polypeptide is the globu CH5/ 3 chimeric influenza hemagglutinin polypeptide is the lar head domain of A / turkey / Turkey / 1 /2005 (H5 ) HA (or the globular head domain of A / Bar headed goose /Quinghai / 1A globular head domain of an A / turkey / Turkey / 1 / 2005 (H5 ) 2005 (H5 ) HA ( or the globular head domain of an A /Bar 35 like influenza virus HA ) . In another specific embodiment, headed goose /Quinghai / 1A / 2005 (H5 ) - like influenza virus the stem domain of a cH5 / 3 chimeric influenza hemagglu HA ). In another specific embodiment, the stem domain of a tinin polypeptide is the stem domain of A /Indiana / 10 / 2011 CH5/ 3 chimeric influenza hemagglutinin polypeptide is the (H3N2 ) HA (or the stem domain of an A / Indiana / 10 / 2011 stem domain of A /harbor seal/ Massachusetts / 1 / 2011 (H3N2 ) - like influenza virus HA ) and the globular head (H3N8 ) ( or the stem domain of an A / harbor seal/Massachu - 40 domain of the cH5 / 3 chimeric influenza hemagglutinin setts / 1 /2011 (H3N8 ) - like influenza virus HA ) HA and the polypeptide is the globular head domain of A /Whooper globular head domain of the cH5/ 3 chimeric influenza swan /Mongolia /244 / 2005 (H5 ) HA (or the globular head hemagglutinin polypeptide is the globular head domain of domain of an A /Whooperswan /Mongolia /244 /2005 (H5 ) A / turkey / Turkey / 1 / 2005 (H5 ) HA (or the globular head like influenza virus HA ) . domain of an A / turkey / Turkey / 1/ 2005 (H5 ) - like influenza 45 In another specific embodiment, the stem domain of a virus HA ) . In another specific embodiment, the stem domain cH5/ 3 chimeric influenza hemagglutinin polypeptide is the of a cH5 /3 chimeric influenza hemagglutinin polypeptide is stem domain of A / Perth / 16 /2009 (H3N2 ) HA (or the stem the stem domain of A /harbor seal/Massachusetts / 1 / 2011 domain of an A /Perth / 16 / 2009 (H3N2 ) -like influenza virus (H3N8 ) HA (or the stem domain of an A /harbor seal / HA ). In another specific embodiment, the stem domain of a Massachusetts / 1 / 2011 (H3N8 )- like influenza virus HA ) and 50 cH5 / 3 chimeric influenza hemagglutinin polypeptide is the the globular head domain of the cH5 / 3 chimeric influenza stem domain of A / Perth / 16 /2009 (H3N2 ) HA (or the stem hemagglutinin polypeptide is the globular head domain of domain of an A / Perth / 16 / 2009 (H3N2 ) - like influenza virus A /Whooperswan /Mongolia / 244 / 2005 (H5 ) HA (or the HA ) and the globular head domain of the cH5/ 3 chimeric globular head domain of an A /Whooperswan /Mongolia / 244 / influenza hemagglutinin polypeptide is the globular head 2005 (H5 ) - like influenza virus HA ) . 55 domain of A /Vietnam / 1203 / 2004 (H5 ) HA ( or the globular In another specific embodiment, the stem domain of a head domain of an A / Vietnam / 1203 / 2004 (H5 ) - like influ cH5 / 3 chimeric influenza hemagglutinin polypeptide is the enza virus HA ) . In another specific embodiment, the stem stem domain of A / Indiana / 10 / 2011 (H3N2 ) HA (or the stem domain of a cH5 /3 chimeric influenza hemagglutinin poly domain of an A / Indiana/ 10 / 2011 (H3N2 ) - like influenza peptide is the stem domain of A / Perth / 16 / 2009 (H3N2 ) HA virus HA ) . In another specific embodiment, the stem domain 60 (or the stem domain of an A / Perth / 16 /2009 (H3N2 ) - like of a cH5 / 3 chimeric influenza hemagglutinin polypeptide is influenza virus HA ) and the globular head domain of the the stem domain of A / Indiana / 10 / 2011 (H3N2 ) HA ( or the cH5/ 3 chimeric influenza hemagglutinin polypeptide is the stem domain of an A / Indiana / 10 / 2011 ( H3N2 ) - like influenza globular head domain of A / Indonesia / 5 /2005 (H5 ) HA (or virus HA ) and the globular head domain of the cH5/ 3 the globular head domain of an A / Indonesia / 5 /2005 (H5 ) chimeric influenza hemagglutinin polypeptide is the globu - 65 like influenza virus HA ) . In another specific embodiment, lar head domain of A /Vietnam / 1203 /2004 (H5 ) HA ( or the the stem domain of a cH5 / 3 chimeric influenza hemagglu globular head domain of an A /Vietnam / 1203/ 2004 (H5 ) - like tinin polypeptide is the stem domain of A /Perth / 16 / 2009 US 10 , 137 , 189 B2 ( H3N2) HA (or the stem domain of an A / Perth / 16 /2009 globular head domain of an A /Netherlands /219 /03 (H7 ) - like (H3N2 ) - like influenza virus HA ) and the globular head influenza virus HA ) . In another specific embodiment, the domain of the cH5 /3 chimeric influenza hemagglutinin stem domain of a cH7/ 3 chimeric influenza hemagglutinin polypeptide is the globular head domain of A / Anhui/ 1 / 2005 polypeptide is the stem domain of A / Victoria / 361/ 2011 (H5 ) HA ( or the globular head domain of an A / Anhui/ 1 / 2005 5 (H3N2 ) HA ( or the stem domain of an A /Victoria /361 / 2011 (H5 ) - like influenza virus HA ) . In another specific embodi - (H3N2 ) - like influenza virus HA ) and the globular head ment, the stem domain of a cH5 / 3 chimeric influenza domain of the cH7/ 3 chimeric influenza hemagglutinin hemagglutinin polypeptide is the stem domain of A / Perth / polypeptide is the globular head domain of A / Canada/ 504 / 16 / 2009 (H3N2 ) HA ( or the stem domain of an A / Perth / 16 / 04 (H7 ) HA ( or the globular head domain of an A / Canada / 2009 (H3N2 ) - like influenza virus HA ) and the globular head 10 504 / 04 (H7 ) - like influenza virus HA ) . In another specific domain of the cH5 / 3 chimeric influenza hemagglutinin embodiment , the stem domain of a cH7 / 3 chimeric influenza polypeptide is the globular head domain of A / Bar headed hemagglutinin polypeptide is the stem domain of A /Victoria / goose/ Quinghai /1A /2005 ( H5) HA ( or the globular head 361/ 2011 ( H3N2) HA ( or the stem domain of an A /Victoria / domain of an A /Bar headed goose /Quinghai / 1A / 2005 (H5 ) - 361 / 2011 (H3N2 ) - like influenza virus HA ) and the globular like influenza virus HA ) . In another specific embodiment, 15 head domain of the cH7 /3 chimeric influenza hemagglutinin the stem domain of a cH5/ 3 chimeric influenza hemagglu polypeptide is the globular head domain of A /Canada /444 / tinin polypeptide is the stem domain of A /Perth / 16 /2009 04 (H7 ) HA (or the globular head domain of an A /Canada / (H3N2 ) HA ( or the stem domain of an A /Perth / 16 / 2009 444 / 04 (17 ) -like influenza virus HA ) . In another specific (H3N2 ) - like influenza virus HA ) and the globular head embodiment, the stem domain of a cH7/ 3 chimeric influenza domain of the cH5 / 3 chimeric influenza hemagglutinin 20 hemagglutinin polypeptide is the stem domain of A /Victoria / polypeptide is the globular head domain of A /turkey / Turkey / 361/ 2011 (H3N2 ) HA ( or the stem domain of an A / Victoria / 1 / 2005 (H5 ) HA (or the globular head domain of an A / tur- 361 /2011 (H3N2 ) - like influenza virus HA ) and the globular key / Turkey / 1 /2005 ( H5 ) - like influenza virus HA ) . In head domain of the cH7/ 3 chimeric influenza hemagglutinin another specific embodiment, the stem domain of a cH5 / 3 polypeptide is the globular head domain of A / chicken / chimeric influenza hemagglutinin polypeptide is the stem 25 Jalisco /CPA1 / 2012 (H7 ) HA ( or the globular head domain of domain of A / Perth / 16 /2009 (H3N2 ) HA (or the stem domain an A / chicken / Jalisco /CPA1 /2012 (H7 ) - like influenza virus of an A / Perth / 16 / 2009 (H3N2 ) - like influenza virus HA ) and HA ) . In another specific embodiment, the stem domain of a the globular head domain of the cH5 / 3 chimeric influenza cH7/ 3 chimeric influenza hemagglutinin polypeptide is the hemagglutinin polypeptide is the globular head domain of stem domain of A /Victoria / 361/ 2011 (H3N2 ) HA (or the A /Whooperswan /Mongolia / 244 /2005 (H5 ) HA (or the 30 stem domain of an A / Victoria / 361/ 2011 (H3N2 ) - like influ globular head domain of an A /Whooperswan /Mongolia / 244 / enza virus HA ) and the globular head domain of the cH7/ 3 2005 (H5 ) - like influenza virus HA ) . chimeric influenza hemagglutinin polypeptide is the globu In specific embodiments , the stem domain of the hemag lar head domain of A /mallard / Alberta / 24 / 2001 (H7 ) HA (or glutinin from an influenza virus of the H3 subtype of a cH5/ 3 the globular head domain of an A /mallard / Alberta/ 24 /2001 chimeric influenza hemagglutinin polypeptide provided 35 (H7 ) - like influenza virus HA ) . In another specific embodi herein is from an H3 subtype that the majority of the ment, the stem domain of a cH7/ 3 chimeric influenza population is naive to . In certain embodiments , the stem hemagglutinin polypeptide is the stem domain of A /Victoria / domain of the hemagglutinin from an influenza virus of the 361/ 2011 (H3N2 ) HA (or the stem domain of an A /Victorial H3 subtype of a cH5/ 3 chimeric influenza hemagglutinin 361/ 2011 (H3N2 ) - like influenza virus HA ) and the globular polypeptide provided herein is from an upcoming H3N2 40 head domain of the cH7 / 3 chimeric influenza hemagglutinin vaccine strain , e . g ., the H3N2 vaccine strain in use in the polypeptide is the globular head domain of A /Rhea /NC / year 2013 , 2014 , 2015 , 2016 , 2017 , 2018 , 2019 , 2020 , 2021 , 39482 / 93 (H7 ) HA (or the globular head domain of an 2022 , 2023 , 2024 , 2025 , 2026 , 2027 , 2028 , 2029 , 2030 , A / Rhea /NC /39482 / 93 (H7 ) - like influenza virus HA ) . In 2031 , 2032 , 2032 , 2033 , 2034 , or 2035 . another specific embodiment, the stem domain of a cH7/ 3 In a specific embodiment, a cH5/ 3 chimeric influenza 45 chimeric influenza hemagglutinin polypeptide is the stem hemagglutinin polypeptide provided herein does not com domain of A /Victoria / 361/ 2011 (H3N2 ) HA ( or the stem prise the globular head domain of A / Vietnam / 1203/ 2004 domain of an A / Victoria / 361/ 2011 (H3N2 ) - like influenza ( H5 ) HA and does not comprise the stem domain of A / Perth / virus HA ) and the globular head domain of the cH7 / 3 16 / 2009 (H3 ) HA . chimeric influenza hemagglutinin polypeptide is the globu In certain embodiments , a chimeric influenza hemagglu - 50 lar head domain of A /mallard /Netherlands / 12 /2000 (H7 ) HA tinin (HA ) polypeptide provided herein comprises ( i) the (or the globular head domain of an A /mallard /Netherlands / stem domain of the hemagglutinin from an influenza virus of 12 / 2000 (H7 ) - like influenza virus HA ) . the H3 subtype and ( ii) the globular head domain of the In another specific embodiment, the stem domain of a hemagglutinin from an influenza virus of the H7 subtype cH7/ 3 chimeric influenza hemagglutinin polypeptide is the ( sometimes referred to herein as a “ cH7 / 3 chimeric influenza 55 stem domain of Alharbor seal/ Massachusetts / 1 / 2011 hemagglutinin polypeptide” ). (H3N8 ) HA ( or the stem domain of an A /harbor seal/ In a specific embodiment, the stem domain of a cH7 / 3 Massachusetts / 1 / 2011 (H3N8 ) - like influenza virus HA ) . In chimeric influenza hemagglutinin polypeptide is the stem another specific embodiment, the stem domain of a cH7/ 3 domain of A / Victoria / 361/ 2011 (H3N2 ) HA ( or the stem chimeric influenza hemagglutinin polypeptide is the stem domain of an A /Victoria / 361/ 2011 (H3N2 ) - like influenza 60 domain of A /harbor seal /Massachusetts / 1 / 2011 (H3N8 ) HA virus HA ) . In another specific embodiment, the stem domain (or the stem domain of an A /harbor seal/ Massachusetts / 1 / of a cH7 / 3 chimeric influenza hemagglutinin polypeptide is 2011 (H3N8 ) - like influenza virus HA ) and the globular head the stem domain of A / Victoria / 361/ 2011 (H3N2 ) HA ( or the domain of the cH7/ 3 chimeric influenza hemagglutinin stem domain of an A / Victoria / 361/ 2011 (H3N2 ) - like influ polypeptide is the globular head domain of A / Netherlands/ enza virus HA ) and the globular head domain of the cH7/ 3 65 219 /03 (H7 ) HA (or the globular head domain of an A /Neth chimeric influenza hemagglutinin polypeptide is the globu - erlands /219 / 03 (H7 ) - like influenza virus HA ) . In another lar head domain of A /Netherlands /219 /03 (H7 ) HA ( or the specific embodiment, the stem domain of a cH7/ 3 chimeric US 10 , 137 , 189 B2 10 influenza hemagglutinin polypeptide is the stem domain of polypeptide is the stem domain of A / Indiana/ 10 /2011 A /harbor seal/ Massachusetts / 1 /2011 (H3N8 ) HA (or the (H3N2 ) HA (or the stem domain of an A / Indiana / 10 / 2011 stem domain of an A /harbor seal/Massachusetts / 1 / 2011 (H3N2 ) - like influenza virus HA ) and the globular head ( H3N8) - like influenza virus HA ) and the globular head domain of the cH7/ 3 chimeric influenza hemagglutinin domain of the cH7/ 3 chimeric influenza hemagglutinin 5 polypeptide is the globular head domain of A / Canada / 504 / polypeptide is the globular head domain of A / Canada/ 504 04 (H7 ) HA (or the globular head domain of an A /Canada / 04 (H7 ) HA ( or the globular head domain of an A / Canada ) 504 /04 (H7 ) - like influenza virus HA ) . In another specific 504 / 04 (H7 ) - like influenza virus HA ) . In another specific embodiment, the stem domain of a cH7 / 3 chimeric influenza embodiment, the stem domain of a cH7/ 3 chimeric influenza hemagglutinin polypeptide is the stem domain of A / Indiana / hemagglutinin polypeptide is the stem domain of A /harbor 10 10 / 2011 (H3N2 ) HA ( or the stem domain of an A / Indiana / seal/Massachusetts / 1 / 2011 (H3N8 ) HA ( or the stem domain 10 / 2011 (H3N2 ) - like influenza virus HA ) and the globular of an A /harbor seal/ Massachusetts / 1 /2011 (H3N8 ) - like head domain of the cH7/ 3 chimeric influenza hemagglutinin influenza virus HA ) and the globular head domain of the polypeptide is the globular head domain of A / Canada/ 444 / cH7/ 3 chimeric influenza hemagglutinin polypeptide is the 04 (H7 ) HA (or the globular head domain of an A /Canada / globular head domain of A / Canada/ 444 /04 (H7 ) HA (or the 15 444 /04 (H7 ) - like influenza virus HA ). In another specific globular head domain of an A / Canada/ 444 /04 (H7 ) - like embodiment, the stem domain of a cH7/ 3 chimeric influenza influenza virus HA ). In another specific embodiment, the hemagglutinin polypeptide is the stem domain of A / Indiana / stem domain of a cH7 /3 chimeric influenza hemagglutinin 10 /2011 (H3N2 ) HA (or the stem domain of an A / Indiana/ polypeptide is the stem domain of A /harbor seal/Massachu - 10 / 2011 (H3N2 ) - like influenza virus HA ) and the globular setts / 1 / 2011 (H3N8 ) HA (or the stem domain of an A /harbor 20 head domain of the cH7/ 3 chimeric influenza hemagglutinin seal/ Massachusetts / 1 /2011 (H3N8 ) - like influenza virus HA ) polypeptide is the globular head domain of A /chicken / and the globular head domain of the cH7/ 3 chimeric influ - Jalisco /CPA1 / 2012 (H7 ) HA ( or the globular head domain of enza hemagglutinin polypeptide is the globular head domain an A / chicken / Jalisco /CPA1 / 2012 (H7 ) - like influenza virus of A / chicken / Jalisco /CPA1 / 2012 (H7 ) HA ( or the globular HA ). In another specific embodiment, the stem domain of a head domain of an A / chicken / Jalisco /CPA1 / 2012 (H7 ) - like 25 cH7 / 3 chimeric influenza hemagglutinin polypeptide is the influenza virus HA ) . In another specific embodiment, the stem domain of A / Indiana / 10 / 2011 (H3N2 ) HA ( or the stem stem domain of a cH7/ 3 chimeric influenza hemagglutinin domain of an A / Indiana / 10 / 2011 (H3N2 ) - like influenza polypeptide is the stem domain of A /harbor seal/ Massachu - virus HA ) and the globular head domain of the cH7 / 3 setts / 1 / 2011 (H3N8 ) HA ( or the stem domain of an A / harbor c himeric influenza hemagglutinin polypeptide is the globu seal/ Massachusetts / 1 /2011 (H3N8 )- like influenza virus HA ) 30 lar head domain of A /mallard / Alberta /24 / 2001 (H7 ) HA (or and the globular head domain of the cH7 /3 chimeric influ the globular head domain of an A /mallard /Alberta / 24 /2001 enza hemagglutinin polypeptide is the globular head domain (H7 ) - like influenza virus HA ) . In another specific embodi of A /mallard / Alberta /24 / 2001 (H7 ) HA (or the globular head ment, the stem domain of a cH7 /3 chimeric influenza domain of an A /mallard / Alberta / 24 /2001 (H7 ) - like influenza hemagglutinin polypeptide is the stem domain of A / Indiana / virus HA ) . In another specific embodiment, the stem domain 35 10 / 2011 (H3N2 ) HA ( or the stem domain of an A / Indiana / of a cH7 / 3 chimeric influenza hemagglutinin polypeptide is 10 / 2011 (H3N2 ) - like influenza virus HA ) and the globular the stem domain of A /harbor seal/ Massachusetts / 1 / 2011 head domain of the cH7/ 3 chimeric influenza hemagglutinin ( H3N8) HA (or the stem domain of an A /harbor seal/ polypeptide is the globular head domain of A /Rhea /NCI Massachusetts / 1 /2011 (H3N8 ) - like influenza virus HA ) and 39482 / 93 (H7 ) HA (or the globular head domain of an the globular head domain of the cH7 / 3 chimeric influenza 40 A / Rhea /NC / 39482 / 93 (H7 ) - like influenza virus HA ) . In hemagglutinin polypeptide is the globular head domain of another specific embodiment, the stem domain of a cH7 / 3 A /Rhea / NC /39482 /93 (H7 ) HA (or the globular head chimeric influenza hemagglutinin polypeptide is the stem domain of an A /Rhea /NC / 39482 / 93 (H7 ) - like influenza domain of A / Indiana / 10 / 2011 (H3N2 ) HA ( or the stem virus HA ) . In another specific embodiment, the stem domain domain of an A / Indiana / 10 / 2011 ( H3N2) - like influenza of a cH7 /3 chimeric influenza hemagglutinin polypeptide is 45 virus HA ) and the globular head domain of the cH7/ 3 the stem domain of A /harbor seal /Massachusetts / 1 / 2011 chimeric influenza hemagglutinin polypeptide is the globu (H3N8 ) HA (or the stem domain of an A /harbor seal/ lar head domain of A /mallard /Netherlands / 12 / 2000 (H7 ) HA Massachusetts / 1 / 2011 (H3N8 ) - like influenza virus HA ) and ( or the globular head domain of an A /mallard /Netherlands / the globular head domain of the cH7 / 3 chimeric influenza 12 / 2000 (H7 ) - like influenza virus HA ) . hemagglutinin polypeptide is the globular head domain of 50 In another specific embodiment, the stem domain of a A /mallard /Netherlands / 12 / 2000 (H7 ) HA ( or the globular cH7 / 3 chimeric influenza hemagglutinin polypeptide is the head domain of an A /mallard /Netherlands / 12 / 2000 (H7 ) - stem domain of A /Perth / 16 / 2009 (H3N2 ) HA (or the stem like influenza virus HA ) . domain of an A / Perth / 16 / 2009 (H3N2 ) - like influenza virus In another specific embodiment, the stem domain of a HA ) . In another specific embodiment, the stem domain of a cH7/ 3 chimeric influenza hemagglutinin polypeptide is the 55 cH7/ 3 chimeric influenza hemagglutinin polypeptide is the stem domain of A / Indiana/ 10 /2011 (H3N2 ) HA (or the stem stem domain of A / Perth / 16 /2009 (H3N2 ) HA (or the stem domain of an A / Indiana / 10 / 2011 (H3N2 ) - like influenza domain of an A /Perth / 16 / 2009 (H3N2 ) - like influenza virus virus HA ). In another specific embodiment, the stem domain HA ) and the globular head domain of the cH7 /3 chimeric of a cH7 / 3 chimeric influenza hemagglutinin polypeptide is influenza hemagglutinin polypeptide is the globular head the stem domain of A / Indiana / 10 / 2011 (H3N2 ) HA ( or the 60 domain of A /Netherlands / 219 / 03 (H7 ) HA (or the globular stem domain of an A / Indiana / 10 / 2011 (H3N2 ) - like influenza head domain of an A /Netherlands /219 /03 (H7 ) - like influ virus HA ) and the globular head domain of the cH73 / e nza virus HA ). In another specific embodiment, the stem chimeric influenza hemagglutinin polypeptide is the globu - domain of a cH7 / 3 chimeric influenza hemagglutinin poly lar head domain of A /Netherlands / 219 / 03 (H7 ) HA ( or the peptide is the stem domain of A /Perth / 16 /2009 (H3N2 ) HA globular head domain of an A /Netherlands /219 / 03 (H7 ) - like 65 ( or the stem domain of an A /Perth / 16 / 2009 (H3N2 ) - like influenza virus HA ) . In another specific embodiment, the influenza virus HA ) and the globular head domain of the stem domain of a cH7 /3 chimeric influenza hemagglutinin cH7/ 3 chimeric influenza hemagglutinin polypeptide is the US 10 , 137 , 189 B2 11 12 globular head domain of A / Canada /504 /04 (H7 ) HA (or the an influenza virus of the H5 subtype ( sometimes referred to globular head domain of an A / Canada / 504 /04 (H7 ) - like herein as a “ cH5/ B chimeric influenza hemagglutinin poly influenza virus HA ). In another specific embodiment, the peptide ” ). stem domain of a cH7/ 3 chimeric influenza hemagglutinin In a specific embodiment , the stem domain of a cH5/ B polypeptide is the stem domain of A /Perth / 16 / 2009 (H3N2 ) 5 chimeric influenza hemagglutinin polypeptide is the stem HA (or the stem domain of an A / Perth / 16 /2009 (H3N2 ) - like domain of B /Malaysia / 2506 / 2004 HA (or the stem domain influenza virus HA ) and the globular head domain of the of an B /Malaysia /2506 / 2004 - like influenza virus HA ) . In another specific embodiment, the stem domain of a cH5 / B CH7 /3 chimeric influenza hemagglutinin polypeptide is the chimeric influenza hemagglutinin polypeptide is the stem globular head domain of A /Canada / 444 /04 (H7 ) HA (or the 10 domain of B /Malaysia /2506 /2004 HA (or the stem domain globular head domain of an A / Canada/ 444 /04 (H7 ) -like of an B /Malaysia /2506 / 2004 - like influenza virus HA ) and influenza virus HA ) . In another specific embodiment, the the globular head domain of the cH5 / B chimeric influenza stem domain of a cH7 / 3 chimeric influenza hemagglutinin hemagglutinin polypeptide is the globular head domain of polypeptide is the stem domain of A /Perth / 16 / 2009 ( H3N2 ) A /Vietnam / 1203 / 2004 (H5 ) HA ( or the globular head HA ( or the stem domain of an A / Perth / 16 /2009 (H3N2 ) - like 15 domain of an A / Vietnam / 1203 / 2004 (15 ) - like influenza influenza virus HA ) and the globular head domain of the virus HA ) . In another specific embodiment the stem domain cH7/ 3 chimeric influenza hemagglutinin polypeptide is the of a cH5 / B chimeric influenza hemagglutinin polypeptide is globular head domain of A / chicken / Jalisco /CPA1 /2012 (H7 ) the stem domain of B /Malaysia / 2506 / 2004 HA ( or the stem HA ( or the globular head domain of an A / chicken /Jalisco domain of an B /Malaysia / 2506 / 2004 - like influenza virus CPA1/ 2012 (H7 ) - like influenza virus HA ) . In another spe - 20 HA ) and the globular head domain of the cH5 / B chimeric cific embodiment, the stem domain of a cH7 / 3 chimeric influenza hemagglutinin polypeptide is the globular head influenza hemagglutinin polypeptide is the stem domain of domain of A / Indonesia / 5 / 2005 (H5 ) HA ( or the globular A / Perth / 16 / 2009 (H3N2 ) HA (or the stem domain of an head domain of an A / Indonesia / 5 / 2005 (H5 ) - like influenza A / Perth / 16 / 2009 (H3N2 ) - like influenza virus HA ) and the virus HA ) . In another specific embodiment, the stem domain globular head domain of the cH7/ 3 chimeric influenza 25 of a cH5/ B chimeric influenza hemagglutinin polypeptide is hemagglutinin polypeptide is the globular head domain of the stem domain of B /Malaysia /2506 / 2004 HA ( or the stem A /mallard / Alberta / 24 / 2001 (H7 ) HA ( or the globular head domain of an B /Malaysia / 2506 / 2004 - like influenza virus domain of an A /mallard /Alberta / 24 /2001 (H7 ) - like influenza HA ) and the globular head domain of the cH5 / B chimeric virus HA ) . In another specific embodiment, the stem domain influenza hemagglutinin polypeptide is the globular head of a cH7 /3 chimeric influenza hemagglutinin polypeptide is 30 domain of A / Anhui/ 1 / 2005 (H5 ) HA (or the globular head the stem domain of A / Perth / 16 / 2009 (H3N2 ) HA (or the domain of an A / Anhui/ 1 / 2005 (H5 ) -like influenza virus stem domain of an A / Perth / 16 /2009 (H3N2 ) - like influenza HA ). In another specific embodiment, the stem domain of a virus HA ) and the globular head domain of the cH7 /3 cH5/ B chimeric influenza hemagglutinin polypeptide is the chimeric influenza hemagglutinin polypeptide is the globu - stem domain of B /Malaysia / 2506 / 2004 HA ( or the stem lar head domain of A /Rhea /NC / 39482/ 93 (H7 ) HA (or the 35 domain of an B /Malaysia /2506 / 2004 - like influenza virus globular head domain of an A /Rhea /NC /39482 / 93 (H7 ) - like HA ) and the globular head domain of the cH5/ B chimeric influenza virus HA ) . In another specific embodiment, the influenza hemagglutinin polypeptide is the globular head stem domain of a cH7/ 3 chimeric influenza hemagglutinin domain of A / Bar headed goose / Quinghai/ 1A / 2005 (H5 ) HA polypeptide is the stem domain of A /Perth / 16 / 2009 (H3N2 ) (or the globular head domain of an A /Bar headed goose ! HA ( or the stem domain of an A /Perth / 16 / 2009 (H3N2 ) -like 40 Quinghai / 1A / 2005 (H5 ) - like influenza virus HA ) . In another influenza virus HA ) and the globular head domain of the specific embodiment, the stem domain of a cH5 / B chimeric cH7/ 3 chimeric influenza hemagglutinin polypeptide is the influenza hemagglutinin polypeptide is the stem domain of globular head domain of A /mallard /Netherlands / 12/ 2000 B /Malaysia / 2506 / 2004 HA ( or the stem domain of an B /Ma ( H7 ) HA ( or the globular head domain of an A /mallard / laysia / 2506 / 2004 - like influenza virus HA ) and the globular Netherlands/ 12 /2000 (H7 )- like influenza virus HA ). 45 head domain of the cH5/ B chimeric influenza hemagglutinin In specific embodiments, the stem domain of the hemag - polypeptide is the globular head domain of A / turkey / Turkey / glutinin from an influenza virus of the H3 subtype of a cH7 /3 1 / 2005 (H5 ) HA ( or the globular head domain of an A / tur chimeric influenza hemagglutinin polypeptide provided key /Turkey / 1/ 2005 (H5 ) - like influenza virus HA ). In herein is from an H3 subtype that the majority of the another specific embodiment, the stem domain of a cH5 /B population is naive to . In certain embodiments , the stem 50 chimeric influenza hemagglutinin polypeptide is the stem domain of the hemagglutinin from an influenza virus of the domain of B /Malaysia /2506 / 2004 HA (or the stem domain H3 subtype of a cH7/ 3 chimeric influenza hemagglutinin of an B /Malaysia / 2506 / 2004 - like influenza virus HA ) and polypeptide provided herein is from an upcoming H3N2 the globular head domain of the cH5/ B chimeric influenza vaccine strain , e . g . , the H3N2 vaccine strain in use in the hemagglutinin polypeptide is the globular head domain of year 2013 , 2014 , 2015 , 2016 , 2017 , 2018 , 2019 , 2020 , 2021 , 55 A /Whooperswan /Mongolia / 244 /2005 (H5 ) HA (or the 2022 , 2023 , 2024 , 2025 , 2026 , 2027 , 2028 , 2029 , 2030 , globular head domain of an A / Whooperswan/ Mongolia /244 / 2031, 2032 , 2032 , 2033 , 2034 , or 2035 . 2005 (H5 ) - like influenza virus HA ) . In a specific embodiment, a cH7 /3 chimeric influenza In another specific embodiment, the stem domain of a hemagglutinin polypeptide does not comprise the globular cH5/ B chimeric influenza hemagglutinin polypeptide is the head domain of A /mallard / Alberta /24 /2001 (H7 ) . In another 60 stem domain of B / Florida/ 4 / 2006 HA ( or the stem domain of specific embodiment, a cH7 / 3 chimeric influenza hemagglu - an B /Florida / 4 /2006 -like influenza virus HA ) . In another tinin polypeptide does not comprise the stem domain of specific embodiment , the stem domain of a cH5/ B chimeric A /Perth / 16 /2009 (H3 ) . influenza hemagglutinin polypeptide is the stem domain of In certain embodiments , a chimeric influenza hemagglu - B / Florida / 4 /2006 HA ( or the stem domain of an B / Florida / tinin (HA ) polypeptide provided herein comprises ( i ) the 65 4 /2006 - like influenza virus HA ) and the globular head stem domain of the hemagglutinin from an influenza B virus domain of the cH5 / B chimeric influenza hemagglutinin and ( ii ) the globular head domain of the hemagglutinin from polypeptide is the globular head domain of A /Vietnam / 1203 / US 10 , 137 , 189 B2 14 2004 (H5 ) HA (or the globular head domain of an A /Viet and the globular head domain of the cH5/ B chimeric influ nam / 1203 / 2004 (H5 ) - like influenza virus HA ) . In another enza hemagglutinin polypeptide is the globular head domain specific embodiment, the stem domain of a cH5 / B chimeric of A / Anhui / 1/ 2005 (H5 ) HA (or the globular head domain of influenza hemagglutinin polypeptide is the stem domain of an A / Anhui/ 1 / 2005 (H5 ) -like influenza virus HA ) . In B /Florida / 4 /2006 HA (or the stem domain of an B / Florida / 5 another specific embodiment, the stem domain of a cH5 /B 4 /2006 - like influenza virus HA ) and the globular head chimeric influenza hemagglutinin polypeptide is the stem domain of the cH5 / B chimeric influenza hemagglutinin domain of B /Wisconsin / 1 /2010 HA (or the stem domain of polypeptide is the globular head domain of A / Indonesia / 5 / an B /Wisconsin / 1 /2010 - like influenza virus HA ) and the 2005 (H5 ) HA ( or the globular head domain of an A / Indo - globular head domain of the cH5 / B chimeric influenza nesia /5 /2005 (H5 ) - like influenza virus HA ) . In another spe - 10 hemagglutinin polypeptide is the globular head domain of cific embodiment, the stem domain of a cH5/ B chimeric A /Bar headed goose / Quinghai/ 1A / 2005 (H5 ) HA ( or the influenza hemagglutinin polypeptide is the stem domain of globular head domain of an A / Bar headed goose /Quinghai / B /Florida /4 /2006 HA (or the stem domain of an B / Florida/ 1A / 2005 (H5 ) - like influenza virus HA ) . In another specific 4 /2006 - like influenza virus HA ) and the globular head embodiment, the stem domain of a cH5 / B chimeric influ domain of the cH5 / B chimeric influenza hemagglutinin 15 enza hemagglutinin polypeptide is the stem domain of polypeptide is the globular head domain of A /Anhui / 1/ 2005 B /Wisconsin / 1 /2010 HA (or the stem domain of an B /Wis (H5 ) HA ( or the globular head domain of an A / Anhui/ 1 / 2005 consin / 1 / 2010 - like influenza virus HA ) and the globular ( H5 )- like influenza virus HA ). In another specific embodi- head domain of the cH5/ B chimeric influenza hemagglutinin ment, the stem domain of a cH5 /B chimeric influenza polypeptide is the globular head domain of A / turkey / Turkey / hemagglutinin polypeptide is the stem domain of B / Florida/ 20 1 / 2005 (H5 ) HA ( or the globular head domain of an A / tur 4 /2006 HA (or the stem domain of an B /Florida / 4 / 2006 - like key / Turkey / 1 /2005 (H5 ) -like influenza virus HA ). In influenza virus HA ) and the globular head domain of the another specific embodiment, the stem domain of a cH5 /B CH5/ B chimeric influenza hemagglutinin polypeptide is the chimeric influenza hemagglutinin polypeptide is the stem globular head domain of A / Bar headed goose / Quinghai/ 1A ) domain of B /Wisconsin / 1 /2010 HA (or the stem domain of 2005 (H5 ) HA ( or the globular head domain of an A / Bar 25 an B /Wisconsin / 1 /2010 - like influenza virus HA ) and the headed goose/ Quinghai /1A / 2005 (H5 ) -like influenza virus globular head domain of the cH5 /B chimeric influenza HA ). In another specific embodiment , the stem domain of a hemagglutinin polypeptide is the globular head domain of CH5 /B chimeric influenza hemagglutinin polypeptide is the A /Whooperswan /Mongolia / 244 /2005 (H5 ) HA ( or the stem domain of B / Florida / 4 / 2006 HA ( or the stem domain of globular head domain of an A / Whooperswan /Mongolia / 244 / an B /Florida / 4 /2006 - like influenza virus HA ) and the globu - 30 2005 (H5 ) - like influenza virus HA ) . lar head domain of the cH5 / B chimeric influenza hemag . In another specific embodiment, the stem domain of a glutinin polypeptide is the globular head domain of A /tur cH5 / B chimeric influenza hemagglutinin polypeptide is the key / Turkey / 1 /2005 ( H5) HA ( or the globular head domain of stem domain of B /Brisbane / 60 / 2008 HA ( or the stem an A /turkey / Turkey / 1/ 2005 (H5 ) - like influenza virus HA ) . domain of an B / Brisbane /60 / 2008 -like influenza virus HA ) . In another specific embodiment, the stem domain of a cH5 / B 35 In another specific embodiment, the stem domain of a cH5 / B chimeric influenza hemagglutinin polypeptide is the stem chimeric influenza hemagglutinin polypeptide is the stem domain of B /Florida /4 /2006 HA (or the stem domain of an domain of B /Brisbane /60 /2008 HA (or the stem domain of B /Florida / 4 / 2006 - like influenza virus HA ) and the globular a n B / Brisbane /60 / 2008 - like influenza virus HA ) and the head domain of the cH5 / B chimeric influenza hemagglutinin globular head domain of the cH5/ B chimeric influenza polypeptide is the globular head domain of A /Whooper - 40 hemagglutinin polypeptide is the globular head domain of swan /Mongolia / 244 / 2005 ( H5 ) HA ( or the globular head A /Vietnam / 1203 /2004 (H5 ) HA ( or the globular head domain of an A /Whooperswan /Mongolia /244 /2005 (H5 )- domain of an A / Vietnam /1203 / 2004 (H5 ) - like influenza like influenza virus HA ) . virus HA ). In another specific embodiment, the stem domain In another specific embodiment, the stem domain of a of a cH5 /B chimeric influenza hemagglutinin polypeptide is cH5 / B chimeric influenza hemagglutinin polypeptide is the 45 the stem domain of B /Brisbane /60 / 2008 HA (or the stem stem domain of B /Wisconsin / 1 /2010 HA (or the stem domain of an B /Brisbane /60 /2008 - like influenza virus HA ) domain of an B /Wisconsin / 1 / 2010 - like influenza virus HA ) . and the globular head domain of the cH5/ B chimeric influ In another specific embodiment, the stem domain of a cH5 / B enza hemagglutinin polypeptide is the globular head domain chimeric influenza hemagglutinin polypeptide is the stem of A /Indonesia / 5 /2005 (H5 ) HA ( or the globular head domain of B /Wisconsin / 1 / 2010 HA ( or the stem domain of 50 domain of an A / Indonesia / 5 / 2005 (H5 ) - like influenza virus an B /Wisconsin / 1 / 2010 - like influenza virus HA ) and the HA ). In another specific embodiment, the stem domain of a globular head domain of the cH5 / B chimeric influenza cH5 / B chimeric influenza hemagglutinin polypeptide is the hemagglutinin polypeptide is the globular head domain of stem domain of B /Brisbane / 60 / 2008 HA ( or the stem A /Vietnam / 1203 / 2004 (H5 ) HA ( or the globular head domain of an B /Brisbane /60 / 2008 - like influenza virus HA ) domain of an A / Vietnam / 1203 / 2004 (H5 ) - like influenza 55 and the globular head domain of the cH5/ B chimeric influ virus HA ) . In another specific embodiment, the stem domain enza hemagglutinin polypeptide is the globular head domain of a cH5 / B chimeric influenza hemagglutinin polypeptide is ofA / Anhui/ 1 / 2005 (H5 ) HA ( or the globular head domain of the stem domain of B /Wisconsin / 1 /2010 HA (or the stem an A / Anhui/ 1 / 2005 (H5 ) - like influenza virus HA ) . In domain of an B /Wisconsin / 1 /2010 - like influenza virus HA ) another specific embodiment, the stem domain of a cH5 / B and the globular head domain of the cH5/ B chimeric influ - 60 chimeric influenza hemagglutinin polypeptide is the stem enza hemagglutinin polypeptide is the globular head domain domain of B /Brisbane / 60 /2008 HA (or the stem domain of of A / Indonesia / 5 / 2005 (H5 ) HA ( or the globular head an B /Brisbane /60 / 2008 - like influenza virus HA ) and the domain of an A / Indonesia / 5 /2005 (H5 ) - like influenza virus globular head domain of the cH5/ B chimeric influenza HA ) . In another specific embodiment, the stem domain of a hemagglutinin polypeptide is the globular head domain of CH5/ B chimeric influenza hemagglutinin polypeptide is the 65 A /Bar headed goose/ Quinghai/ 1A / 2005 ( H5) HA ( or the stem domain of B /Wisconsin / 1 / 2010 HA (or the stem globular head domain of an A / Bar headed goose / Quinghai/ domain of an B /Wisconsin / 1 /2010 - like influenza virus HA ) 1A / 2005 (H5 ) - like influenza virus HA ). In another specific US 10 , 137 , 189 B2 15 16 embodiment, the stem domain of a cH5/ B chimeric influ Alberta / 24 /2001 (H7 ) HA ( or the globular head domain of enza hemagglutinin polypeptide is the stem domain of an A /mallard / Alberta /24 /2001 (H7 ) - like influenza virus B /Brisbane / 60 /2008 HA (or the stem domain of an B /Bris - HA ) . In another specific embodiment, the stem domain of a bane /60 /2008 - like influenza virusHA ) and the globular head cH7 /B chimeric influenza hemagglutinin polypeptide is the domain of the cH5 / B chimeric influenza hemagglutinin 5 stem domain of B /Malaysia /2506 /2004 HA ( or the stem polypeptide is the globular head domain of A / turkey / Turkey domain of an B /Malaysia /2506 /2004 - like influenza virus 1 /2005 (H5 ) HA (or the globular head domain of an A / tur - HA ) and the globular head domain of the cH7 / B chimeric key / Turkey/ 1 /2005 (H5 ) - like influenza virus HA ) . In influenza hemagglutinin polypeptide is the globular head another specific embodiment, the stem domain of a cH5 / B domain of A /Rhea /NC /39482 /93 (H7 ) HA ( or the globular chimeric influenza hemagglutinin polypeptide is the stem 10 head domain of an A /Rhea /NC /39482 / 93 (H7 ) - like influenza domain of B /Brisbane /60 / 2008 HA (or the stem domain of virus HA ) . In another specific embodiment, the stem domain an B /Brisbane /60 /2008 - like influenza virus HA ) and the of a cH7 / B chimeric influenza hemagglutinin polypeptide is globular head domain of the cH5 /B chimeric influenza the stem domain of B /Malaysia / 2506 / 2004 HA (or the stem hemagglutinin polypeptide is the globular head domain of domain of an B /Malaysia /2506 /2004 - like influenza virus A / Whooperswan /Mongolia /244 /2005 (H5 ) HA ( or the 15 HA ) and the globular head domain of the cH7 /B chimeric globular head domain of an A /Whooperswan /Mongolia / 244 ) influenza hemagglutinin polypeptide is the globular head 2005 ( H5 ) -like influenza virus HA ) . domain of A /mallard /Massachusetts / 12 / 2000 (H7 ) HA ( or In certain embodiments , a chimeric influenza hemagglu - the globular head domain of an A /mallard /Massachusetts tinin (HA ) polypeptide provided herein comprises ( i) the 12 /2000 (H7 ) - like influenza virus HA ). stem domain of the hemagglutinin from an influenza B virus 20 In another specific embodiment, the stem domain of a and ( ii ) the globular head domain of the hemagglutinin from cH7 / B chimeric influenza hemagglutinin polypeptide is the an influenza virus of the H7 subtype ( sometimes referred to stem domain of B / Florida / 4 / 2006 HA ( or the stem domain of herein as a “ cH7/ B chimeric influenza hemagglutinin poly - an B /Florida / 4 / 2006 - like influenza virus HA ). In another peptide” ). specific embodiment , the stem domain of a cH7 / B chimeric In a specific embodiment, the stem domain of a cH7/ B 25 influenza hemagglutinin polypeptide is the stem domain of chimeric influenza hemagglutinin polypeptide is the stem B / Florida / 4 /2006 HA ( or the stem domain of an B / Florida / domain of B /Malaysia / 2506 / 2004 HA ( or the stem domain 4 / 2006 - like influenza virus HA ) and the globular head of an B /Malaysia / 2506 /2004 - like influenza virus HA ) . In domain of the cH7/ B chimeric influenza hemagglutinin another specific embodiment, the stem domain of a cH7 / B polypeptide is the globular head domain of A /Netherlands / chimeric influenza hemagglutinin polypeptide is the stem 30 219 / 03 (H7 ) HA (or the globular head domain of an A /Neth domain of B /Malaysia /2506 / 2004 HA (or the stem domain erlands /219 /03 (H7 ) - like influenza virus HA ) . In another of an B /Malaysia /2506 /2004 - like influenza virus HA ) and specific embodiment, the stem domain of a cH7/ B chimeric the globular head domain of the cH7/ B chimeric influenza influenza hemagglutinin polypeptide is the stem domain of hemagglutinin polypeptide is the globular head domain of B /Florida / 4 /2006 HA (or the stem domain of an B /Florida / A /Netherlands / 219 /03 (H7 ) HA ( or the globular head 35 4 / 2006 - like influenza virus HA ) and the globular head domain of an A /Netherlands / 219 /03 ( H7) - like influenza domain of the cH7/ B chimeric influenza hemagglutinin virus HA ) . In another specific embodiment, the stem domain polypeptide is the globular head domain of A / Canada / 504 / of a cH7/ B chimeric influenza hemagglutinin polypeptide is 04 (H7 ) HA (or the globular head domain of an A / Canada / the stem domain of B /Malaysia / 2506 / 2004 HA ( or the stem 504 /04 (H7 ) - like influenza virus HA ) . In another specific domain of an B /Malaysia / 2506 / 2004 - like influenza virus 40 embodiment, the stem domain of a cH7 / B chimeric influ HA ) and the globular head domain of the cH7/ B chimeric enza hemagglutinin polypeptide is the stem domain of influenza hemagglutinin polypeptide is the globular head B /Florida / 4 /2006 HA (or the stem domain of an B /Florida / domain of A / Canada /504 /04 (H7 ) HA (or the globular head 4 /2006 - like influenza virus HA ) and the globular head domain of an A / Canada /504 / 04 (H7 ) - like influenza virus domain of the cH7 / B chimeric influenza hemagglutinin HA ). In another specific embodiment, the stem domain of a 45 polypeptide is the globular head domain of A /Canada / 444 / CH7/ B chimeric influenza hemagglutinin polypeptide is the 04 (H7 ) HA (or the globular head domain of an A /Canada / stem domain of B /Malaysia / 2506 / 2004 HA (or the stem 444 / 04 (H7 ) - like influenza virus HA ) . In another specific domain of an B /Malaysia /2506 /2004 - like influenza virus embodiment, the stem domain of a cH7/ B chimeric influ HA ) and the globular head domain of the cH7/ B chimeric enza hemagglutinin polypeptide is the stem domain of influenza hemagglutinin polypeptide is the globular head 50 B / Florida/ 4 /2006 HA (or the stem domain of an B /Florida / domain of A / Canada/ 444 / 04 (H7 ) HA ( or the globular head 4 / 2006 - like influenza virus HA ) and the globular head domain of an A / Canada /444 /04 (H7 ) - like influenza virus domain of the cH7/ B chimeric influenza hemagglutinin HA ) . In another specific embodiment, the stem domain of a polypeptide is the globular head domain of A / chicken / cH7 /B chimeric influenza hemagglutinin polypeptide is the Jalisco /CPA1 / 2012 (H7 ) HA ( or the globular head domain of stem domain of B /Malaysia / 2506 / 2004 HA (or the stem 55 an A / chicken / Jalisco /CPA1 / 2012 (H7 ) - like influenza virus domain of an B /Malaysia /2506 / 2004 - like influenza virus HA ) . In another specific embodiment, the stem domain of a HA ) and the globular head domain of the cH7/ B chimeric CH7/ B chimeric influenza hemagglutinin polypeptide is the influenza hemagglutinin polypeptide is the globular head stem domain of B / Florida/ 4 /2006 HA ( or the stem domain of domain of A / chicken / Jalisco /CPA1 / 2012 (H7 ) HA ( or the an B / Florida / 4 / 2006 -like influenza virus HA ) and the globu globular head domain of an A / chicken / Jalisco /CPA1 / 2012 60 lar head domain of the cH7/ B chimeric influenza hemag (H7 ) - like influenza virus HA ) . In another specific embodi - glutinin polypeptide is the globular head domain of A /mal ment, the stem domain of a cH7 / B chimeric influenza lard / Alberta / 24 / 2001 (H7 ) HA ( or the globular head domain hemagglutinin polypeptide is the stem domain of B /Malay - of an A /mallard / Alberta /24 /2001 (H7 ) - like influenza virus sia / 2506 /2004 HA ( or the stem domain of an B /Malaysia / HA ). In another specific embodiment, the stem domain of a 2506 / 2004 -like influenza virus HA ) and the globular head 65 CH7/ B chimeric influenza hemagglutinin polypeptide is the domain of the cH7 / B chimeric influenza hemagglutinin stem domain of B / Florida/ 4 / 2006 HA (or the stem domain of polypeptide is the globular head domain of A /mallard a n B / Florida / 4 / 2006 - like influenza virus HA ) and the globu US 10 , 137 , 189 B2 17 18 lar head domain of the cH7/ B chimeric influenza hemag - chimeric influenza hemagglutinin polypeptide is the stem glutinin polypeptide is the globular head domain of A /Rhea / domain of B /Wisconsin / 1 / 2010 HA (or the stem domain of NC /39482 /93 (H7 ) HA (or the globular head domain of an an B /Wisconsin / 1 /2010 -like influenza virus HA ) and the A / Rhea /NC /39482 /93 (H7 ) - like influenza virus HA ) . In globular head domain of the cH7/ B chimeric influenza another specific embodiment, the stem domain of a cH7/ B 5 hemagglutinin polypeptide is the globular head domain of chimeric influenza hemagglutinin polypeptide is the stem A /mallard /Massachusetts / 12 / 2000 (H7 ) HA (or the globular domain of B / Florida / 4 / 2006 HA ( or the stem domain of an head domain of an A / mallard /Massachusetts /12 / 2000 ( H7 ) B / Florida / 4 / 2006 - like influenza virus HA ) and the globular like influenza virus HA ) . head domain of the cH7 / B chimeric influenza hemagglutinin In another specific embodiment, the stem domain of a polypeptide is the globular head domain of A /mallard / 10 cH7 / B chimeric influenza hemagglutinin polypeptide is the Massachusetts / 12 / 2000 (H7 ) HA ( or the globular head stem domain of B /Brisbane /60 / 2008 HA ( or the stem domain of an A /mallard /Massachusetts / 12 / 2000 (H7 ) - like domain of an B / Brisbane /60 / 2008 - like influenza virus HA ) . influenza virus HA ). In another specific embodiment, the stem domain of a cH7/ B In another specific embodiment, the stem domain of a chimeric influenza hemagglutinin polypeptide is the stem cH7/ B chimeric influenza hemagglutinin polypeptide is the 15 domain of B /Brisbane /60 /2008 HA ( or the stem domain of stem domain of B /Wisconsin / 1 /2010 HA ( or the stem an B /Brisbane /60 /2008 - like influenza virus HA ) and the domain of an B /Wisconsin / 1 / 2010 - like influenza virus HA ) . globular head domain of the cH7/ B chimeric influenza In another specific embodiment, the stem domain of a cH7 / B hemagglutinin polypeptide is the globular head domain of chimeric influenza hemagglutinin polypeptide is the stem A /Netherlands / 219 /03 (H7 ) HA ( or the globular head domain of B /Wisconsin / 1 / 2010 HA ( or the stem domain of 20 domain of an A /Netherlands / 219 /03 (H7 ) - like influenza an B /Wisconsin / 1 / 2010 - like influenza virus HA ) and the virus HA ). In another specific embodiment, the stem domain globular head domain of the cH7/ B chimeric influenza of a cH7/ B chimeric influenza hemagglutinin polypeptide is hemagglutinin polypeptide is the globular head domain of the stem domain of B /Brisbane / 60 / 2008 HA (or the stem A /Netherlands / 219 /03 (H7 ) HA ( or the globular head domain of an B /Brisbane /60 /2008 - like influenza virus HA ) domain of an A /Netherlands / 219 / 03 (H7 ) - like influenza 25 and the globular head domain of the cH7/ B chimeric influ virus HA ). In another specific embodiment, the stem domain enza hemagglutinin polypeptide is the globular head domain of a cH7/ B chimeric influenza hemagglutinin polypeptide is of A /Canada / 504 /04 (H7 ) HA (or the globular head domain the stem domain of B /Wisconsin / 1 /2010 HA (or the stem of an A /Canada / 504 /04 (H7 )- like influenza virus HA ). In domain of an B / Wisconsin / 1 / 2010 - like influenza virus HA ) another specific embodiment, the stem domain of a cH7 / B and the globular head domain of the cH7 /B chimeric influ - 30 chimeric influenza hemagglutinin polypeptide is the stem enza hemagglutinin polypeptide is the globular head domain domain of B /Brisbane / 60 /2008 HA (or the stem domain of of A /Canada / 504 /04 (H7 ) HA (or the globular head domain an B /Brisbane / 60 /2008 - like influenza virus HA ) and the of an A / Canada/ 504 /04 (H7 ) - like influenza virus HA ). In globular head domain of the cH7/ B chimeric influenza another specific embodiment, the stem domain of a cH7/ B hemagglutinin polypeptide is the globular head domain of chimeric influenza hemagglutinin polypeptide is the stem 35 A / Canada/ 444 /04 (H7 ) HA (or the globular head domain of domain of B /Wisconsin / 1 / 2010 HA (or the stem domain of an A / Canada /444 /04 (H7 ) - like influenza virus HA ) . In an B /Wisconsin / 1 / 2010 - like influenza virus HA ) and the another specific embodiment, the stem domain of a cH7 /B globular head domain of the cH7/ B chimeric influenza chimeric influenza hemagglutinin polypeptide is the stem hemagglutinin polypeptide is the globular head domain of domain of B /Brisbane / 60 /2008 HA (or the stem domain of A / Canada /444 / 04 (H7 ) HA (or the globular head domain of 40 an B / Brisbane/ 60 / 2008 - like influenza virus HA ) and the an A / Canada/ 444 / 04 (H7 ) - like influenza virus HA ). In globular head domain of the cH7/ B chimeric influenza another specific embodiment, the stem domain of a cH7/ B hemagglutinin polypeptide is the globular head domain of chimeric influenza hemagglutinin polypeptide is the stem A / chicken /Jalisco /CPA1 / 2012 (H7 ) HA (or the globular domain of B /Wisconsin / 1 / 2010 HA ( or the stem domain of head domain of an A /chicken / Jalisco /CPA1 / 2012 (H7 ) - like an B /Wisconsin / 1 /2010 - like influenza virus HA ) and the 45 influenza virus HA ) . In another specific embodiment, the globular head domain of the cH7 / B chimeric influenza stem domain of a cH7 / B chimeric influenza hemagglutinin hemagglutinin polypeptide is the globular head domain of polypeptide is the stem domain of B /Brisbane /60 / 2008 HA A /chicken /Jalisco / CPA1/ 2012 (H7 ) HA (or the globular (or the stem domain of an B / Brisbane/ 60 /2008 - like influenza head domain of an A / chicken / Jalisco /CPA1 / 2012 (H7 ) - like virus HA ) and the globular head domain of the cH7 / B influenza virus HA ) . In another specific embodiment, the 50 chimeric influenza hemagglutinin polypeptide is the globu stem domain of a cH7/ B chimeric influenza hemagglutinin lar head domain of A /mallard / Alberta /24 / 2001 (H7 ) HA (or polypeptide is the stem domain of B /Wisconsin / 1 / 2010 HA the globular head domain of an A /mallard / Alberta / 24 / 2001 ( or the stem domain of an B /Wisconsin / 1 /2010 -like influ (H7 ) - like influenza virus HA ) . In another specific embodi enza virus HA ) and the globular head domain of the cH7/ B ment, the stem domain of a cH7/ B chimeric influenza chimeric influenza hemagglutinin polypeptide is the globu - 55 hemagglutinin polypeptide is the stem domain of B /Bris lar head domain of A / mallard / Alberta / 24 /2001 ( H7) HA (or bane /60 / 2008 HA ( or the stem domain of an B / Brisbane /60 / the globular head domain of an A /mallard / Alberta / 24 / 2001 2008 - like influenza virus HA ) and the globular head domain (H7 ) -like influenza virus HA ). In another specific embodi of the cH7/ B chimeric influenza hemagglutinin polypeptide ment, the stem domain of a cH7/ B chimeric influenza is the globular head domain of A /Rhea /NC / 39482 / 93 (H7 ) hemagglutinin polypeptide is the stem domain of B /Wis - 60 HA ( or the globular head domain of an A /Rhea / NC /39482 / consin /1 /2010 HA ( or the stem domain of an B /Wisconsin 93 (H7 ) - like influenza virus HA ) . In another specific 1 /2010 - like influenza virus HA ) and the globular head embodiment, the stem domain of a cH7 / B chimeric influ domain of the cH7/ B chimeric influenza hemagglutinin enza hemagglutinin polypeptide is the stem domain of polypeptide is the globular head domain of A / Rhea /NC B / Brisbane /60 / 2008 HA ( or the stem domain of an B /Bris 39482 / 93 ( H7) HA (or the globular head domain of an 65 bane/ 60 / 2008 - like influenza virus HA ) and the globular head A / Rhea /NC /39482 / 93 (H7 ) - like influenza virus HA ) . In domain of the cH7/ B chimeric influenza hemagglutinin another specific embodiment, the stem domain of a cH7/ B polypeptide is the globular head domain of A /mallard / US 10 , 137 , 189 B2 19 20 Massachusetts / 12 / 2000 (H7 ) HA (or the globular head lar head domain of B / seal/Netherlands / 1 / 99 HA ( or the domain of an A /mallard /Massachusetts / 12 / 2000 (H7 ) - like globular head domain of a B /seal / Netherlands / 1 / 99 - like influenza virus HA ) . influenza virus ). In certain embodiments , a chimeric influenza hemagglu - In another specific embodiment, the stem domain of a tinin (HA ) polypeptide provided herein comprises ( i ) the 5 cB / B chimeric influenza hemagglutinin polypeptide is the stem domain of the hemagglutinin from an influenza B virus stem domain of B /Brisbane /60 / 2008 HA (or the stem and ( ii ) the globular head domain of the hemagglutinin from domain of an B / Brisbane /60 /2008 - like influenza virus HA ) . In another specific embodiment, the stem domain of a cB / B a different influenza B virus strain ( sometimes referred to chimeric influenza hemagglutinin polypeptide is the stem herein as a “ cB / B chimeric influenza hemagglutinin poly 10 domain of B /Brisbane /60 / 2008 HA ( or the stem domain of peptide” ) . an B /Brisbane /60 /2008 - like influenza virus HA ) and the In a specific embodiment, the stem domain of a cB / B globular head domain of the cB / B chimeric influenza chimeric influenza hemagglutinin polypeptide is the stem hemagglutinin polypeptide is the globular head domain of domain of B /Malaysia /2506 / 2004 HA (or the stem domain B /Lee / 1940 HA ( or the globular head domain of a B /Lee ) of an B /Malaysia /2506 /2004 - like influenza virusvirus HA );. In 15 1940 - like influenza virus ). In another specific embodiment, another specific embodiment, the stem domain of a cB / B the stem domain of a cB / B chimeric influenza hemagglutinin chimeric influenza hemagglutinin polypeptide is the stem polypeptide is the stem domain of B / Brisbane /60 / 2008 HA domain of B /Malaysia / 2506 / 2004 HA ( or the stem domain ( or the stem domain of an B /Brisbane /60 /2008 - like influenza of an B /Malaysia / 2506 /2004 - like influenza virus HA ) and virus HA ) and the globular head domain of the cB / B the globular head domain of the cB / B chimeric influenza 20 chimeric influenza hemagglutinin polypeptide is the globu hemagglutinin polypeptide is the globular head domain of lar head domain of B /seal / Netherlands / 1/ 99 HA (or the B / Lee / 1940 HA (or the globular head domain of an B /Leel globular head domain of a B /seal /Netherlands / 1 / 99 - like 1940 - like influenza virus HA ) . In another specific embodi - influenza virus ) . ment, the stem domain of a cB / B chimeric influenza hemag In specific embodiments , the chimeric influenza hemag glutinin polypeptide is the stem domain of B /Malaysia / 25 glutinin polypeptides described herein are soluble , e . g . , are 2506 / 2004 HA (or the stem domain of an B /Malaysia /2506 / soluble in compositions , e . g ., the compositions described 2004 - like influenza virus HA ) and the globular head domain herein . Exemplary methods for generating soluble chimeric of the cB / B chimeric influenza hemagglutinin polypeptide is influenza hemagglutinin polypeptides are described in Sec the globular head domain of B / seal/ Netherlands / 1 /99 HA (or tion 6 .6 . 1 . 2 , infra . the globular head domain of a B / seal/ Netherlands / 1/ 99 - like 30 When designing the foregoing chimeric influenza HA influenza virus ) . polypeptides, care should be taken to maintain the stability In another specific embodiment, the stem domain of a of the resulting protein . In this regard , in certain embodi cB / B chimeric influenza hemagglutinin polypeptide is the ments , it is recommended that for chimeric influenza hemag stem domain of B /Florida / 4 / 2006 HA ( or the stem domain of glutinin polypeptides comprising stem domains from influ an B /Florida / 4 / 2006 -like influenza virus HA ). In another 35 enza A viruses , the cysteine residues identified as Ap and Aq specific embodiment, the stem domain of a cB / B chimeric in FIG . 1 be maintained since they contribute to the stability influenza hemagglutinin polypeptide is the stem domain of of the HA stalk as discussed in more detail in Section 5 . 1 B / Florida / 4 / 2006 HA ( or the stem domain of an B / Florida/ infra . For example , for the best stability , it is preferred to 4 /2006 - like influenza virus HA ) and the globular head “ swap ” the HA globular domain as a whole (between the Ap domain of the cB / B chimeric influenza hemagglutinin poly - 40 and Aq cysteine residues as shown in FIG . 1 ) since the peptide is the globular head domain of B /Lee / 1940 HA ( or resulting conformation would be closest to the native struc the globular head domain of a B /Lee / 1940 - like influenza ture . Similarly , chimeric influenza hemagglutinin polypep virus ) . In another specific embodiment, the stem domain of tides comprising the stem domains of influenza B viruses a cB / B chimeric influenza hemagglutinin polypeptide is the may utilize cysteines present in the globular head domains stem domain of B /Florida / 4 /2006 HA ( or the stem domain of 45 of the influenza A virus from which the globular head an B /Florida / 4 /2006 -like influenza virus HA ) and the globu - domain of the chimeric influenza hemagglutinin polypeptide lar head domain of the cB /B chimeric influenza hemagglu - is obtained (see , e. g ., FIG . 36 ) . tinin polypeptide is the globular head domain of B / seal/ In another aspect, provided herein are immunogenic com Netherlands / 1 / 99 HA (or the globular head domain of a positions ( e . g ., vaccine formulations ) comprising one , two , B / seal/ Netherlands/ 1 / 99 -like influenza virus ) . 50 or more of the chimeric influenza hemagglutinin polypep In another specific embodiment, the stem domain of a tides described herein . In certain embodiments , the immu cB /B chimeric influenza hemagglutinin polypeptide is the nogenic compositions ( e . g . , vaccine formulations ) provided stem domain of B /Wisconsin / 1 / 2010 HA (or the stem herein may comprise chimeric influenza hemagglutinin domain of an B /Wisconsin / 1 / 2010 - like influenza virus HA ) . polypeptide ( s ) described herein , influenza viruses ( e . g . , live In another specific embodiment, the stem domain of a cB / B 55 or killed virus ) that comprise a chimeric influenza hemag chimeric influenza hemagglutinin polypeptide is the stem glutinin polypeptide ( s ) described herein or a genome engi domain of B /Wisconsin / 1 / 2010 HA ( or the stem domain of neered to encode chimeric influenza hemagglutinin poly an B /Wisconsin / 1/ 2010 -like influenza virus HA ) and the peptide (s ) described herein ; or vectors or cells that comprise globular head domain of the cB / B chimeric influenza a chimeric influenza hemagglutinin polypeptide ( s ) described hemagglutinin polypeptide is the globular head domain of 60 herein or a genome engineered to encode chimeric influenza B /Lee / 1940 HA ( or the globular head domain of a B /Leel hemagglutinin polypeptide( s ) described herein . In certain 1940 - like influenza virus ). In another specific embodiment, embodiments , the immunogenic compositions provided the stem domain of a cB / B chimeric influenza hemagglutinin herein may comprise ( i ) a cH5 / 1 chimeric influenza hemag polypeptide is the stem domain of B /Wisconsin / 1 / 2010 HA glutinin polypeptide described herein , a cH5 / 3 chimeric (or the stem domain of an B /Wisconsin / 1 /2010 - like influ - 65 influenza hemagglutinin polypeptide described herein , a enza virus HA ) and the globular head domain of the cB / B cH7/ 3 chimeric influenza hemagglutinin polypeptide chimeric influenza hemagglutinin polypeptide is the globu - described herein , a cH5 /B chimeric influenza hemagglutinin US 10 , 137 , 189 B2 21 22 polypeptide described herein , a cH7/ B chimeric influenza polypeptides. Such " universal” vaccines can be used to hemagglutinin polypeptide described herein , or a cHB / B induce and / or boost cross - protective immune responses chimeric influenza hemagglutinin polypeptide described across influenza virus subtypes. herein ; ( ii) a combination of a cH5/ 1 chimeric influenza In another aspect, provided herein are methods of immu hemagglutinin polypeptide described herein and a cH5 / 3 5 nizing a subject against an influenza virus disease or infec chimeric influenza hemagglutinin polypeptide described tion comprising administering to the subject a composition herein ; or a combination of a cH5 / 1 chimeric influenza comprising one or more of the chimeric influenza hemag hemagglutinin polypeptide described herein and a cH7/ 3 glutinin (HA ) polypeptides described herein or a vaccine chimeric influenza hemagglutinin polypeptide described formulation described herein . In certain embodiments , a herein ; ( iii ) a combination of a cH5 / 1 chimeric influenza 10 subject is primed with a first composition comprising one or hemagglutinin polypeptide described herein and a cH5 / 3 more of the chimeric influenza hemagglutinin (HA ) poly chimeric influenza hemagglutinin polypeptide described peptides described herein or a vaccine formulation described herein and either of a cH5 / B , a cH7/ B , or a cB /B chimeric herein , and later boosted with the same or a different influenza hemagglutinin polypeptide described herein ; or composition ( e .g ., a composition comprising a different (iv ) a combination of a cH5 / 1 chimeric influenza hemag - 15 chimeric influenza hemagglutinin (HA ) polypeptide ; a com glutinin polypeptide described herein and a cH7 / 3 chimeric position comprising the same chimeric influenza hemagglu influenza hemagglutinin polypeptide described herein and tinin (HA ) polypeptide but in a different context ( e . g . , the either of a cH5/ B , a cH7/ B , or a cB / B chimeric influenza first composition comprises a subunit vaccine comprising a hemagglutinin polypeptide described herein . chimeric influenza hemagglutinin (HA ) polypeptide and the In a specific embodiment, provided herein are vaccine 20 different composition comprises a viral vector that com formulations comprising one or more of the chimeric influ - prises the same chimeric influenza hemagglutinin (HA ) enza hemagglutinin polypeptides described herein . In a polypeptide ), or a composition comprising a different chi specific embodiment, provided herein is a monovalent vac meric influenza hemagglutinin (HA ) polypeptide in a dif cine comprising one of the chimeric influenza hemagglutinin ferent context) comprising one or more of the chimeric polypeptides described herein . In another specific embodi- 25 influenza hemagglutinin (HA ) polypeptides described herein ment, provided herein is a bivalent vaccine comprising two or a vaccine formulation described herein . The subject may of the chimeric influenza hemagglutinin polypeptides be boosted once , or more than once with a composition described herein ( i. e ., two distinct chimeric influenza comprising one or more of the chimeric influenza hemag hemagglutinin polypeptides ) . In another specific embodi- glutinin (HA ) polypeptides described herein or a vaccine ment, provided herein is a trivalent vaccine comprising three 30 formulation described herein . In certain embodiments , when of the chimeric influenza hemagglutinin polypeptides the subject is boosted more than once , the first and the described herein ( i. e ., three distinct chimeric influenza second boosts are with different compositions comprising hemagglutinin polypeptides ) . one or more of the chimeric influenza hemagglutinin (HA ) The vaccine formulations provided herein may comprise polypeptides described herein or a vaccine formulation the chimeric influenza hemagglutinin polypeptides 35 described herein , and each boost comprises a different described herein in any form . For example , the vaccine composition than the composition comprising one or more formulations provided herein may comprise subunit vac of the chimeric influenza hemagglutinin (HA ) polypeptides cines comprising one or more of the chimeric influenza described herein or a vaccine formulation described herein hemagglutinin polypeptides described herein ( e. g ., compo - used to prime the subject. sitions comprising chimeric influenza hemagglutinin poly - 40 In a specific embodiment, provided herein is a method of peptides, e. g . , soluble chimeric influenza hemagglutinin immunizing a subject ( e . g . , a human subject) against influ polypeptides ) ; live influenza viruses ( e . g . , live attenuated enza virus comprising administering to the subject a first influenza viruses ) that express one or more of the chimeric dose of an effective amount of a chimeric influenza hemag influenza hemagglutinin polypeptides described herein ; live glutinin (HA ) polypeptide described herein , a vector influenza viruses ( e . g . , live attenuated influenza viruses ) 45 described herein , an immunogenic composition described comprising a genome that encodes one or more of the herein , or a vaccine formulation described herein and admin chimeric influenza hemagglutinin polypeptides described istering to the subject a second dose of an effective amount herein ; killed influenza viruses that comprise one or more of of a chimeric influenza hemagglutinin (HA ) polypeptide the chimeric influenza hemagglutinin polypeptides described herein , a vector described herein , an immunogenic described herein ; killed influenza viruses comprising a 50 composition described herein , or a vaccine formulation genome that encodes one or more of the chimeric influenza described herein 30 days to 6 months after the subject has hemagglutinin polypeptides described herein ; virus/ viral received the first dose , wherein ( i) the chimeric influenza like particles (“ VLPs" ) that contain one or more of the hemagglutinin (HA ) polypeptide or the chimeric influenza chimeric influenza hemagglutinin polypeptides described hemagglutinin (HA ) polypeptide of the vector, the immu herein ; split virus vaccines , wherein said virus expresses one 55 nogenic composition , or vaccine formulation in the first and or more of the chimeric influenza hemagglutinin polypep - second doses are the same or different ( e . g ., the globular tides described herein and /or comprises a genome that head of the chimeric influenza hemagglutinin (HA ) poly encodes one or more of the chimeric influenza hemaggluti - peptide administered in the first dose is different than the the nin polypeptides described herein ; viral expression vectors globular head of the chimeric influenza hemagglutinin (HA ) ( e . g . , non - influenza virus expression vectors ) that express 60 polypeptide administered in the second dose ) ; and/ or ( ii ) the one or more of the chimeric influenza hemagglutinin poly - type of immunogenic composition or vector or vaccine peptides described herein ; and bacterial expression vectors formulation administered in both doses are the same or that express one or more of the chimeric influenza hemag - different. In certain embodiments , the method comprises glutinin polypeptides described herein . administering to the subject a third dose of an effective The vaccine formulations described herein can elicit 65 amount of a chimeric influenza hemagglutinin (HA ) poly highly potent and broadly neutralizing antibodies against the peptide described herein , a vector described herein , an HA stem domain of the chimeric influenza hemagglutinin immunogenic composition described herein , or a vaccine US 10 , 137 , 189 B2 23 24 formulation described herein 30 days to 6 months after the are administered as part of the first, second , and / or third subject has received the second dose , wherein ( i) the chi doses, wherein each chimeric HA polypeptide in a dose is meric influenza hemagglutinin (HA ) polypeptide or the different from each other. In some embodiments , the first , chimeric influenza hemagglutinin (HA ) polypeptide of the second , and / or third dose of the vector , the immunogenic vector , the immunogenic composition , or vaccine formula - 5 composition , or vaccine formulation comprises two , three , tion is the same or different than the chimeric influenza or more chimeric influenza hemagglutinin (HA ) polypep hemagglutinin (HA ) polypeptide in the first and/ or second tides , wherein each chimeric influenza hemagglutinin (HA ) dose ; and ( ii ) the type of immunogenic composition or polypeptide in the vector, the immunogenic composition , or vector or vaccine formulation administered in both doses are vaccine formulation administered in a dose is different from the same or different. In certain embodiments , two , three , or 10 each other ( e . g . , the globular head of the chimeric influenza more chimeric influenza hemagglutinin (HA ) polypeptides hemagglutinin (HA ) polypeptide administered in the first are administered as part of the first , second, and/ or third dose is different than the the globular head of the chimeric doses , wherein each chimeric HA polypeptide in a dose is influenza hemagglutinin (HA ) polypeptide administered in different from each other . In some embodiments , the first , the second dose , etc . ). second , and / or third dose of the vector , the immunogenic 15 In another aspect, provided herein are kits comprising one composition , or vaccine formulation comprises two, three , or more of the chimeric influenza hemagglutinin (HA ) or more chimeric influenza hemagglutinin (HA ) polypep - polypeptides described herein or a vaccine formulation tides, wherein each chimeric influenza hemagglutinin (HA ) described herein . The kits provided herein may further polypeptide in the vector , the immunogenic composition , or comprise one or more additional components , e . g ., an anti vaccine formulation administered in a dose is different from 20 body that specifically binds one or more of the chimeric each other ( e . g ., the globular head of the chimeric influenza influenza hemagglutinin (HA ) polypeptides provided in the hemagglutinin (HA ) polypeptide administered in the first kit. dose is different than the the globular head of the chimeric The working Examples (e . g. , Section 6 , Examples ) dem influenza hemagglutinin (HA ) polypeptide administered in onstrate , inter alia , the production of constructs encoding the second dose , etc .) . 25 chimeric influenza HA polypeptides comprising an HA stem In another specific embodiment, provided herein is a domain and displaying a heterologous HA globular head method of immunizing a 1 -5 year old human subject against domain , and the production of stable chimeric HA polypep influenza virus comprising administering to the subject a tides from these constructs which are cross - reactive with first dose of an effective amount a chimeric influenza hemag - antibodies to both the stem domain and the head domain . glutinin (HA ) polypeptide described herein , a vector 30 The working Examples also illustrate the use of such con described herein , an immunogenic composition described structs in the generation of a protective immune response in herein , or a vaccine formulation described herein and admin subjects against multiple different strains and subtypes of istering to the subject a second dose of an effective amount influenza virus, i . e ., the Examples demonstrate that the of a chimeric influenza hemagglutinin (HA ) polypeptide chimeric influenza HA polypeptides described herein can be described herein , a vector described herein , an immunogenic 35 used as a universal influenza vaccine . composition described herein , or a vaccine formulation 3 . 1 Terminology described herein 30 days to 6 months after the subject has The terms “ about” or “ approximate , " when used in ref received the first dose , wherein ( i ) the chimeric influenza erence to an amino acid position refer to the particular amino hemagglutinin (HA ) polypeptide or the chimeric influenza acid position in a sequence or any amino acid that is within hemagglutinin (HA ) polypeptide of the vector, the immu - 40 five , four , three , two , or one residues of that amino acid nogenic composition , or vaccine formulation in the first and position , either in an N -terminal direction or a C -terminal second doses are the same or different ( e . g ., the globular direction . head of the chimeric influenza hemagglutinin (HA ) poly - As used herein , the term “ about” or “ approximately ” peptide administered in the first dose is different than the the when used in conjunction with a number refers to any globular head of the chimeric influenza hemagglutinin (HA ) 45 number within 1 , 5 or 10 % of the referenced number . In polypeptide administered in the second dose ) ; and / or (ii ) the certain embodiments , the term " about " encompasses the type of immunogenic composition or vector or vaccine exact number recited . formulation administered in both doses are the same or As used herein , the term “ fragment” in the context of a different. In certain embodiments , the method comprises nucleic acid sequence refers to a nucleotide sequence com administering to the subject a third dose of an effective 50 prising a portion of consecutive nucleotides from a parent amount of a chimeric influenza hemagglutinin (HA ) poly - sequence . In a specific embodiment, the term refers to a peptide described herein , a vector described herein , an nucleotide sequence of 5 to 15 , 5 to 25 , 10 to 30 , 15 to 30 , immunogenic composition described herein , or a vaccine 10 to 60 , 25 to 100 , 150 to 300 or more consecutive formulation described herein 30 days to 6 months after the nucleotides from a parent sequence . In another embodiment, subject has received the second dose , wherein ( i ) the chi- 55 the term refers to a nucleotide sequence of at least 5 , 10 , 15 , meric influenza hemagglutinin (HA ) polypeptide or the 20 , 25 , 30 , 35 , 40 , 45 , 50 , 55 , 60 , 65 , 70 , 75 , 80 , 85 , 90 , 95 , chimeric influenza hemagglutinin (HA ) polypeptide of the 100 , 110 , 125 , 150 , 175 , 200 , 250 , 275, 300 , 325 , 350 , 375 , vector, the immunogenic composition , or vaccine formula 400 , 425 , 450 or 475 consecutive nucleotides of a parent tion in the first and second doses are the same or different sequence . ( e . g . , the globular head of the chimeric influenza hemagglu - 60 As used herein , the term “ fragment" in the context of an tinin (HA ) polypeptide administered in the first dose is amino acid sequence refers to an amino acid sequence different than the the globular head of the chimeric influenza comprising a portion of consecutive amino acid residues hemagglutinin (HA ) polypeptide administered in the second from a parent sequence . In a specific embodiment, the term dose ); and /or (ii ) the type of immunogenic composition or refers to an amino acid sequence of 2 to 30 , 5 to 30 , 10 to vector or vaccine formulation administered in both doses are 65 60 , 25 to 100 , 150 to 300 or more consecutive amino acid the same or different . In certain embodiments , two, three , or residues from a parent sequence . In another embodiment , the more chimeric influenza hemagglutinin (HA ) polypeptides term refers to an amino acid sequence of at least 5 , 10 , 15 , US 10 , 137 ,189 B2 25 26 20 , 25, 30 , 35 , 40 , 45 , 50 , 55 , 60 , 65 , 70 , 75 , 80 , 85 , 90 , 95 , 3 to 7 logs , 3 to 8 logs, 3 to 9 logs, 4 to 6 logs , 4 to 8 logs, 100 , 110 , 125 , 150 , 175 , or 200 consecutive amino acid 4 to 9 logs, 5 to 6 logs, 5 to 7 logs , 5 to 8 logs, 5 to 9 logs, residues of a parent sequence . 6 to 7 logs , 6 to 8 logs , 6 to 9 logs , 7 to 8 logs , 7 to 9 logs , As used herein , the terms “ disease” and “ disorder ” are or 8 to 9 logs. Benefits of a reduction in the titer, number or used interchangeably to refer to a condition in a subject . In 5 total burden of influenza virus include , but are not limited to , specific embodiments, a term “ disease ” refers to the patho - less severe symptoms of the infection , fewer symptoms of logical state resulting from the presence of the virus in a cell the infection and a reduction in the length of the disease or a subject , or by the invasion of a cell or subject by the associated with the infection . virus. In certain embodiments , the condition is a disease in “ Hemagglutinin ” and “ HA ” refer to any hemagglutinin a subject, the severity of which is decreased by inducing an 10 known to those of skill in the art. In certain embodiments , immune response in the subject through the administration the hemagglutinin is influenza hemagglutinin , such as an of an immunogenic composition . influenza A hemagglutinin , an influenza B hemagglutinin , or As used herein , the term " effective amount” in the context an influenza Chemagglutinin . A typical hemagglutinin of administering a therapy to a subject refers to the amount comprises domains known to those of skill in the art of a therapy which has a prophylactic and /or therapeutic 15 including a signal peptide (optional herein ), a stem domain , effect ( s ) . In certain embodiments , an “ effective amount” in a globular head domain , a luminal domain (optional herein ) , the context of administration of a therapy to a subject refers a transmembrane domain (optional herein ) and a cytoplas to the amount of a therapy which is sufficient to achieve one , mic domain (optional herein ) . In certain embodiments, a two, three , four, or more of the following effects : ( i ) reduce hemagglutinin consists of a single polypeptide chain , such or ameliorate the severity of an influenza virus infection , 20 as HAO . In certain embodiments , a hemagglutinin consists disease or symptom associated therewith ; ( ii ) reduce the of more than one polypeptide chain in quaternary associa duration of an influenza virus infection , disease or symptom tion , e . g . HA1 and HA2. Those of skill in the art will associated therewith ; (iii ) prevent the progression of an recognize that an immature HAO might be cleaved to release influenza virus infection , disease or symptom associated a signal peptide ( approximately 20 amino acids ) yielding a therewith ; ( iv ) cause regression of an influenza virus infec - 25 mature hemagglutinin HAO . A hemagglutinin HAO might be tion , disease or symptom associated therewith ; (v ) prevent cleaved at another site to yield HA1 polypeptide (approxi the development or onset of an influenza virus infection , mately 320 amino acids , including the globular head domain disease or symptom associated therewith ; (vi ) prevent the and a portion of the stem domain ) and HA2 polypeptide recurrence of an influenza virus infection , disease or symp - (approximately 220 amino acids, including the remainder of tom associated therewith ; ( vii ) reduce or prevent the spread 30 the stem domain , a luminal domain , a transmembrane of an influenza virus from one cell to another cell , one tissue domain and a cytoplasmic domain ) . In certain embodiments , to another tissue, or one organ to another organ ; ( ix ) prevent a hemagglutinin comprises a signal peptide , a transmem or reduce the spread of an influenza virus from one subject brane domain and a cytoplasmic domain . In certain embodi to another subject; ( x ) reduce organ failure associated with ments , a hemagglutinin lacks a signal peptide, i. e . the an influenza virus infection ; ( xi) reduce hospitalization of a 35 hemagglutinin is a mature hemagglutinin . In certain embodi subject; (xii ) reduce hospitalization length ; (xiii ) increase ments , a hemagglutinin lacks a transmembrane domain or the survival of a subject with an influenza virus infection or cytoplasmic domain , or both . As used herein , the terms disease associated therewith ; (xiv ) eliminate an influenza “ hemagglutinin " and " HA " encompass hemagglutinin poly virus infection or disease associated therewith ; (xv ) inhibit peptides that are modified by post- translational processing or reduce influenza virus replication ; (xvi ) inhibit or reduce 40 such as signal peptide cleavage , disulfide bond formation , the entry of an influenza virus into a host cell ( s ) ; (xviii ) glycosylation ( e . g . , N - linked glycosylation ), protease cleav inhibit or reduce replication of the influenza virus genome; age and lipid modification ( e . g . S - palmitoylation ) . (xix ) inhibit or reduce synthesis of influenza virus proteins; As used herein , the terms " chimeric influenza virus (xx ) inhibit or reduce assembly of influenza virus particles; hemagglutinin polypeptide, " " chimeric influenza virus HA ( xxi) inhibit or reduce release of influenza virus particles 45 polypeptide , " " chimeric hemagglutinin polypeptide” and from a host cell( s ) ; (xxii ) reduce influenza virus titer ; and / or " chimeric influenza hemagglutinin polypeptide ” refer to an ( xxiii ) enhance or improve the prophylactic or therapeutic influenza hemagglutinin that comprises an influenza virus effect ( s ) of another therapy . hemagglutinin stem domain and an influenza virus hemag In certain embodiments , the effective amount does not glutinin globular head domain , wherein the influenza virus result in complete protection from an influenza virus dis - 50 hemagglutinin head domain is heterologous to the influenza ease, but results in a lower titer or reduced number of virus hemagglutinin stem domain ( i. e ., the globular head influenza viruses compared to an untreated subject. In cer - domain of the chimeric influenza virus hemagglutinin poly tain embodiments , the effective amount results in a 0 . 5 fold , peptide is from a different strain or subtype of influenza 1 fold , 2 fold , 4 fold , 6 fold , 8 fold , 10 fold , 15 fold , 20 fold , virus than the stem domain of the chimeric influenza virus 25 fold , 50 fold , 75 fold , 100 fold , 125 fold , 150 fold , 175 55 hemagglutinin polypeptide ) . fold , 200 fold , 300 fold , 400 fold , 500 fold , 750 fold , or “HAI N -terminal stem segment ” refers to a polypeptide 1, 000 fold or greater reduction in titer of influenza virus segment that corresponds to the amino - terminal portion of relative to an untreated subject. In some embodiments , the the stem domain of an influenza hemagglutinin HA1 poly effective amount results in a reduction in titer of influenza peptide . In certain embodiments , an HA1 N - terminal stem virus relative to an untreated subject of approximately 1 log 60 segment consists of amino acid residues corresponding or more , approximately 2 logs or more, approximately 3 logs approximately to amino acids HA1N - term through A , of an or more , approximately 4 logs or more , approximately 5 logs HA1 domain . HA1N - term is the N - terminal amino acid of or more , approximately 6 logs or more , approximately 7 logs HA1 as recognized by those of skill in the art . A , is the or more , approximately 8 logs or more , approximately 9 logs cysteine residue in the HA1 N - terminal stem segment that or more , approximately 10 logs or more , 1 to 3 logs, 1 to 5 65 forms or is capable of forming a disulfide bond with a logs , 1 to 8 logs , 1 to 9 logs , 2 to 10 logs , 2 to 5 logs , 2 to cysteine residue in an HA1 C - terminal stem segment. Resi 7 logs, 2 logs to 8 logs, 2 to 9 logs, 2 to 10 logs 3 to 5 logs, due A , is identified in influenza A hemagglutinin polypep US 10 , 137 ,189 B2 27 28 tides in FIG . 1 . Exemplary HA1 N - terminal stem segments the term “ in combination ” does not restrict the order in are described herein . In certain embodiments , an HA1 which therapies are administered to a subject. For example , N - terminal stem segment consists of amino acid residues a first therapy ( e . g ., a first prophylactic or therapeutic agent ) corresponding approximately to amino acids 1 - 52 of HA1 can be administered prior to (e . g ., 5 minutes, 15 minutes, 30 from an H3 hemagglutinin . Note that , in this numbering 5 minutes , 45 minutes , 1 hour, 2 hours , 4 hours , 6 hours , 12 system , 1 refers to the N - terminal amino acid of the mature hours , 16 hours , 24 hours , 48 hours , 72 hours , 96 hours , 1 HAO protein , from which the signal peptide has been week , 2 weeks , 3 weeks, 4 weeks, 5 weeks , 6 weeks, 8 removed . Those of skill in the art will readily be able weeks, or 12 weeks before ), concomitantly with , or subse recognize the amino acid residues that correspond to the quent to ( e . g . , 5 minutes, 15 minutes, 30 minutes, 45 HA1 N - terminal stem segment of other influenza HA poly - 10 minutes , 1 hour, 2 hours , 4 hours, 6 hours , 12 hours , 16 peptides , e . g ., the amino acid residues that correspond to the hours, 24 hours , 48 hours , 72 hours , 96 hours , 1 week , 2 HA1 N - terminal stem segment of HA1 from an H1 hemag - weeks , 3 weeks , 4 weeks, 5 weeks, 6 weeks , 8 weeks, or 12 glutinin (see , e . g ., FIG . 1 ) . weeks after) the administration of a second therapy to a “ HA1 C - terminal stem segment” refers to a polypeptide subject. segment that corresponds to the carboxy - terminal portion of 15 As used herein , the term " infection ” means the invasion the stem domain of an influenza hemagglutinin HA1 poly - by , multiplication and / or presence of a virus in a cell or a peptide . In certain embodiments , an HA1 C -terminal stem subject. In one embodiment, an infection is an " active " segment consists of amino acid residues corresponding infection , i . e . , one in which the virus is replicating in a cell approximately to amino acids A , through HA1C -term of an or a subject. Such an infection is characterized by the spread HA1 domain . HA1C- term is the C - terminal amino acid of the 20 of the virus to other cells , tissues , and / or organs, from the HA1 domain as recognized by those of skill in the art. cells , tissues , and / or organs initially infected by the virus . An Residue A , is identified in influenza A hemagglutinin poly - infection may also be a latent infection , i. e . , one in which the peptides in FIG . 1 . Exemplary HAI C - terminal stem seg virus is not replicating . ments are described herein . In certain embodiments , an HA1 As used herein , the term “ influenza virus disease ” refers C - terminal stem segment consists of amino acid residues 25 to the pathological state resulting from the presence of an corresponding approximately to amino acids 277 - 329 of influenza virus ( e . g . , influenza A or B virus ) in a cell or HA1 from an H3 hemagglutinin . Note that, in this number - subject or the invasion of a cell or subject by an influenza ing system , 1 refers to the N - terminal amino acid of the virus . In specific embodiments , the term refers to a respira mature HAO protein , from which the signal peptide has been tory illness caused by an influenza virus. removed . Those of skill in the art will readily be able 30 As used herein , the phrases “ IFN deficient system " or recognize the amino acid residues that correspond to the “ IFN -deficient substrate ” refer to systems, e . g . , cells , cell HA1 C - terminal stem segment of other influenza HA poly - lines and animals , such as pigs, mice , chickens, turkeys, peptides , e . g ., the amino acid residues that correspond to the rabbits , rats , etc ., which do not produce IFN or produce low HA1 C - terminal stem segment of HA1 from an H1 hemag - levels of IFN ( i . e . , a reduction in IFN expression of 5 - 10 % , glutinin ( see , e . g ., FIG . 1 ) . 35 10 - 20 % , 20 - 30 % , 30 - 40 % , 40 -50 % , 50 -60 % , 60 - 70 % , “ HA2” refers to a polypeptide domain that corresponds to 70 - 80 % , 80 - 90 % or more when compared to IFN -competent the HA2 domain of an influenza hemagglutinin polypeptide systems under the same conditions ), do not respond or known to those of skill in the art . In certain embodiments , an respond less efficiently to IFN , and / or are deficient in the HA2 consists of a stem domain , a luminal domain , a activity of one or more antiviral genes induced by IFN . transmembrane domain and a cytoplasmic domain ( see , e . g ., 40 As used herein , the term " like , " when used in the context Scheiffle et al ., 2007 , EMBO J. 16 ( 18 ) :5501 -5508 , the of an “ influenza - like virus ,” refers an influenza virus that contents of which are incorporated by reference in their represents a different isolate of the referenced influenza entirety ) . In certain embodiments , an HA2 consists of a stem virus , wherein the amino acid sequence of said different domain , a luminal domain and a transmembrane domain . In isolate , or of the amino acid sequence of the HA of said certain embodiments , an HA2 consists of a stem domain and 45 different isolate , is identical to , or nearly identical to , the a luminal domain ; in such embodiments , the HA2 might be amino acid sequence of the referenced influenza virus or the soluble. In certain embodiments , an HA2 consists of a stem amino acid sequence of the HA of the referenced influenza domain ; in such embodiments , the HA2 might be soluble . virus ; and / or the immune response against said different As used herein , the term “ heterologous ” in the context of isolate confers full protection against the referenced influ a polypeptide, nucleic acid or virus refers to a polypeptide , 50 enza virus , and vice versa . In certain embodiments , an nucleic acid or virus , respectively, that is not normally found influenza virus isolate that has an amino acid sequence that in nature or not normally associated in nature with a poly - is nearly identical to the amino acid sequence of a referenced peptide , nucleic acid or virus of interest. For example , a influenza virus has an amino acid sequence that is at least " heterologous polypeptide” may refer to a polypeptide 90 % , 91 % 92 % , 93 % , 94 % , 95 % , 96 % , 97 % , 98 % , 99 % , or derived from a different virus, e . g ., a different influenza 55 99. 5 % identical to the amino acid sequence of the referenced strain or subtype, or an unrelated virus or different species. influenza virus. In certain embodiments , an influenza virus In specific embodiments , when used in the context of a isolate that represents an " influenza - like virus ” comprises an globular head domain of a chimeric influenza virus hemag - HA that has an amino acid sequence that is nearly identical glutinin described herein , the term heterologous refers to an to the amino acid sequence of the HA of a referenced influenza HA globular head domain that is associated with 60 influenza virus , e . g . , the HA of the influenza -like virus has an influenza HA stem domain that it would not normally be an amino acid sequence that is at least 90 % , 91 % , 92 % , found associated with ( e . g . , the head and stem domains of 93 % , 94 % , 95 % , 96 % , 97 % , 98 % , 99 % , or 99 . 5 % identical the HA would not be found together in nature ). to the amino acid sequence of the HA of the referenced As used herein , the term " in combination , ” in the context influenza virus . of the administration of two or more therapies to a subject , 65 As used herein , the numeric term “ log” refers to logio . refers to the use of more than one therapy ( e . g . , more than As used herein , the phrase “ majority of the population is one prophylactic agent and /or therapeutic agent ). The use of naive to ,” in reference to a strain or subtype (e . g ., an H1 US 10 , 137 , 189 B2 29 30 subtype ) of influenza virus, refers to a strain or subtype of peptide, an influenza hemagglutinin head domain polypep influenza virus that greater than 50 % of the human popula tide , and / or a chimeric influenza hemagglutinin polypeptide tion has presumably not been exposed to . In specific is isolated . embodiments , the phrase " majority of the population is As used herein , the terms “ replication ,” “ viral replication ” naive to , ” refers to a strain or subtype of influenza virus that 5 and “ virus replication ” in the context of a virus refer to one at least 60 % , 70 % , 75 % , 80 % , 85 % , 90 % , 95 % , or 99 % f the or more , or all of the stages of a viral life cycle which result human population has presumably not been exposed to . in the propagation of virus. The steps of a viral life cycle As used herein , the phrase " multiplicity of infection ” or “ MOI” is the average number of infectious virus particles include, but are not limited to , virus attachment to the host per infected cell . The MOI is determined by dividing the 10 cell surface , penetration or entry of the host cell ( e . g . , number of infectious virus particles added (ml addedxPFU / through receptor mediated endocytosis or membrane ml) by the number of cells added (ml addedxcells /ml ) . fusion ), uncoating ( the process whereby the viral capsid is As used herein , the term “ nucleic acid ” is intended to removed and degraded by viral enzymes or host enzymes include DNA molecules ( e . g . , cDNA or genomic DNA ) and thus releasing the viral genomic nucleic acid ) , genome RNA molecules (eg , mRNA ) and analogs of the DNA or 15 replication , synthesis of viral messenger RNA (mRNA ), RNA generated using nucleotide analogs . The nucleic acid viral protein synthesis , and assembly of viral ribonucleop can be single - stranded or double - stranded . rotein complexes for genome replication , assembly of virus As used herein , the term “ polypeptide” refers to a polymer particles , post -translational modification of the viral pro of amino acids linked by amide bonds as is known to those teins, and release from the host cell by lysis or budding and of skill in the art. As used herein , the term polypeptide can 20 acquisition of a phospholipid envelope which contains refer to a single polypeptide chain linked by covalent amide embedded viral glycoproteins . In some embodiments , the bonds. The term can also refer to multiple polypeptide terms “ replication , " " viral replication ” and “ virus replica chains associated by non - covalent interactions such as ionic tion ” refer to the replication of the viral genome. In other contacts , hydrogen bonds, Van der Waals contacts and embodiments , the terms “ replication , " " viral replication ” hydrophobic contacts . Those of skill in the art will recognize 25 and “ virus replication ” refer to the synthesis of viral pro that the term includes polypeptides that have been modified , teins. for example by post- translational processing such as signal As used herein , the terms “ stem domain polypeptide, ” peptide cleavage , disulfide bond formation , glycosylation “ HA stem domain ,” “ influenza virus hemagglutinin stem ( e . g . , N - linked glycosylation ) , protease cleavage and lipid domain polypeptide" and " HA stalk domain ” refer to poly modification ( e .g . S -palmitoylation ) . 30 peptide comprising or consisting of one or more polypeptide As used herein , the terms " prevent, " " preventing ” and chains that make up a stem domain of an influenza hemag " prevention " in the context of the administration of a glutinin . A stem domain polypeptide might be a single therapy (ies ) to a subject to prevent an influenza virus disease polypeptide chain , two polypeptide chains or more polypep refer to one or more of the prophylactic /beneficial effects tide chains . Typically , a stem domain polypeptide is a single resulting from the administration of a therapy or a combi- 35 polypeptide chain (i .e . corresponding to the stem domain of nation of therapies . In a specific embodiment, the terms a hemagglutinin HAO polypeptide ) or two polypeptide " prevent, " " preventing ” and “ prevention ” in the context of chains ( i. e . corresponding to the stem domain of a hemag the administration of a therapy ( ies ) to a subject to prevent an glutinin HA1 polypeptide in association with a hemagglu influenza virus disease refer to one or more of the following tinin HA2 polypeptide ). In specific embodiments , a stem effects resulting from the administration of a therapy or a 40 domain polypeptide is derived from an influenza AH1 or H3 combination of therapies : ( i ) the inhibition of the develop influenza virus hemagglutinin , or an influenza B influenza ment or onset of an influenza virus disease or a symptom virus hemagglutinin . thereof; ( ii ) the inhibition of the recurrence of an influenza As used herein , the terms “ influenza virus hemagglutinin virus disease or a symptom associated therewith ; and ( iii ) head domain polypeptide , " " influenza virus hemagglutinin the reduction or inhibition in influenza virus infection and / or 45 head domain , ” “ HA globular head domain , " and “ HA head replication . domain ” refer to the globular head domain of an influenza As used herein , the terms " purified ” and “ isolated ” when hemagglutinin polypeptide . For example , for influenza A used in the context of a polypeptide ( including an antibody ) virus , the globular head domain is generally understood to that is obtained from a natural source , e . g . , cells , refers to a be present between two key cysteine residues in the HA1 polypeptide which is substantially free of contaminating 50 portion of the HA molecule . These cysteine residues are materials from the natural source , e. g . , soil particles , min - identified as “ Ap ” and “ Aq” in FIG . 1 for various influenza erals , chemicals from the environment , and/ or cellular mate A viruses. rials from the natural source, such as but not limited to cell As used herein , the terms “ subject” or “ patient” are used debris, cell wall materials , membranes , organelles, the bulk interchangeably to refer to an animal ( e . g ., birds, reptiles, of the nucleic acids , carbohydrates , proteins , and / or lipids 55 and mammals ) . In a specific embodiment, a subject is a bird . present in cells . Thus, a polypeptide that is isolated includes In another embodiment, a subject is a mammal including a preparations of a polypeptide having less than about 30 % , non - primate ( e . g . , a camel, donkey, zebra, cow , pig , horse , 20 % , 10 % , 5 % , 2 % , or 1 % (by dry weight ) of cellular goat, sheep , cat, dog , rat , and mouse ) and a primate ( e . g . , a materials and / or contaminating materials . As used herein , monkey, chimpanzee , and a human ) . In certain embodi the terms " purified ” and “ isolated ” when used in the context 60 ments , a subject is a non - human animal. In some embodi of a polypeptide ( including an antibody ) that is chemically ments , a subject is a farm animal or pet . In another embodi synthesized refers to a polypeptide which is substantially ment, a subject is a human . In another embodiment, a subject free of chemical precursors or other chemicals which are is a human infant. In another embodiment, a subject is a involved in the syntheses of the polypeptide . In a specific human child . In another embodiment, a subject is a human embodiment, a chimeric influenza hemagglutinin (HA ) 65 adult . In another embodiment, a subject is an elderly human . polypeptide is chemically synthesized . In another specific In another embodiment, a subject is a premature human embodiment, an influenza hemagglutinin stem domain poly infant. US 10 , 137 , 189 B2 31 32 As used herein , the term “ premature human infant” refers thesis of influenza virus proteins; (xv ) the inhibition or to a human infant born at less than 37 weeks of gestational reduction in the release of influenza virus particles from a age . host cell ( s ) ; and / or ( xvi) the enhancement or improvement As used herein , the term “ human infant” refers to a the therapeutic effect of another therapy . newborn to 1 year old human . As used herein , in some embodiments , the phrase " wild As used herein , the term “ human child ” refers to a human type” in the context of a virus refers to the types of a virus that is 1 year to 18 years old . that are prevalent, circulating naturally and producing typi As used herein , the term “ human adult” refers to a human cal outbreaks of disease . In other embodiments , the term that is 18 years or older. " wild - type” in the context of a virus refers to a parental As used herein , the term " elderly human ” refers to a 10 virus. human 65 years or older . As used herein , the term “ seasonal influenza virus strain ” 4 . BRIEF DESCRIPTION OF THE DRAWINGS refers to a strain of influenza virus to which a subject population is exposed to on a seasonal basis . In specific FIG . 1A , FIG . 1B , and FIG . 1C present a sequence embodiments , the term seasonal influenza virus strain refers 15 alignment by CLUSTALW of representative sequences of 17 to a strain of influenza A virus . In specific embodiments , the subtypes of influenza virus A hemagglutinin (SEQ ID NOS : term seasonal influenza virus strain refers to a strain of 1 - 16 and 35 , respectively ) . The residue designated A , is the influenza virus that belongs to the H1 or the H3 subtype , i . e . , cysteine residue in the HA1 N - terminal stem segment that the two subtypes that presently persist in the human subject forms or is capable of forming a disulfide bond with the population . In other embodiments , the term seasonal influ - 20 residue designated Ag, a cysteine residue in an HA1 C - ter enza virus strain refers to a strain of influenza B virus . minal stem segment . The residue designated B , represents As used herein , the terms " therapies ” and “ therapy" can the approximate N - terminal amino acid of the HA1 C - ter refer to any protocol( s ), method ( s ) , compound ( s ) , composi- minal short stem segments described herein . The residue tion ( s ), formulation ( s ) , and / or agent( s ) that can be used in designated C , represents the approximate N - terminal amino the prevention or treatment of a viral infection or a disease 25 acid of the HA1 C - terminal long stem segments described or symptom associated therewith . In certain embodiments , herein . The residue designated Cy represents the approxi the terms “ therapies ” and “ therapy ” refer to biological mate C -terminal amino acid of the HA1 N -terminal long therapy , supportive therapy , and / or other therapies useful in stem segments described herein . treatment or prevention of a viral infection or a disease or FIG . 2 provides a schematic of chimeric HAs with a symptom associated therewith known to one of skill in the 30 conserved H1 stalk domain and different globular head art. In some embodiments , the term “ therapy ” refers to ( i ) a domains from distinct subtype HAS . nucleic acid encoding a chimeric influenza hemagglutinin FIG . 3A and FIG . 3B provide a novel influenza vaccine (HA ) polypeptide, ( ii ) a chimeric influenza hemagglutinin and diagnostic tool platform to induce and analyze antibod (HA ) polypeptide, or ( iii ) a vector or composition compris - ies and reactive sera . FIG . 3A : Expression of chimeric HAs . ing a nucleic acid encoding a chimeric influenza hemagglu - 35 Chimeric HAs consisting of the stalk domain of A / PR8/ 34 tinin (HA ) polypeptide or comprising a chimeric influenza HA and the globular head domain of A / California / 4 /09 hemagglutinin (HA ) polypeptide. In some embodiments , the (chimeric HA ) as well as wild type HAS ( PR8- HA and term “ therapy ” refers to an antibody that specifically binds CALO9 -HA ) and a GFP control were expressed in 293T to a chimeric influenza virus hemagglutinin polypeptide. cells . The upper Western blot was probed with a PRS As used herein , the terms “ treat, ” “ treatment, ” and “ treat - 40 specific antibody (PY102 ) whereas the blot on the lower side ing ” refer in the context of administration of a therapy ( ies ) was probed with an antibody specific for Cal09 ( 39C2 ). FIG . to a subject to treat an influenza virus disease or infection to 3B : Schematic drawing of HA constructs expressed in A . obtain a beneficial or therapeutic effect of a therapy or a The chimeric HA is composed of the A / PR / 8 / 34 HA stalk combination of therapies. In specific embodiments , such domain and the 2009 A / California /04 /09 globular head terms refer to one , two , three , four, five or more of the 45 domain . following effects resulting from the administration of a FIG . 4A and FIG . 4B provide a schematic of chimeric therapy or a combination of therapies : ( i) the reduction or HAS . FIG . 4A : Basic structure of a chimeric HA . The amelioration of the severity of an influenza virus infection or globular head can be exchanged conveniently at disulfide a disease or a symptom associated therewith ; ( ii ) the reduc - bond Cys 52 - Cys 277 . FIG . 4B : Prime - boost regime with tion in the duration of an influenza virus infection or a 50 sequential administration of chimeric HAS consisting of a disease or a symptom associated therewith ; ( iii ) the regres - completely conserved stalk domain and a varying globular sion of an influenza virus infection or a disease or a head domain . symptom associated therewith ; ( iv ) the reduction of the titer FIG . 5 describes generation of a chimeric HA with the of an influenza virus; ( v ) the reduction in organ failure stalk of an H1 HA and the globular head of an H3 HA . A associated with an influenza virus infection or a disease 55 chimeric HA consisting of the stalk domain of A / PR8/ 34 HA associated therewith ; ( vi) the reduction in hospitalization of and the globular head domain of HK /68 (chimeric H3 ) as a subject; ( vii ) the reduction in hospitalization length ; (viii ) well as wild type HAS (PRS -HA and HK68 HA ) were the increase in the survival of a subject; ( ix ) the elimination expressed in 293T cells . The upper Western blot was probed of an influenza virus infection or a disease or symptom with a PR8 -specific antibody whereas the blot on the lower associated therewith ; ( x ) the inhibition of the progression of 60 side was probed with an antibody specific for H3 . an influenza virus infection or a disease or a symptom FIG . 6 depicts a sequence comparison of the hemagglu associated therewith ; ( xi) the prevention of the spread of an tinin protein sequences of A /Hong Kong/ 1 / 1968 (H3 ) , influenza virus from a cell, tissue , organ or subject to another A / Perth / 16 / 2009 (H3 ) , A / PR /8 / 34 (H1 ) , A / Cal/ 4 /09 (H1 ) , cell, tissue, organ or subject; (xii ) the inhibition or reduction A /Viet Nam / 1203/ 04 (H5 ) , and A /mallard / Alberta / 24 /01 in the entry of an influenza virus into a host cell( s ) ; ( xiii) the 65 (H7 ) . The Cys52 and Cys277 amino acid residues are inhibition or reduction in the replication of an influenza specified ( based on H3 numbering ) . The black shade indi virus genome; (xiv ) the inhibition or reduction in the syn - cates conserved amino acids. The black wavy line represents US 10 , 137 , 189 B2 33 34 the globular head region of HAs. The starting points of HA1 infection immuno - stained to reveal plaque phenotype using and HA2 are indicated . Amino acid sequences from the the antibody against A /NP (HT103 ) . N - terminus to Cys52 of the HA of each of A /Hong Kong FIG . 11A , FIG . 11B , FIG . 11C , FIG . 11D , FIG . 11E , and 1 / 1968 (H3 ) , A /Perth / 16 / 2009 (H3 ) , A / PR / 8 / 34 (H1 ) , A /Cal / FIG . 11F depict an immunofluorescence analysis of cells 4 /09 (H1 ) , A / Viet Nam / 1203 / 04 (H5 ) , and A /mallard / Al- 5 transfected with chimeric H6 hemagglutinin . 293T cells berta /24 /01 (H7 ) are presented , and correspond to SEQ ID were transfected with 1 ug of PCAGGS plasmid expressing NOs. 23 - 28 , respectively . Amino acid sequences from chimeric H6 hemagglutinin . Sera from animals that received Cys277 of the HA of each of A /Hong Kong / 1 / 1968 (H3 ) , DNA (FIG . 11A ), Cal/ 09 infection (FIG . 11B ) , DNA and A /Perth / 16 / 2009 (H3 ) , A / PR / 8 / 34 (H1 ) , A / Cal/ 4 /09 (H1 ) , Cal/ 09 infection (FIG . 11C ) , or Cal/ 09 split vaccine (FIG . A / Viet Nam / 1203 / 04 (H5 ) , and A /mallard / Alberta /24 /01 10 11D ) were added to transfected cells and visualized by (H7 ) to the C - terminus are presented , and correspond to fluorescence microscopy following incubation with an SEQ ID NOs . 29 -37 , respectively . Alexa Fluor 594 - conjugated anti- mouse IgG . As controls , FIG . 7A and FIG . 7B depict a schematic of chimeric the cross - reactive H1 stem antibody C179 (FIG . 11E ) or the hemagglutinins . FIG . 7A : Construction diagram of the chi- antibody PY102 ( FIG . 11F ) directed against the globular meric PR8 - cH1 HA . The chimeric HA was constructed by 15 head of PR8 were added to transfected cells and visualized swapping the globular head domain located between Cys52 by fluorescence microscopy followed by incubation with an and Cys277 of A /PR / 8 / 34 (H1 ) HA with that of the A / Cali - Alexa Fluor 594 - conjugated anti -mouse IgG . fornia / 4 /09 ( H1 ) HA . The resulting chimeric HA has the stalk FIG . 12 demonstrates that DNA prime and chimeric virus region of A /PR8 / 34 (H1 ) HA with a globular head domain boost confer protection to animals challenged with lethal of the A / California / 4 / 09 (H1 ) HA designated as PRS - CH1. 20 influenza virus challenge . Animals were either treated with FIG . 7B : Schematic of the folded structures of the different DNA alone, chimeric H9 virus alone , DNA prime and wild type and chimeric HAs, such as wild the type PR8 HA , chimeric H9 virus boost, or with inactivated PR8 virus. Mice the chimeric PR8 - cH1 HA , the chimeric PR8 -cH5 HA , the were then challenged with 5x104PFU of PR8 virus, instilled wild type Perth HA , and the chimeric Perth - CH7 HA ( from intranasally , and the weight of the animals was monitored left to right) . The full -length HA structures were down - 25 for 14 days. loaded from the Protein Database (PDB ) : PRS HA (PDB ID FIG . 13 demonstrates reactivity of stalk specific antibod 1RU7) and Perth HA ( represented by HK68 HA , PDB ID ies to cH6 protein as determined by ELISA . 1MQN ). Final images were generated with PyMol (Delano FIG . 14A and FIG . 14B depict a schematic representation Scientific ). of chimeric HA ( CHA ) proteins (FIG . 14A ) and CHA expres FIG . 8A and FIG . 8B depict the surface expression and 30 sion in MDCK cells ( FIG . 14B ) . Chimeric HA ( CHA ) functional analysis of chimeric HA constructs . FIG . 8A : proteins and recombinant chimeric virus. FIG . 14A : Sche Surface expression of chimeric HA constructs was evaluated matic representation of cHAs. The globular head domain is in transiently transfected cells . At 24 h post -transfection , defined as the intervening amino acid sequence between 293T cells were trypsinized and cell surface expression of residues C52 and C277 (H3 numbering ) . Using this disulfide chimeric HA proteins were analyzed by flow cytometry. In 35 bond as the demarcation between head and stalk , exotic HA the upper panels , mock - transfected cells ( left shaded region ) heads were introduced atop heterologous stalks. The stalk are compared to cells transfected with PRS HA (right ) or domain is defined as the remaining portions of HA1 and cells transfected with PRE - CH1 ( right) or PR8 -cH5 ( right ). HA2 subunits. CT, cytoplasmic tail ; SP , signal peptide ; TM , In the bottom panels , mock - transfected cells (left shaded transmembrane domain . The full - length HA structures were region ) are compared to cells transfected with Perth and 40 downloaded from the Protein Database (PDB ) : PR8 (H1 ) Perth -cH7 constructs ( right) . FIG . 8B : Luciferase -encoding HA (PDB ID 1RU7) and A /guinea fowl/Hong Kong /WF10 / pseudo - particles expressing chimeric HAs were used to 99 HA [represented by A / swine/ Hong Kong/ 9 / 98 (H9 ; PDB infect MDCK cells . The relative light units (RLU ) generated ID 1JSD ) ]. Final images were generated with PyMol in the luciferase assay indicate that pseudo - particles express (Delano Scientific ). Because no structure of an H6 HA has ing chimeric HAS were able to enter the cells . 45 been published , the image of the head - folding of the PR8 FIG . 9A and FIG . 9B : describe the generation of recom HA is used for the cH6 / 1 construct. FIG . 14B : Immunofluo binant viruses bearing chimeric hemagglutinins . FIG . 9A : rescence to confirm expression of cHA . MDCK cells were Western blot analysis of the recombinant viruses . Extracts infected with either WT PR8 or cH9 / 1 N3 virus , or they were from MDCK cells mock infected or infected with the mock - infected . Antibodies specific for the head and stalk of indicated viruses ( 16 hpi ) at an MOI of 2 were prepared and 50 PR8 virus as well as an antibody with H9 reactivity were probed with antibodies : anti- A / PRS /HA (H1 ) ( PY102 ) , anti- used to confirm cHA expression . (Magnification bar : 40x ) . A / Cal/09 /HA (H1 ) (29C1 ) , anti - A / VN /HA (H5 ) (M08 ) , anti - FIG . 15A , FIG . 15B , FIG . 15C , FIG . 15D and FIG . 15E H3/HA ( 12D1) , anti -H7 (NR - 3125 ), anti- A /NP (HT103 ) and show that adult patients infected with pandemic H1N1 virus anti -GAPDH as an internal loading control. FIG . 9B : Immu- have high titers of neutralizing antibodies that are reactive nofluorescence analysis of the MDCK cells infected with 55 with the HA stalk . Reactivity of sera of pH1N1- infected recombinant viruses using antibodies : anti - A /NP (HT103 ) , adults ( n = 9 ) , children not infected with pH1N1 ( n = 5 ) , and anti- A /H1 HA (6F12 ) , anti - A / PR8 /HA (PY102 ) , anti- A /Cal / adults not infected with pH1N1 virus ( n = 11 ) with cH6 / 1 09 /HA (29C1 ) , anti- A /VN /HA (M08 ), anti -H3 /HA (12D1 ) , protein (FIG . 15A ), cH9/ 1 protein ; (FIG . 15B ), the LAH of and anti - A /H7 virus (NR - 3152 ) . the HA2 protein ( anti -LAH antibody was used as a positive FIG . 10A and FIG . 10B : describe the growth kinetics and 60 control; (FIG . 15C ) , H5 HA protein (mouse polyclonal plaque phenotypes of recombinant viruses . FIG . 10A : serum raised against H5 HA was used as a positive control 10 - day old embryonated chicken eggs were infected with and a pan -H3 antibody , 12D1, was used as negative control; wild -type or recombinant virus with 100 pfu per egg and (FIG . 15D ) (13 ) , or H3 HA protein (12D1 was used as a viral growth monitored for 72 hours post infection . FIG . positive control and mouse polyclonal serum raised against 10B : The plaque phenotype of recombinant viruses was 65 H5 HA was used as a negative control ; (FIG . 15E ) . All were assessed by plaque assay . MDCK cells were infected with assessed by ELISA ; data points represent average titers with either a wild - type or recombinant virus and at 48 hours post SE or reactivity of pooled samples . US 10 , 137 , 189 B2 35 36 FIG . 16A , FIG . 16B , and FIG . 16C show that adult compared for full length HA , as well as the globular head patients infected with pandemic H1N1 virus have high titers and stalk domains . Grey bars indicate 100 % identity . of neutralizing antibodies that are specific for the HA stalk FIG . 21 shows the surface expression of chimeric HA ( FIG . 16A and FIG . 16B ) . Sera from pH1N1- infected ( n = 14 ) constructs . Surface expression of chimeric HA constructs and adults not infected with pHIN1 ( n = 5 ) were pooled 5 was evaluated in transiently transfected or infected cells . At separately , and total IgG from both pools was purified . 48 h post- transfection , 293T cells were trypsinized and cell Neutralizing capability of stalk antibodies was assessedsessed by surface expression of chimeric HA proteins were analyzed plaque reduction assay using cH9/ 1 N3 virus . Data points by flow cytometry . In the upper panels , mock - transfected represent the mean and SE of two experiments . Plaques were cells (grey ) are compared to cells transfected with PRS HA 10 (black line ) or cells transfected with cH1/ 1 ( black line) or immunostained with anti -H9 antibody G1- 26 . (FIG . 16B ) CH5 / 1 (black line ) . In the center panels , mock - transfected shows plaque reduction of the four dilutions of sera shown cells ( grey ) are compared to cells transfected with Perth / 09 , along the top . (FIG . 16C ) Pseudotype particle neutralization CH7/ 3 (black line ) and cH5 / 3 constructs (black line ) . In the assay measures neutralizing antibody activity of the human bottom panels , MDCK cells were infected with Perth /09 , purified IgG preparations ( sera from pH1N1- infectedcted adults 15 cH7 / 3 and cH5 /3 expressing recombinant viruses . At 12 h and adults not infected with pH1N1) . Total IgG concentra post- infection the cell surface expression of the different tions were 50 , 10 , and 2 ug /mL . As a positive control, the HAs were analyzed using flow cytometry . stalk -specific monoclonal antibody 6F12 was used . FIG . 22 demonstrates the ability of the chimeric HAs to FIG . 17A , FIG . 17B , and FIG . 17C show expression and enter MDCK cells . Luciferase - encoding pseudoparticles function of cH6 / 1 and cH9/ 1 protein . FIG . 17A : Coomasie 20 expressing chimeric HAs were used to transduce MDCK gel of 2 ug cH6 / 1 and cH9 / 1 protein . M , marker proteins. cells. The relative light units (RLU ) generated in the FIG . 17B : Western blot analysis of baculovirus expressed luciferase assay indicates that pseudoparticles expressing CHA proteins. Lane 1 , cH6 / 1 protein ; lane 2 , cH9/ 1 protein ; chimeric HAs are able to enter cells . lane 3 , WT PRS HA ; lane 4 , WT H3 HA . Blots were probed FIG . 23 shows a Western blot analysis of cells infected with antibodies known to react with the stalk of PR8 virus 25 with the recombinant cHA - expressing viruses . Extracts from ( rabbit polyclonal anti- HA2 ) or H3 viruses (mouse mAb MDCK cells mock infected or infected with the indicated 12D1) and the globular head of H6 ( goat polyclonal anti -H6 viruses at an MOI of 2 were prepared and probed with or H9 viruses (mouse mAb G1- 26 ) to confirm the identity of antibodies at 16 hpi: anti - A /PRS /HA (H1 ) (PY102 ) , anti - A / baculovirus expressed cHAs. mAb 12D1 reacts with both Cal /09 /HA (H1 ) ( 29E3 ) , anti - A / VN /HA (H5 ) (mAb # 8 ) , HAO and HA2 (H3 protein preparation is cleaved , resulting 30 anti -H3 /HA ( 12D1) , anti -H7 (NR -3152 ) , anti - A /NP in two distinct bands) . FIG . 17C : Plaque assay of cH9/ 1 N3 (HT103 ) and anti- GAPDH as an loading control. reassortant virus. Reassortant cH9/ 1 N3 virus plaque phe - FIG . 24 depicts an immunofluorescence analysis of notype is similar to plaques made by WT PR8 virus. Plaques MDCK cells infected with recombinant viruses using anti were immunostained with PY102 and anti -H9 antibody bodies : anti - A /NP (HT103 ) , anti - A /H1 HA (6F12 ) , anti - A / G1- 26 . 35 PRS /HA (PY102 ) , anti - A /Cal / 09 /HA ( 29E3 ) , anti - A / VN / FIG . 18A , FIG . 18B , FIG . 18C , and FIG . 18D show that HA (mAb # 8 ), anti -H3 / HA (12D1 ) , and anti - A /H7 virus monoclonal antibodies directed against the stalk of influenza (NR -3152 ) . virus HA bind and neutralize cHAs . FIG . 18A : Stalk anti FIG . 25A and FIG . 25B depict the growth kinetics and body C179 was used to test reactivity to cH6 / 1 baculovirus - plaque phenotypes of wild type and recombinant viruses. expressed protein by ELISA . C179 reacted with cH9/ 1 in a 40 FIG . 25A : 10 -day old embryonated chicken eggs were dose - dependentmanner . FIG . 18B : Stalk antibody C179 was infected with 100 pfu per egg of wild -type or recombinant used to test reactivity to cH9 / 1 baculovirus - expressed pro - virus and viral growth was monitored for 72 hours post tein by ELISA . C179 reacted with cH9/ 1 in a dose -depen - infection . Data points represent the average and standard dent manner (FIG . 18C and FIG . 18D ) . Antibody 6F12 deviation of experimental replicates. FIG . 25B : The plaque neutralizes cH9/ 1 N3 virus replication . 6F12 was used to 45 phenotypes of recombinant viruses were assessed by plaque assess the ability of stalk - specific monoclonal antibodies to assay . MDCK cells were infected with either a wild - type or neutralize cH9/ 1 N3 virus by plaque reduction assay. FIG . recombinant virus . Cells were fixed 48 hours post infection 18D shows plaque reduction of cH9/ 1 N3 virus using five and immunostained to reveal plaque phenotypes using the dilutions of mAb 6F12 ( 100, 20 , 4 , 0 . 8 , and 0 . 16 ug /mL ) . antibody against A /NP (HT103 ) . Plaques were immunostained with anti -H9 antibody G1- 26 . 50 FIG . 26A and FIG . 26B depict that stalk - specific mono FIG . 19A and FIG . 19B depict schematics of chimeric clonal antibody neutralizes cHA - expressing viruses and hemagglutinins. FIG . 19A shows a diagram of wild - type and pseudotype particles . The ability of a mAb ( KB2) to neu cH1/ 1 viruses . The chimeric HA was constructed by swap - tralize cHA - expressing viruses or pseudotype particles was ping the globular head domain located between Cys52 and assessed by plaque reduction assay (FIG . 26A ) or Cys277 of PR8 ( H1 ) HA with that of the A / California / 4 /09 55 pseudotype particle inhibition assay ( FIG . 26B ) . MDCK (H1 ) HA . The resulting chimeric HA has the stalk region of cells were infected or transduce with CHA - expressing A / PR8 / 34 (H1 ) HA with a globular head domain of the viruses or pseudotype particles in the presence of the indi A /California / 4 /09 (H1 ) HA and is designated as cH1/ 1 . FIG . cated amount ( ug /mL ) of the mAb or without antibody . 19B shows theoretical schematics of the folded structures of Plaque formation or luciferase activity was used as a readout the different wild type and chimeric HAs. From left to right: 60 to determine the degree of inhibition by the mAb . FIG . 26A : wild type PR8 HA , the chimeric cH1/ 1 HA , the chimeric The mAb neutralizes cH1/ 1 (black boxes ) and cH5/ 1 (black cH5 / 1 HA , the wild type Perth HA , the chimeric cH7 / 3 HA , triangles ) virus replication in a dose dependent manner, with and the chimeric cH5/ 3 HA . 100 % inhibition at concentrations above 100 ug / mL . Data FIG . 20 depicts a table comparing amino acid identity points represent the average and standard deviation of between H1, H3, H5 and H7 HAs used in this study. Percent 65 experimental replicates . FIG . 26B : The mAb also inhibits amino acid identity was calculated using Clustal W ( exclud - entry of cH1/ 1 (black boxes ) pseudotype particles in a dose ing the signal peptide ). Percent amino acid identity is dependent manner , with complete inhibition above 4 ug /mL . US 10 , 137 , 189 B2 37 38 Data points represent the average and standard deviation of HA + BSA cohort ( p = 0 . 06 ) . FIG . 29B : Length of survival experimental replicates . The pseudotype inhibition assays was on average longer in animals inoculated with YAM -HA were processed independently . and vaccinated with cH6 / 1 than animals vaccinated with FIG . 27A , FIG . 27B , and FIG . 27C demonstrate that BSA ( p = 0 .037 ) , as well as naïve and WT YAM /BSA con sequential vaccination with CHA constructs elicits HA stalk - 5 trols ( p < 0 . 001 ). FIG . 29C : ELISA plates were coated with specific antibodies and provides protection from lethal chal cH5/ 1 N1 virus in order to assess the degree of stalk lenge . Mice were primed with 20 ug of cH9/ 1 protein , reactivity elicited through vaccination . 1 :50 serum dilutions administered with adjuvant intranasally and intraperitone were plotted against % maximum weight loss . One value ally. Three weeks later, mice were boosted with 20 ug cH6 / 1 protein , administered with adjuvant intranasally and intrap - 10 was determined to be an outlier and was omitted from eritoneally . As controls, mice were primed and boosted in a analysis . For linear regression , R2 = 0 . 56 and p = 0 .02 . similar fashion using BSA , or given inactivated FM1 virus FIG . 30A , FIG . 30B , FIG . 30C , FIG . 30D , FIG . 30E , FIG . intramuscularly . Animals were bled and challenged three 30F, FIG . 30G , FIG . 3011 , FIG . 301, and FIG . 30J demon weeks after the last vaccination with 5LD50 of A /Fort strate that vaccination with CHA elicits stalk - specific immu Monmouth / 1 / 1947 (FM1 ) virus . FIG . 27A : ELISA plates 15 nity that mediates protection from H1N1 virus challenge . were coated with cH5/ 1 N1 virus in order to assess the ( FIG . 30A - FIG . 30F ) Animals were primed with DNA degree of stalk reactivity elicited through vaccination encoding cH9 / 1 and then were vaccinated with cH6 / 1 and (BSA + BSA is the bottom line of the graph ). FIG . 27B : Mice boosted with cH5 / 1 soluble protein ( n = 10 ) or BSA ( n = 5 ), were weighed daily for 14 days to assess protection from while positive control mice received inactivated virus intra challenge . FIG . 27C : Kaplan Meier curve depicting survival 20 muscularly ( n = 5 ) . FIG . 30A : Animals were vaccinated and rate post challenge . cH9/ 1 + cH6 / 1 vaccinated mice had a challenged with FM1 virus; mice were weighed daily , and statistically higher survival rate compared to BSA controls weight loss over time is shown as change in percentage of ( p = 0 .0003 ) initial weight. FIG . 30B : Graph depicting survival of chal FIG . 28A , FIG . 28B , FIG . 28C , FIG . 28D , and FIG . 28E lenged mice in ( A ). FIG . 30C : Animals were vaccinated and demonstrate that vaccination with cH6 / 1 elicits stalk -spe - 25 challenged with pH1N1 virus ; mice were weighed daily , and cific immunity that mediates protection from cH9 / 1 N1 viral weight loss over time is shown as change in percentage of challenge . Animals were inoculated with YAM -HA virus in initial weight. FIG . 30D : Graph depicting survival of chal order to simulate prior infection with or vaccination against lenged mice in FIG . 30C . FIG . 30E : Animals were vacci influenza virus . Three weeks later , animals were vaccinated nated and challenged with PR8 virus ; mice were weighed with cH6 / 1 or BSA with adjuvant, intranasally and intrap - 30 daily , and weight loss over time is shown as change in eritoneally . Control animals were inoculated with wild - type percentage of initial weight. FIG . 30F : Graph depicting B / Yamagata / 16 / 1988 and vaccinated in a similar fashion survival of challenged mice in FIG . 30E . FIG . 30G : Reac with BSA , or given inactivated cH9 / 1 N1 virus intramus - tivity to H1 HA of serum from animals vaccinated as cularly . Animals were bled and challenged with 250LDso described above in FIG . 30A - FIG . 30F and below in FIG . cH9/ 1 N1 virus three weeks after vaccination . FIG . 28A : 35 30H - FIG . 301 and challenged with 5 LD : n of A / FM / 1 / 1947 Animals were weighed for 8 days in order to assess protec - (FIG . 30A , FIG . 30B ) , 10 LD50 of A /Netherland /602 / 2009 tion from challenge . On days 3 - 5 , YAM - HA + CH6 / 1 animals (FIG . 30C , FIG . 30D ) , or 5 LDs, of A /PR / 8 / 1934 ( FIG . 30E , demonstrated statistically less weight loss compared to the FIG . 30F , FIG . 30H , FIG . 301) . FIG . 30H : Animals were YAM -HA + BSA cohort ( p < 0 .05 ) . FIG . 28B : Kaplan Meier vaccinated as described above in FIG . 30A - FIG . 30F curve depicting survival. Statistically different survival rates 40 (square , n = 4 ) or were naive (triangle , n = 3 ) , while positive were seen in the YAM -HA + CH6 / 1 group compared to the controlmice received inactivated PR8 virus intramuscularly YAM -HA + BSA cohort ( p = 0 .038 ) , as well as naïve and WT ( X mark , n = 5 ) . CD8 T cells were depleted prior to challenge YAM + BSA animals (p < 0 .0001 ) . Survival rate of YAM -HA + with PR8 virus. Mice were weighed daily , and weight loss BSA cohort was not statistically different from that of the over time is shown as change in percentage of initial weight. WT- YAM + BSA cohort ( p = 0 . 058 ) . FIG . 28C : ELISA plates 45 FIG . 301: Graph depicting survival of challenged mice in were coated with cH5 / 1 N1 virus in order to assess the FIG . 30H . FIG . 30J : Animals were vaccinated as described degree of stalk reactivity elicited through vaccination . FIG . for FIG . 30A - FIG . 30F . Total IgG was purified for use in 28D : Results of a plaque reduction assay using the cH5 / 1 H2 -based pseudoparticle entry inhibition assay. Percent virus are depicted . FIG . 28E : Animals were vaccinated , bled inhibition was assessed as a decrease in luciferase expres and total IgG was harvested for H5 - based pseudoparticle 50 sion compared to controls . Fab fragment CR6261 was used entry inhibition assay . Percent inhibition was assessed as a as a positive control. decrease in luciferase expression compared to controls . FIG . 31A , FIG . 31B , and FIG . 31C . Schematic of wild FIG . 29A , FIG . 29B , and FIG . 29C demonstrate that type HA and expression constructs . FIG . 31A : Uncleaved vaccination with cH6 / 1 protects mice from lethal H5 influ - full length influenza virus hemagglutinin . The signal peptide enza virus challenge . Animals were inoculated with YAM - 55 is the leftmost component, the HA ectodomain is the middle HA virus in order to simulate prior infection with or vacci- component and the transmembrane - and endodomain are the nation against influenza virus. Three weeks later, animals rightmost component. FIG . 31B : Expression construct with were vaccinated with cH6 / 1 or BSA with adjuvant, intrana - trimerization domain . The transmembrane - and endodomain sally and intraperitoneally . Control animals were inoculated was swapped with a thrombin cleavage site ( third compo with wild -type B / Yamagata / 16 / 1988 and vaccinated in a 60 nent from left ), a T4 trimerization domain (fourth compo similar fashion with BSA or given inactivated cH5/ 1 N1 nent from left ) and a hexahistidine tag (6xhis tag , fifth virus intramuscularly . Animals were bled and challenged component from left ) at position V503 (H3 numbering ) . with 10LD50 of the 2 : 6 H5 reassortant in the PR8 back - FIG . 31C : Expression construct without trimerization ground (see , e . g ., Steel et al. , 2009, J Virol 83 : 1742 - 1753 ) . domain . The transmembrane - and endodomain was swapped FIG . 29A : Kaplan Meier curve depicting survival. Differ - 65 with a hexahistidine tag (6xhis tag, rightmost component) at ences in survival rates approached statistical significance amino acid position 509 (H1 , H2 and H5 ) or 508 (H3 ) when comparing the YAM -HA + CH6 / 1 group to the YAM respectively (H3 numbering ). US 10 , 137 , 189 B2 39 40 FIG . 32A , FIG . 32B , and FIG . 32C . Introduction of a domain and a globular HA head domain that is heterologous trimerization domain influences stability and formation of to the stem domain ( i . e . the head and stem domains are oligomers in recombinant HAs. FIG . 32A : Analysis of derived from different strains and /or subtypes of influenza recombinant HAs with and without trimerization domain by virus) . reducing , denaturing SDS - PAGE . Recombinant HAs that 5 In another aspect, provided herein are compositions com are expressed with trimerization domain ( + ) show higher prising one or more of the chimeric influenza hemagglutinin stability than HAs expressed without ( - ) . Uncleaved HA polypeptides described herein ( e . g . , compositions compris (HAO ) and cleavage products (HA1 / degr. product; HA2 ) are ing soluble chimeric influenza hemagglutinin polypeptides indicated by arrows. FIG . 32B : Reducing , denaturing SDS - described herein , viruses comprising the chimeric influenza PAGE analysis of crosslinked HAs . Different species of HA 10 hemagglutinin polypeptides described herein , viruses com are indicated in the blot. High molecular multimers are prising genomes engineered to encode the chimeric influ indicated by H , trimers by T , dimers by D and monomers by enza hemagglutinin polypeptides described herein , expres M . FIG . 32C : Left panel ( boxes 1 - 4 ) : Western blot analysis sion vectors comprising the chimeric influenza of reduced , denatured and cross - linked group 1 HAs from B hemagglutinin polypeptides described herein , expression probed with a anti -hexahistidine - tag antibody. Right panel 15 vectors comprising genomes engineered to encode the chi ( rightmost box ): Cross - linking control (IgG ) with BS3 ana - meric influenza hemagglutinin polypeptides described lyzed on a SDS -PAGE . Different species ( full antibody, herein , nucleic acids encoding the chimeric influenza heavy chain , light chain ) are indicated by arrows. Molecular hemagglutinin polypeptides described herein , etc .) . weights of the marker bands are indicated on the left of each In another aspect, provided herein are vaccine formula panel. 20 tions comprising one or more of the chimeric influenza FIG . 33A and FIG . 33B . Binding of stalk -reactive anti- hemagglutinin polypeptides described herein . In a specific bodies to recombinant PR8 (H1 ) and Cal09 (H1 ) HAS. FIG . embodiment, provided herein is a monovalent vaccine com 33A : Binding of stalk - reactive antibodies C179 , CR6261 prising one of the chimeric influenza hemagglutinin poly and 6F12 and head - reactive antibody PY102 and PR8 anti - peptides described herein . In another specific embodiment, serum to recombinant soluble PRS HA without ( w / o T4 trim . 25 provided herein is a bivalent vaccine comprising two of the domain , triangle lines) or with ( w / T4 trim . domain , boxed chimeric influenza hemagglutinin polypeptides described lines ) trimerization domain . FIG . 33B : Binding of stalk - herein ( i . e . , two distinct chimeric influenza hemagglutinin reactive antibodies C179 , CR6261 and 6F12 and head - polypeptides) . In another specific embodiment, provided reactive antibody 7B2 and Cal09 antiserum to recombinant herein is a trivalent vaccine comprising three of the chimeric soluble Cal09 HA without ( w / o T4 trim . domain , triangle 30 influenza hemagglutinin polypeptides described herein ( i .e . , lines ) or with ( w / T4 trim . domain , boxed lines ) trimeriza - three distinct chimeric influenza hemagglutinin polypep tion domain . tides ) . The vaccine formulations provided herein may com FIG . 34A and FIG . 34B . Binding of stalk -reactive anti prise , for example , subunit vaccines comprising one or more bodies to recombinant JAP57 (H2 ) and VN04 (H5 ) HAS. of the chimeric influenza hemagglutinin polypeptides FIG . 34A : Binding of stalk - reactive antibodies C179 and 35 described herein (e .g ., compositions comprising chimeric CR6261 and head -reactive antibody 8F8 and H2 antiserum influenza hemagglutinin polypeptides , e . g . , soluble chimeric to recombinant soluble JAP57 HÀ without (w /o T4 trim . influenza hemagglutinin polypeptides ); live influenza domain , triangle lines ) or with ( w / T4 trim . domain , boxed viruses ( e . g . , live attenuated influenza viruses ) that express lines ) trimerization domain . FIG . 34B : Binding of stalk - one or more of the chimeric influenza hemagglutinin poly reactive antibodies C179 and CR6261 and head - reactive 40 peptides described herein ; live influenza viruses ( e . g ., live antibody mAb # 8 and H5 antiserum to recombinant soluble attenuated influenza viruses ) comprising a genome that VN04 HA without ( w / o T4 trim . domain , triangle lines ) or encodes one or more of the chimeric influenza hemaggluti with (w / T4 trim . domain , boxed lines ) trimerization nin polypeptides described herein ; killed influenza viruses domain . that express one or more of the chimeric influenza hemag FIG . 35A and FIG . 35B . Binding of stalk -reactive anti - 45 glutinin polypeptides described herein ; killed influenza bodies to group 2 HAs. FIG . 35A : Binding of stalk -reactive viruses comprising a genome that encodes one or more of antibodies 12D1 and CR8020 and head -reactive antibody the chimeric influenza hemagglutinin polypeptides XY102 and H3 antiserum to recombinant soluble HK68 HA described herein ; virus/ viral - like particles (“ VLPs” ) that without ( w / o T4 trim . domain , triangle lines ) or with ( w / T4 contain one or more of the chimeric influenza hemagglutinin trim . domain , boxed lines ) trimerization domain . FIG . 35B : 50 polypeptides described herein ; split virus vaccines , wherein Binding of stalk - reactive antibodies 12D1 and CR8020 and said virus expresses one or more of the chimeric influenza H3 antiserum to recombinant soluble Wisc05 HA without hemagglutinin polypeptides described herein and/ or com ( wlo T4 trim . domain , triangle lines ) or with ( w / T4 trim . prises a genome that encodes one or more of the chimeric domain , boxed lines ) trimerization domain . influenza hemagglutinin polypeptides described herein ; viral FIG . 36 depicts an exemplary chimeric influenza virus 55 expression vectors ( e . g . , non - influenza virus expression vec hemagglutinin polypeptide ( SEQ ID NO : 21 ) comprising the tors ) that express one or more of the chimeric influenza stem domain of an influenza B virus ( B /Florida / 4 / 2006 ) and hemagglutinin polypeptides described herein ; and bacterial the globular head domain of an influenza A virus of the H5 expression vectors that express one or more of the chimeric subtype ( A / Vietnam / 1203/ 2004 ) . influenza hemagglutinin polypeptides described herein . 60 The vaccine formulations described herein can elicit 5 . DETAILED DESCRIPTION highly potent and broadly neutralizing antibodies against the HA stem domain of the chimeric influenza hemagglutinin In one aspect, provided herein are chimeric influenza polypeptides. Such “ universal” vaccines can be used to hemagglutinin (HA ) polypeptides that induce a cross -pro - induce and / or boost cross -protective immune responses tective immune response against the conserved HA stem 65 across influenza virus subtypes . domain of influenza viruses . The chimeric influenza HA In another aspect, provided herein are methods of immu polypeptides provided herein comprise a stable HA stem nizing a subject against an influenza virus disease or infec US 10 , 137 , 189 B2 41 42 tion comprising administering to the subject a composition nia / 4 /2009 (H1N1 ) HA ( or the stem domain of an A / Cali comprising one or more of the chimeric influenza hemag - fornia / 4 / 2009 -like influenza virus HA ) and the globular head glutinin (HA ) polypeptides described herein or a vaccine domain of the cH5/ 1 chimeric influenza hemagglutinin formulation described herein . polypeptide is the globular head domain of A / Anhui/ 1/ 2005 In another aspect , provided herein are kits comprising one 5 (H5 ) HA . In another specific embodiment, the stem domain or more of the chimeric influenza hemagglutinin (HA ) of a cH5 /1 chimeric influenza hemagglutinin polypeptide is polypeptides described herein or a vaccine formulation the stem domain of A /California / 4 /2009 (H1N1 ) HA (or the described herein . The kits provided herein may further comprise one or more additional components , e .g ., an anti stem domain of an A /California / 4 / 2009- like influenza virus body that specifically binds one or more of the chimeric 10 HA ) and the globular head domain of the cH5/ 1 chimeric influenza hemagglutinin (HA ) polypeptides provided in the influenza hemagglutinin polypeptide is the globular head kit . domain of A / Bar headed goose / Quinghai/ 1A / 2005 (H5 ) HA . 5 . 1 Chimeric Influenza Virus Hemagglutinin Polypeptides In another specific embodiment, the stem domain of a cH5 / 1 Provided herein are chimeric influenza virus hemagglu chimeric influenza hemagglutinin polypeptide is the stem tinin polypeptides comprising or consisting of an influenza 15 domainqon of A / California / 4/ 2009 (H1N1 ) HA (or the stem virus hemagglutinin globular head domain polypeptide and domain of an A / California / 4 /2009 -like influenza virus HA ) an influenza virus hemagglutinin stem domain polypeptide , and the globular head domain of the cH5/ 1 chimeric influ wherein said influenza virus hemagglutinin head domain e nza hemagglutinin polypeptide is the globular head domain polypeptide is heterologous to said influenza virus hemag of A /turkey / Turkey / 1 / 2005 (H5 ) HA . In another specific glutinin stem domain polypeptide ( e . g . , the influenza virus 20 embodiment, the stem domain of a cH5 / 1 chimeric influenza hemagglutinin globular head domain polypeptide and the hemagglutinin polypeptide is the stem domain of A /Califor influenza virus hemagglutinin stem domain polypeptide are n ia / 4 /2009 (H1N1 ) HA ( or the stem domain of an A / Cali derived from different influenza virus hemagglutinin sub - fornia / 4 / 2009 - like influenza virus HA ) and the globular head types ) . domain of the cH5/ 1 chimeric influenza hemagglutinin A full - length influenza hemagglutinin typically comprises 25 polypeptide is the globular head domain of A / Whooper an HA1 domain and an HA2 domain . The stem domain is swan /Mongolia / 244 / 2005 (H5 ) HA . formed by two segments of the HA1 domain and most or all In certain embodiments , a chimeric influenza hemagglu of the HA2 domain . The two segments of the HA1 domain tinin (HA ) polypeptide provided herein comprises (i ) the are separated , in primary sequence , by the globular head stem domain of the hemagglutinin from an influenza virus of domain ( see, e . g . , the amino acid residues between the 30 the H3 subtype and ( ii ) the globular head domain of the residues designated A , and A , in FIG . 1 ) . In certain embodi- hemagglutinin from an influenza virus of the H5 subtype ments , the chimeric influenza virus hemagglutinin polypep - (sometimes referred to herein as a " cH5 / 3 chimeric influenza tides described herein maintain such a structure. That is, in hemagglutinin polypeptide ” ) . In a specific embodiment , the certain embodiments , the chimeric influenza virus hemag - stem domain of a cH5 /3 chimeric influenza hemagglutinin glutinin polypeptides described herein comprise a stable 35 polypeptide is the stem domain of A /Victoria / 361/ 2011 stem structure composed of an HA1 domain and an HA2 (H3N2 ) HA . In another specific embodiment, the stem domain , and a globular head domain separating the two domain of a cH5/ 3 chimeric influenza hemagglutinin poly segments of the HA1 domain ( in primary sequence ), peptide is the stem domain of A /Victoria / 361/ 2011 (H3N2 ) wherein said globular head domain is heterologous to the HA and the globular head domain of the cH5 / 3 chimeric stem domain formed by the other segments of the HA1 40 influenza hemagglutinin polypeptide is the globular head domain and the HA2 domain . domain of A /Vietnam / 1203 / 2004 (H5 ) HA . In another spe In certain embodiments , a chimeric influenza hemagglu - cific embodiment, the stem domain of a cH5/ 3 chimeric tinin (HA ) polypeptide provided herein comprises (i ) the influenza hemagglutinin polypeptide is the stem domain of stem domain of the hemagglutinin from an influenza virus of A / Victoria / 361/ 2011 (H3N2 ) HA and the globular head the H1 subtype and ( ii ) the globular head domain of the 45 domain of the cH5 /3 chimeric influenza hemagglutinin hemagglutinin from an influenza virus of the H5 subtype polypeptide is the globular head domain of A / Indonesia / 5 / ( sometimes referred to herein as a " cH5 / 1 chimeric influenza 2005 (H5 ) HA . In another specific embodiment, the stem hemagglutinin polypeptide” ). In a specific embodiment, the domain of a cH5 / 3 chimeric influenza hemagglutinin poly stem domain of a cH5 / 1 chimeric influenza hemagglutinin peptide is the stem domain of A /Victoria / 361/ 2011 (H3N2 ) polypeptide is the stem domain of A / California / 4 / 2009 50 HA and the globular head domain of the cH5/ 3 chimeric (H1N1 ) HA (or the stem domain of an A / California / 4 / 2009 - influenza hemagglutinin polypeptide is the globular head like influenza virus HA ) . In another specific embodiment, domain of A / Anhui/ 1/ 2005 (H5 ) HA . In another specific the stem domain of a cH5/ 1 chimeric influenza hemagglu - embodiment, the stem domain of a cH5/ 3 chimeric influenza tinin polypeptide is the stem domain of A /California /4 / 2009 hemagglutinin polypeptide is the stem domain of A /Victoria / (H1N1 ) HA ( or the stem domain of an A / California / 4 / 2009 - 55 361/ 2011 (H3N2 ) HA and the globular head domain of the like influenza virus HA ) and the globular head domain of the cH5 / 3 chimeric influenza hemagglutinin polypeptide is the cH5 / 1 chimeric influenza hemagglutinin polypeptide is the globular head domain of A /Bar headed goose / Quinghai/ 1A / globular head domain of A / Vietnam / 1203/ 2004 (H5 ) HA . In 2005 (15 ) HA . In another specific embodiment, the stem another specific embodiment, the stem domain of a cH5 / 1 domain of a cH5 / 3 chimeric influenza hemagglutinin poly chimeric influenza hemagglutinin polypeptide is the stem 60 peptide is the stem domain of A /Victoria / 361/ 2011 (H3N2 ) domain of A / California / 4 /2009 (H1N1 ) HA (or the stem HA and the globular head domain of the cH5 /3 chimeric domain of an A /California / 4 / 2009 - like influenza virus HA ) influenza hemagglutinin polypeptide is the globular head and the globular head domain of the cH5 / 1 chimeric influ domain of A / turkey / Turkey / 1 /2005 (H5 ) HA . In another enza hemagglutinin polypeptide is the globular head domain specific embodiment , the stem domain of a cH5/ 3 chimeric of A / Indonesia / 5 / 2005 (H5 ) HA . In another specific embodi - 65 influenza hemagglutinin polypeptide is the stem domain of ment, the stem domain of a cH5 / 1 chimeric influenza A /Victoria /361 / 2011 (H3N2 ) HA and the globular head hemagglutinin polypeptide is the stem domain of A /Califor - domain of the cH5 / 3 chimeric influenza hemagglutinin US 10 , 137 , 189 B2 43 44 polypeptide is the globular head domain of A /Whooper - 10 / 2011 (H3N2 ) HA and the globular head domain of the swan /Mongolia / 244 /2005 (H5 ) HA . CH5/ 3 chimeric influenza hemagglutinin polypeptide is the In another specific embodiment, the stem domain of a globular head domain of A / turkey / Turkey / 1 / 2005 (H5 ) HA . CH5/ 3 chimeric influenza hemagglutinin polypeptide is the In another specific embodiment, the stem domain of a cH5/ 3 stem domain of A / harbor seal/Massachusetts / 1 / 2011 5 chimeric influenza hemagglutinin polypeptide is the stem (H3N8 ) HA . In another specific embodiment, the stem domain of A / Indiana / 10 / 2011 (H3N2 ) HA and the globular domain of a cH5 / 3 chimeric influenza hemagglutinin poly - head domain of the cH5 / 3 chimeric influenza hemagglutinin peptide is the stem domain of A /harbor seal/ Massachusetts polypeptide is the globular head domain of A /Whooper 1 /2011 (H3N8 ) HA and the globular head domain of the swan /Mongolia /244 /2005 (H5 ) HA . CH5/ 3 chimeric influenza hemagglutinin polypeptide is the 10 In a specific embodiment, a cH5/ 3 chimeric influenza globular head domain of A / Vietnam / 1203 / 2004 (H5 ) HA . In hemagglutinin polypeptide provided herein does not com another specific embodiment, the stem domain of a cH5 / 3 prise the globular head domain of A /Vietnam / 1203 /2004 chimeric influenza hemagglutinin polypeptide is the stem (H5 ) HA . In another specific embodiment, a cH5/ 3 chimeric domain of A /harbor seal/ Massachusetts / 1 / 2011 (H3N8 ) HA influenza hemagglutinin polypeptide does not comprise the and the globular head domain of the cH5 / 3 chimeric influ - 15 stem domain of A /Perth / 16 / 2009 (H3 ) HA . enza hemagglutinin polypeptide is the globular head domain In another specific embodiment, the stem domain of a of A / Indonesia / 5 /2005 (H5 ) HA . In another specific embodi- cH5/ 3 chimeric influenza hemagglutinin polypeptide is the ment, the stem domain of a cH5/ 3 chimeric influenza stem domain of A / Perth / 16 /2009 (H3N2 ) HA . In another hemagglutinin polypeptide is the stem domain of A /harbor specific embodiment, the stem domain of a cH5 / 3 chimeric seal/ Massachusetts / 1 /2011 (H3N8 ) HA and the globular 20 influenza hemagglutinin polypeptide is the stem domain of head domain of the cH5/ 3 chimeric influenza hemagglutinin A /Perth / 16 /2009 (H3N2 ) HA and the globular head domain polypeptide is the globular head domain of A /Anhui / 1/ 2005 of the cH5/ 3 chimeric influenza hemagglutinin polypeptide (H5 ) HA . In another specific embodiment, the stem domain is the globular head domain of A /Vietnam / 1203 /2004 (H5 ) of a cH5 /3 chimeric influenza hemagglutinin polypeptide is HA . In another specific embodiment, the stem domain of a the stem domain of A /harbor seal/Massachusetts / 1 /2011 25 cH5/ 3 chimeric influenza hemagglutinin polypeptide is the (H3N8 ) HA and the globular head domain of the cH5 /3 stem domain of A /Perth /16 / 2009 (H3N2 ) HA and the globu chimeric influenza hemagglutinin polypeptide is the globu - lar head domain of the cH5 / 3 chimeric influenza hemagglu lar head domain of A /Bar headed goose / Quinghai/ 1A /2005 tinin polypeptide is the globular head domain of A / Indone (H5 ) HA . In another specific embodiment , the stem domain sia / 5 / 2005 (H5 ) HA . In another specific embodiment , the of a cH5 /3 chimeric influenza hemagglutinin polypeptide is 30 stem domain of a cH5 /3 chimeric influenza hemagglutinin the stem domain of A /harbor seal/ Massachusetts / 1 / 2011 polypeptide is the stem domain of A /Perth / 16 / 2009 (H3N2 ) (H3N8 ) HA and the globular head domain of the cH5 / 3 HA and the globular head domain of the cH5 / 3 chimeric chimeric influenza hemagglutinin polypeptide is the globu - influenza hemagglutinin polypeptide is the globular head lar head domain of A / turkey / Turkey / 1 /2005 (H5 ) HA . In domain of A / Anhui/ 1 / 2005 (H5 ) HA . In another specific another specific embodiment, the stem domain of a cH5/ 3 35 embodiment, the stem domain of a cH5/ 3 chimeric influenza chimeric influenza hemagglutinin polypeptide is the stem hemagglutinin polypeptide is the stem domain of A / Perth / domain of A /harbor seal/ Massachusetts / 1 / 2011 (H3N8 ) HA 16 / 2009 (H3N2 ) HA and the globular head domain of the and the globular head domain of the cH5 /3 chimeric influ - cH5 /3 chimeric influenza hemagglutinin polypeptide is the enza hemagglutinin polypeptide is the globular head domain globular head domain of A / Bar headed goose /Quinghai / 1A / of A /Whooperswan /Mongolia / 244 / 2005 (H5 ) HA . 40 2005 (H5 ) HA . In another specific embodiment, the stem In another specific embodiment, the stem domain of a domain of a cH5 / 3 chimeric influenza hemagglutinin poly cH5 / 3 chimeric influenza hemagglutinin polypeptide is the peptide is the stem domain of A / Perth / 16 / 2009 (H3N2 ) HA stem domain of A /Indiana / 10 /2011 (H3N2 ) HA . In another and the globular head domain of the cH5 /3 chimeric influ specific embodiment, the stem domain of a cH5/ 3 chimeric e nza hemagglutinin polypeptide is the globular head domain influenza hemagglutinin polypeptide is the stem domain of 45 of A / turkey / Turkey / 1 / 2005 (H5 ) HA . In another specific A / Indiana / 10 / 2011 (H3N2 ) HA and the globular head embodiment, the stem domain of a cH5/ 3 chimeric influenza domain of the cH5 / 3 chimeric influenza hemagglutinin hemagglutinin polypeptide is the stem domain of A /Perth / polypeptide is the globular head domain of A /Vietnam / 1203 / 16 / 2009 (H3N2 ) HA and the globular head domain of the 2004 (H5 ) HA . In another specific embodiment, the stem cH5/ 3 chimeric influenza hemagglutinin polypeptide is the domain of a cH5/ 3 chimeric influenza hemagglutinin poly - 50 globular head domain of A /Whooperswan /Mongolia / 244 / peptide is the stem domain of A / Indiana / 10 /2011 (H3N2 ) 2005 (H5 ) HA . HA and the globular head domain of the cH5/ 3 chimeric In certain embodiments , a chimeric influenza hemagglu influenza hemagglutinin polypeptide is the globular head tinin (HA ) polypeptide provided herein comprises (i ) the domain of A / Indonesia / 5 / 2005 (H5 ) HA . In another specific stem domain of the hemagglutinin from an influenza virus of embodiment, the stem domain of a cH5 / 3 chimeric influenza 55 the H3 subtype and ( ii ) the globular head domain of the hemagglutinin polypeptide is the stem domain of A / Indiana/ hemagglutinin from an influenza virus of the H7 subtype 10 / 2011 (H3N2 ) HA and the globular head domain of the (sometimes referred to herein as a “ cH7 / 3 chimeric influenza cH5 /3 chimeric influenza hemagglutinin polypeptide is the hemagglutinin polypeptide ” ). In a specific embodiment, the globular head domain of A / Anhui/ 1 / 2005 (H5 ) HA . In stem domain of a cH7/ 3 chimeric influenza hemagglutinin another specific embodiment , the stem domain of a cH5 / 3 60 polypeptide is the stem domain of A /Victoria / 361/ 2011 chimeric influenza hemagglutinin polypeptide is the stem (H3N2 ) HA . In another specific embodiment, the stem domain of A / Indiana / 10 / 2011 (H3N2 ) HA and the globular domain of a cH7 / 3 chimeric influenza hemagglutinin poly head domain of the cH5 / 3 chimeric influenza hemagglutinin peptide is the stem domain of A / Victoria / 361/ 2011 (H3N2 ) polypeptide is the globular head domain of A / Bar headed HA and the globular head domain of the cH7/ 3 chimeric goose / Quinghai/ 1A / 2005 (H5 ) HA . In another specific 65 influenza hemagglutinin polypeptide is the globular head embodiment, the stem domain of a cH5 / 3 chimeric influenza domain of A / Netherlands/ 219 / 03 (H7 ) HA . In another spe hemagglutinin polypeptide is the stem domain of A / Indiana / cific embodiment, the stem domain of a cH7/ 3 chimeric US 10 , 137 , 189 B2 45 46 influenza hemagglutinin polypeptide is the stem domain of and the globular head domain of the cH7 /3 chimeric influ A /Victoria / 361/ 2011 (H3N2 ) HA and the globular head enza hemagglutinin polypeptide is the globular head domain domain of the cH7 /3 chimeric influenza hemagglutinin of A /Rhea /NC /39482 /93 (H7 ) HA . In another specific polypeptide is the globular head domain of A / Canada /504 ) embodiment, the stem domain of a cH7/ 3 chimeric influenza 04 (H7 ) HA . In another specific embodiment, the stem 5 hemagglutinin polypeptide is the stem domain of A / harbor domain of a cH7/ 3 chimeric influenza hemagglutinin poly - seal/ Massachusetts / 1 / 2011 (H3N8 ) HA and the globular peptide is the stem domain of A / Victoria /361 / 2011 (H3N2 ) head domain of the cH7 / 3 chimeric influenza hemagglutinin HA and the globular head domain of the cH7/ 3 chimeric polypeptide is the globular head domain of A /mallard / influenza hemagglutinin polypeptide is the globular head Netherlands/ 12 / 2000 (H7 ) HA . domain of A / Canada /444 /04 (H7 ) HA . In another specific 10 In another specific embodiment, the stem domain of a embodiment, the stem domain of a cH7 / 3 chimeric influenza cH7 / 3 chimeric influenza hemagglutinin polypeptide is the hemagglutinin polypeptide is the stem domain of A / Victoria / stem domain of A / Indiana / 10 /2011 (H3N2 ) HA . In another 361/ 2011 (H3N2 ) HA and the globular head domain of the specific embodiment, the stem domain of a cH7 /3 chimeric cH7 / 3 chimeric influenza hemagglutinin polypeptide is the influenza hemagglutinin polypeptide is the stem domain of globular head domain of A / chicken / Jalisco /CPA1 / 2012 (H7 ) 15 A / Indiana / 10 / 2011 (H3N2 ) HA and the globular head HA . In another specific embodiment, the stem domain of a domain of the cH7 /3 chimeric influenza hemagglutinin cH7 / 3 chimeric influenza hemagglutinin polypeptide is the polypeptide is the globular head domain of A /Netherlands stem domain of A /Victoria / 361 / 2011 (H3N2 ) HA and the 219 /03 (H7 ) HA . In another specific embodiment, the stem globular head domain of the cH7/ 3 chimeric influenza domain of a cH7 / 3 chimeric influenza hemagglutinin poly hemagglutinin polypeptide is the globular head domain of 20 peptide is the stem domain of A / Indiana/ 10 / 2011 (H3N2 ) A /mallard /Alberta /24 / 2001 (H7 ) HA . In another specific HA and the globular head domain of the cH7 / 3 chimeric embodiment, the stem domain of a cH7/ 3 chimeric influenza influenza hemagglutinin polypeptide is the globular head hemagglutinin polypeptide is the stem domain of A / Victoria domain of A / Canada/ 504 /04 (17 ) HA . In another specific 361/ 2011 (H3N2 ) HA and the globular head domain of the embodiment, the stem domain of a cH7/ 3 chimeric influenza cH7/ 3 chimeric influenza hemagglutinin polypeptide is the 25 hemagglutinin polypeptide is the stem domain of A / Indiana / globular head domain of A /Rhea /NC /39482 / 93 (H7 ) HA . In 10 /2011 (H3N2 ) HA and the globular head domain of the another specific embodiment, the stem domain of a cH7 / 3 cH7/ 3 chimeric influenza hemagglutinin polypeptide is the chimeric influenza hemagglutinin polypeptide is the stem globular head domain of A / Canada /444 /04 (H7 ) HA . In domain of A / Victoria / 361/ 2011 (H3N2 ) HA and the globular another specific embodiment, the stem domain of a cH7/ 3 head domain of the cH7/ 3 chimeric influenza hemagglutinin 30 chimeric influenza hemagglutinin polypeptide is the stem polypeptide is the globular head domain of A /mallard / domain of A /Indiana / 10 / 2011 (H3N2 ) HA and the globular Netherlands / 12 / 2000 (H7 ) HA . head domain of the cH7 / 3 chimeric influenza hemagglutinin In another specific embodiment, the stem domain of a polypeptide is the globular head domain of A /chicken / cH7/ 3 chimeric influenza hemagglutinin polypeptide is the Jalisco /CPA1 / 2012 (H7 ) HA . In another specific embodi stem domain of A / harbor seal/Massachusetts / 1 / 2011 35 ment , the stem domain of a cH7/ 3 chimeric influenza (H3N8 ) HA . In another specific embodiment, the stem hemagglutinin polypeptide is the stem domain of A / Indiana / domain of a cH7/ 3 chimeric influenza hemagglutinin poly - 10 / 2011 (H3N2 ) HA and the globular head domain of the peptide is the stem domain of A /harbor seal/ Massachusetts / cH7/ 3 chimeric influenza hemagglutinin polypeptide is the 1 /2011 (H3N8 ) HA and the globular head domain of the globular head domain of A /mallard / Alberta /24 /2001 (H7 ) cH7/ 3 chimeric influenza hemagglutinin polypeptide is the 40 HA . In another specific embodiment, the stem domain of a globular head domain of A /Netherlands / 219 / 03 (H7 ) HA . In cH7/ 3 chimeric influenza hemagglutinin polypeptide is the another specific embodiment, the stem domain of a cH7 /3 stem domain of A / Indiana / 10 /2011 ( H3N2 ) HA and the chimeric influenza hemagglutinin polypeptide is the stem globular head domain of the cH7 /3 chimeric influenza domain of A /harbor seal/Massachusetts / 1 / 2011 (H3N8 ) HA hemagglutinin polypeptide is the globular head domain of and the globular head domain of the cH7/ 3 chimeric influ - 45 A / Rhea /NC / 39482/ 93 (H7 ) HA . In another specific embodi enza hemagglutinin polypeptide is the globular head domain ment, the stem domain of a cH7/ 3 chimeric influenza of A /Canada /504 /04 (H7 ) HA . In another specific embodi- hemagglutinin polypeptide is the stem domain of A / Indiana / ment, the stem domain of a cH7/ 3 chimeric influenza 10 / 2011 (H3N2 ) HA and the globular head domain of the hemagglutinin polypeptide is the stem domain of A / harbor CH7 / 3 chimeric influenza hemagglutinin polypeptide is the seal/ Massachusetts / 1 /2011 (H3N8 ) HA and the globular 50 globular head domain of A /mallard /Netherlands / 12 /2000 head domain of the cH7/ 3 chimeric influenza hemagglutinin ( H7) HA . polypeptide is the globular head domain of A /Canada /444 / In another specific embodiment, the stem domain of a 04 (H7 ) HA . In another specific embodiment, the stem cH7 /3 chimeric influenza hemagglutinin polypeptide is the domain of a cH7/ 3 chimeric influenza hemagglutinin poly - stem domain of A /Perth / 16 /2009 (H3N2 ) HA . In another peptide is the stem domain of A /harbor seal/ Massachusetts / 55 specific embodiment, the stem domain of a cH7 / 3 chimeric 1 / 2011 (H3N8 ) HA and the globular head domain of the influenza hemagglutinin polypeptide is the stem domain of cH7 / 3 chimeric influenza hemagglutinin polypeptide is the A /Perth / 16 / 2009 (H3N2 ) HA and the globular head domain globular head domain of A / chicken / Jalisco/ CPA1/ 2012 (H7 ) of the cH7/ 3 chimeric influenza hemagglutinin polypeptide HA . In another specific embodiment, the stem domain of a is the globular head domain of A /Netherlands /219 / 03 (H7 ) cH7/ 3 chimeric influenza hemagglutinin polypeptide is the 60 HA . In another specific embodiment, the stem domain of a stem domain of A / harbor seal/Massachusetts / 1 /2011 cH7/ 3 chimeric influenza hemagglutinin polypeptide is the ( H3N8 ) HA and the globular head domain of the cH7/ 3 stem domain of A /Perth / 16 / 2009 (H3N2 ) HA and the globu chimeric influenza hemagglutinin polypeptide is the globu - lar head domain of the cH7/ 3 chimeric influenza hemagglu lar head domain of A /mallard / Alberta / 24 / 2001 (H7 ) HA . In tinin polypeptide is the globular head domain of A /Canada / another specific embodiment, the stem domain of a cH7/ 3 65 504 /04 (H7 ) HA . In another specific embodiment, the stem chimeric influenza hemagglutinin polypeptide is the stem domain of a cH7 / 3 chimeric influenza hemagglutinin poly domain of A /harbor seal/ Massachusetts / 1 /2011 (H3N8 ) HA peptide is the stem domain of A / Perth / 16 / 2009 (H3N2 ) HA US 10 , 137 , 189 B2 47 48 and the globular head domain of the cH7/ 3 chimeric influ embodiment, the stem domain of a cH5 / B chimeric influ enza hemagglutinin polypeptide is the globular head domain enza hemagglutinin polypeptide is the stem domain of of A /Canada / 444 /04 (H7 ) HA . In another specific embodi B /Malaysia / 2506 /2004 HA and the globular head domain of ment, the stem domain of a cH7/ 3 chimeric influenza the cH5/ B chimeric influenza hemagglutinin polypeptide is hemagglutinin polypeptide is the stem domain of A / Perth / 5 the globular head domain of A / Whooperswan /Mongolia / 16 / 2009 (H3N2 ) HA and the globular head domain of the 244 / 2005 (H5 ) HA . cH7/ 3 chimeric influenza hemagglutinin polypeptide is the In another specific embodiment, the stem domain of a globular head domain of A /chicken /Jalisco /CPA1 / 2012 (H7 ) CH5 /B chimeric influenza hemagglutinin polypeptide is the HA . In another specific embodiment, the stem domain of a stem domain of B / Florida / 4 /2006 HA . In another specific cH7/ 3 chimeric influenza hemagglutinin polypeptide is the 10 embodiment, the stem domain of a cH5 / B chimeric influ stem domain of A /Perth / 16 /2009 (H3N2 ) HA and the globu - enza hemagglutinin polypeptide is the stem domain of lar head domain of the cH7 / 3 chimeric influenza hemagglu - B / Florida / 4 / 2006 HA and the globular head domain of the tinin polypeptide is the globular head domain of A /mallard / cH5/ B chimeric influenza hemagglutinin polypeptide is the Alberta / 24 / 2001 (H7 ) HA . In another specific embodiment, globular head domain of A /Vietnam / 1203 / 2004 (H5 ) HA . In the stem domain of a cH7/ 3 chimeric influenza hemagglu - 15 another specific embodiment, the stem domain of a cH5 /B tinin polypeptide is the stem domain of A / Perth / 16 /2009 chimeric influenza hemagglutinin polypeptide is the stem ( H3N2 ) HA and the globular head domain of the cH7/ 3 domain of B / Florida / 4 / 2006 HA and the globular head chimeric influenza hemagglutinin polypeptide is the globu - domain of the cH5/ B chimeric influenza hemagglutinin lar head domain of A /Rhea /NC /39482 / 93 (H7 ) HA . In polypeptide is the globular head domain of A / Indonesia / 5 / another specific embodiment, the stem domain of a cH7/ 3 20 2005 (H5 ) HA . In another specific embodiment, the stem chimeric influenza hemagglutinin polypeptide is the stem domain of a cH5 / B chimeric influenza hemagglutinin poly domain of A / Perth / 16 /2009 (H3N2 ) HA and the globular peptide is the stem domain of B / Florida / 4 /2006 HA and the head domain of the cH7/ 3 chimeric influenza hemagglutinin globular head domain of the cH5 /B chimeric influenza polypeptide is the globular head domain of A /mallard / hemagglutinin polypeptide is the globular head domain of Netherlands/ 12 /2000 ( H7) HA . 25 A / Anhui/ 1 / 2005 (H5 ) HA . In another specific embodiment , In a specific embodiment, a cH7 /3 chimeric influenza the stem domain of a cH5/ B chimeric influenza hemagglu hemagglutinin polypeptide provided herein does not com - tinin polypeptide is the stem domain of B / Florida / 4 / 2006 prise the globular head domain of A /mallard /Alberta / 24 / HA and the globular head domain of the cH5/ B chimeric 2001 (H7 ) HA . In another specific embodiment, a cH7/ 3 influenza hemagglutinin polypeptide is the globular head chimeric influenza hemagglutinin polypeptide does not 30 domain of A / Bar headed goose / Quinghai/ 1A / 2005 (H5 ) HA . comprise the stem domain of A / Perth / 16 /2009 (H3 ) HA . In another specific embodiment, the stem domain of a cH5 / B In certain embodiments , a chimeric influenza hemagglu - chimeric influenza hemagglutinin polypeptide is the stem tinin (HA ) polypeptide provided herein comprises (i ) the domain of B /Florida / 4 /2006 HA and the globular head stem domain of the hemagglutinin from an influenza B virus domain of the cH5/ B chimeric influenza hemagglutinin and ( ii ) the globular head domain of the hemagglutinin from 35 polypeptide is the globular head domain of A / turkey / Turkey / an influenza virus of the H5 subtype ( sometimes referred to 1 / 2005 (H5 ) HA . In another specific embodiment, the stem herein as a " cH5 / B chimeric influenza hemagglutinin poly - domain of a cH5 / B chimeric influenza hemagglutinin poly peptide ” ) . In a specific embodiment, the stem domain of a peptide is the stem domain of B / Florida / 4 / 2006 and the cH5 / B chimeric influenza hemagglutinin polypeptide is the globular head domain of the cH5/ B chimeric influenza stem domain of B /Malaysia /2506 / 2004 HA . In another 40 hemagglutinin polypeptide is the globular head domain of specific embodiment, the stem domain of a cH5 / B chimeric A / Whooperswan /Mongolia / 244 / 2005 (H5 ) HA . influenza hemagglutinin polypeptide is the stem domain of In another specific embodiment, the stem domain of a B /Malaysia / 2506 / 2004 HA and the globular head domain of cH5/ B chimeric influenza hemagglutinin polypeptide is the the cH5/ B chimeric influenza hemagglutinin polypeptide is stem domain of B /Wisconsin / 1 /2010 HA . In another specific the globular head domain of A /Vietnam / 1203 /2004 (H5 ) 45 embodiment, the stem domain of a cH5 / B chimeric influ HA . In another specific embodiment, the stem domain of a enza hemagglutinin polypeptide is the stem domain of cH5 / B chimeric influenza hemagglutinin polypeptide is the B /Wisconsin / 1 / 2010 HA and the globular head domain of stem domain of B /Malaysia / 2506 / 2004 HA and the globular the cH5/ B chimeric influenza hemagglutinin polypeptide is head domain of the cH5 / B chimeric influenza hemagglutinin the globular head domain of A /Vietnam / 1203 / 2004 (H5 ) polypeptide is the globular head domain of A / Indonesia / 5 / 50 HA . In another specific embodiment, the stem domain of a 2005 (H5 ) HA . In another specific embodiment, the stem cH5/ B chimeric influenza hemagglutinin polypeptide is the domain of a cH5 / B chimeric influenza hemagglutinin poly - stem domain of B /Wisconsin / 1 / 2010 HA and the globular peptide is the stem domain of B /Malaysia / 2506 /2004 HA head domain of the cH5/ B chimeric influenza hemagglutinin and the globular head domain of the cH5 / B chimeric influ - polypeptide is the globular head domain of A /Indonesia / 5 / enza hemagglutinin polypeptide is the globular head domain 55 2005 (H5 ) HA . In another specific embodiment, the stem of A /Anhui / 1 /2005 (H5 ) HA . In another specific embodi domain of a cH5/ B chimeric influenza hemagglutinin poly ment, the stem domain of a cH5 / B chimeric influenza peptide is the stem domain of B /Wisconsin / 1 / 2010 HA and hemagglutinin polypeptide is the stem domain of B /Malay - the globular head domain of the cH5 / B chimeric influenza sia / 2506 /2004 HA and the globular head domain of the hemagglutinin polypeptide is the globular head domain of cH5 / B chimeric influenza hemagglutinin polypeptide is the 60 A / Anhui/ 1 /2005 (H5 ) HA . In another specific embodiment, globular head domain of A / Bar headed goose / Quinghai/ 1A ) the stem domain of a cH5 / B chimeric influenza hemagglu 2005 (H5 ) HA . In another specific embodiment, the stem tinin polypeptide is the stem domain of B /Wisconsin / 1 /2010 domain of a cH5/ B chimeric influenza hemagglutinin poly - HA and the globular head domain of the cH5/ B chimeric peptide is the stem domain of B /Malaysia / 2506 / 2004 HA influenza hemagglutinin polypeptide is the globular head and the globular head domain of the cH5 / B chimeric influ - 65 domain of A /Bar headed goose / Quinghai/ 1A / 2005 (H5 ) HA . enza hemagglutinin polypeptide is the globular head domain In another specific embodiment, the stem domain of a cH5 / B of A / turkey / Turkey / 1 /2005 (H5 ) HA . In another specific chimeric influenza hemagglutinin polypeptide is the stem US 10 , 137 , 189 B2 49 50 domain of B /Wisconsin / 1/ 2010 HA and the globular head enza hemagglutinin polypeptide is the globular head domain domain of the cH5/ B chimeric influenza hemagglutinin of A / Canada/ 444 /04 (H7 ) HA . In another specific embodi polypeptide is the globular head domain of A / turkey / Turkey / ment, the stem domain of a cH7 /B chimeric influenza 1 / 2005 (H5 ) HA . In another specific embodiment, the stem hemagglutinin polypeptide is the stem domain of B /Malay domain of a cH5 / B chimeric influenza hemagglutinin poly - 5 sia /2506 /2004 HA and the globular head domain of the peptide is the stem domain of B /Wisconsin / 1 / 2010 HA and cH7/ B chimeric influenza hemagglutinin polypeptide is the the globular head domain of the cH5/ B chimeric influenza globular head domain of A / chicken / Jalisco /CPA1 / 2012 (H7 ) hemagglutinin polypeptide is the globular head domain of HA . In another specific embodiment, the stem domain of a A /Whooperswan /Mongolia /244 /2005 (H5 ) HA . CH7/ B chimeric influenza hemagglutinin polypeptide is the In another specific embodiment, the stem domain of a 10 stem domain of B /Malaysia / 2506 /2004 HA and the globular CH5 / B chimeric influenza hemagglutinin polypeptide is the head domain of the cH7 / B chimeric influenza hemagglutinin stem domain of B /Brisbane /60 / 2008 HA . In another specific polypeptide is the globular head domain of A /mallard / embodiment, the stem domain of a cH5/ B chimeric influ - Alberta / 24 /2001 (H7 ) HA . In another specific embodiment, enza hemagglutinin polypeptide is the stem domain of the stem domain of a cH7 / B chimeric influenza hemagglu B /Brisbane /60 /2008 HA and the globular head domain of the 15 tinin polypeptide is the stem domain of B /Malaysia / 2506 / cH5/ B chimeric influenza hemagglutinin polypeptide is the 2004 HA and the globular head domain of the cH7 /B globular head domain of A / Vietnam / 1203/ 2004 (H5 ) HA . In chimeric influenza hemagglutinin polypeptide is the globu another specific embodiment, the stem domain of a cH5/ B lar head domain of A /Rhea / NC /39482 /93 (H7 ) HA . In chimeric influenza hemagglutinin polypeptide is the stem another specific embodiment, the stem domain of a cH7 / B domain of B /Brisbane / 60 /2008 HA and the globular head 20 chimeric influenza hemagglutinin polypeptide is the stem domain of the cH5/ B chimeric influenza hemagglutinin domain of B /Malaysia / 2506 / 2004 HA and the globular head polypeptide is the globular head domain of A / Indonesia / 5 / domain of the cH7/ B chimeric influenza hemagglutinin 2005 (H5 ) HA . In another specific embodiment, the stem polypeptide is the globular head domain of A /mallard / domain of a cH5 / B chimeric influenza hemagglutinin poly - Massachusetts / 12 / 2000 (H7 ) HA . peptide is the stem domain of B / Brisbane/ 60 / 2008 HA and 25 In another specific embodiment, the stem domain of a the globular head domain of the cH5 /B chimeric influenza cH7 /B chimeric influenza hemagglutinin polypeptide is the hemagglutinin polypeptide is the globular head domain of stem domain of B /Florida /4 /2006 HA . In another specific A / Anhui/ 1/ 2005 (H5 ) HA . In another specific embodiment, embodiment, the stem domain of a cH7 /B chimeric influ the stem domain of a cH5/ B chimeric influenza hemagglu - enza hemagglutinin polypeptide is the stem domain of tinin polypeptide is the stem domain of B /Brisbane / 60 /2008 30 B /Florida / 4 /2006 HA and the globular head domain of the HA and the globular head domain of the cH5 / B chimeric cH7 / B chimeric influenza hemagglutinin polypeptide is the influenza hemagglutinin polypeptide is the globular head globular head domain of A /Netherlands / 219 / 03 (H7 ) HA . In domain of A /Bar headed goose / Quinghai / 1A / 2005 (H5 ) HA . another specific embodiment, the stem domain of a cH7/ B In another specific embodiment, the stem domain of a cH5 / B chimeric influenza hemagglutinin polypeptide is the stem chimeric influenza hemagglutinin polypeptide is the stem 35 domain of B /Florida / 4 /2006 HA and the globular head domain of B / Brisbane/ 60 / 2008 HA and the globular head domain of the cH7/ B chimeric influenza hemagglutinin domain of the cH5 / B chimeric influenza hemagglutinin polypeptide is the globular head domain of A / Canada /504 / polypeptide is the globular head domain of A / turkey / Turkey 04 (H7 ) HA . In another specific embodiment, the stem 1 / 2005 (H5 ) HA . In another specific embodiment, the stem domain of a cH7/ B chimeric influenza hemagglutinin poly domain of a cH5 /B chimeric influenza hemagglutinin poly - 40 peptide is the stem domain of B / Florida / 4 / 2006 HA and the peptide is the stem domain of B /Brisbane / 60 /2008 HA and globular head domain of the cH7/ B chimeric influenza the globular head domain of the cH5 / B chimeric influenza hemagglutinin polypeptide is the globular head domain of hemagglutinin polypeptide is the globular head domain of A / Canada/ 444 /04 (H7 ) HA . In another specific embodiment, A /Whooperswan /Mongolia /244 /2005 (H5 ) HA . the stem domain of a cH7 / B chimeric influenza hemagglu In certain embodiments, a chimeric influenza hemagglu - 45 tinin polypeptide is the stem domain of B / Florida / 4 /2006 tinin ( HA ) polypeptide provided herein comprises (i ) the HA and the globular head domain of the cH7/ B chimeric stem domain of the hemagglutinin from an influenza B virus influenza hemagglutinin polypeptide is the globular head and ( ii ) the globular head domain of the hemagglutinin from domain of A / chicken / Jalisco / CPA1 / 2012 ( H7) HA . In an influenza virus of the H7 subtype ( sometimes referred to another specific embodiment , the stem domain of a cH7 / B herein as a “ CH7/ B chimeric influenza hemagglutinin poly - 50 chimeric influenza hemagglutinin polypeptide is the stem peptide ” ) . In a specific embodiment, the stem domain of a domain of B / Florida / 4 /2006 HA and the globular head CH7/ B chimeric influenza hemagglutinin polypeptide is the domain of the cH7/ B chimeric influenza hemagglutinin stem domain of B /Malaysia / 2506 / 2004 HA . In another polypeptide is the globular head domain of A /mallard / specific embodiment, the stem domain of a cH7/ B chimeric Alberta / 24 / 2001 (H7 ) HA . In another specific embodiment, influenza hemagglutinin polypeptide is the stem domain of 55 the stem domain of a cH7 / B chimeric influenza hemagglu B /Malaysia / 2506 /2004 HA and the globular head domain of tinin polypeptide is the stem domain of B / Florida / 4 /2006 the cH7 / B chimeric influenza hemagglutinin polypeptide is HA and the globular head domain of the cH7/ B chimeric the globular head domain of A /Netherlands / 219 / 03 (H7 ) influenza hemagglutinin polypeptide is the globular head HA . In another specific embodiment, the stem domain of a domain of A /Rhea /NC /39482 / 93 (H7 ) HA . In another spe cH7/ B chimeric influenza hemagglutinin polypeptide is the 60 cific embodiment, the stem domain of a cH7/ B chimeric stem domain of B /Malaysia / 2506 /2004 HA and the globular influenza hemagglutinin polypeptide is the stem domain of head domain of the cH7 / B chimeric influenza hemagglutinin B / Florida / 4 / 2006 HA and the globular head domain of the polypeptide is the globular head domain of A / Canada/ 504 / cH7 / B chimeric influenza hemagglutinin polypeptide is the 04 (H7 ) HA . In another specific embodiment, the stem globular head domain of A /mallard / Massachusetts / 12/ 2000 domain of a cH7 /B chimeric influenza hemagglutinin poly - 65 (H7 ) HA . peptide is the stem domain of B /Malaysia / 2506 / 2004 HA In another specific embodiment, the stem domain of a and the globular head domain of the cH7/ B chimeric influ - cH7 / B chimeric influenza hemagglutinin polypeptide is the US 10 , 137 , 189 B2 5) 52 stem domain of B /Wisconsin / 1 / 2010 HA . In another specific polypeptide is the globular head domain of A / mallard / embodiment, the stem domain of a cH7 / B chimeric influ Alberta / 24 /2001 (H7 ) HA . In another specific embodiment, enza hemagglutinin polypeptide is the stem domain of the stem domain of a cH7/ B chimeric influenza hemagglu B /Wisconsin / 1 /2010 HA and the globular head domain of tinin polypeptide is the stem domain of B /Brisbane /60 /2008 the cH7 / B chimeric influenza hemagglutinin polypeptide is 5 HA and the globular head domain of the cH7 / B chimeric the globular head domain of A /Netherlands / 219 /03 (H7 ) influenza hemagglutinin polypeptide is the globular head HA . In another specific embodiment, the stem domain of a domain of A /Rhea /NC /39482 / 93 (H7 ) HA . In another spe CH7/ B chimeric influenza hemagglutinin polypeptide is the cific embodiment, the stem domain of a cH7/ B chimeric stem domain of B / Wisconsin / 1 /2010 HA and the globular influenza hemagglutinin polypeptide is the stem domain of head domain of the cH7/ B chimeric influenza hemagglutinin 10 B /Brisbane /60 / 2008 HA and the globular head domain of the polypeptide is the globular head domain of A /Canada / 5047 c H7/ B chimeric influenza hemagglutinin polypeptide is the 04 (H7 ) HA . In another specific embodiment, the stem globular head domain of A /mallard /Massachusetts / 12 / 2000 domain of a cH7 /B chimeric influenza hemagglutinin poly - (H7 ) HA . peptide is the stem domain of B /Wisconsin / 1 / 2010 HA and In certain embodiments , a chimeric influenza hemagglu the globular head domain of the cH7/ B chimeric influenza 15 tinin (HA ) polypeptide provided herein comprises ( i ) the hemagglutinin polypeptide is the globular head domain of stem domain of the hemagglutinin from an influenza B virus A / Canada /444 /04 (H7 ) HA . In another specific embodiment, and ( ii ) the globular head domain of the hemagglutinin from the stem domain of a cH7/ B chimeric influenza hemagglu - a different influenza B virus strain ( sometimes referred to tinin polypeptide is the stem domain of B /Wisconsin / 1 / 2010 herein as a “ cB / B chimeric influenza hemagglutinin poly HA and the globular head domain of the cH7/ B chimeric 20 peptide ” ) . In a specific embodiment, the stem domain of a influenza hemagglutinin polypeptide is the globular head cB / B chimeric influenza hemagglutinin polypeptide is the domain of A / chicken / Jalisco /CPA1 / 2012 (17 ) HA . In stem domain of B /Malaysia /2506 /2004 HA . In another another specific embodiment, the stem domain of a cH7/ B specific embodiment, the stem domain of a cB / B chimeric chimeric influenza hemagglutinin polypeptide is the stem influenza hemagglutinin polypeptide is the stem domain of domain of B / Wisconsin / 1 /2010 HA and the globular head 25 B /Malaysia / 2506 /2004 HA and the globular head domain of domain of the cH7 / B chimeric influenza hemagglutinin the cB / B chimeric influenza hemagglutinin polypeptide is polypeptide is the globular head domain of A /mallard / the globular head domain of B / Lee / 1940 HA . In another Alberta / 24 / 2001 (H7 ) HA . In another specific embodiment, specific embodiment, the stem domain of a cB / B chimeric the stem domain of a cH7 / B chimeric influenza hemagglu - influenza hemagglutinin polypeptide is the stem domain of tinin polypeptide is the stem domain of B /Wisconsin / 1/ 2010 30 B /Malaysia / 2506 / 2004 HA and the globular head domain of HA and the globular head domain of the cH7/ B chimeric the cB / B chimeric influenza hemagglutinin polypeptide is influenza hemagglutinin polypeptide is the globular head the globular head domain of B /seal / Netherlands / 1 / 99 HA (or domain of A /Rhea /NC /39482 /93 (H7 ) HA . In another spe - a B / seal/ Netherlands / 1 /99 - like influenza virus ). cific embodiment, the stem domain of a cH7/ B chimeric In another specific embodiment, the stem domain of a influenza hemagglutinin polypeptide is the stem domain of 35 cB / B chimeric influenza hemagglutinin polypeptide is the B /Wisconsin / 1 /2010 HA and the globular head domain of stem domain of B / Florida /4 / 2006 HA . In another specific the cH7/ B chimeric influenza hemagglutinin polypeptide is embodiment, the stem domain of a cB / B chimeric influenza the globular head domain of A /mallard /Massachusetts / 12 / hemagglutinin polypeptide is the stem domain of B /Florida / 2000 (H7 ) HA . 4 / 2006 HA and the globular head domain of the cB / B In another specific embodiment, the stem domain of a 40 chimeric influenza hemagglutinin polypeptide is the globu CH7 / B chimeric influenza hemagglutinin polypeptide is the lar head domain of B /Lee / 1940 HA . In another specific stem domain of B /Brisbane /60 / 2008 HA . In another specific embodiment, the stem domain of a cB / B chimeric influenza embodiment, the stem domain of a cH7/ B chimeric influ - hemagglutinin polypeptide is the stem domain of B / Florida/ enza hemagglutinin polypeptide is the stem domain of 4 / 2006 HA and the globular head domain of the cB / B B /Brisbane /60 / 2008 HA and the globular head domain of the 45 chimeric influenza hemagglutinin polypeptide is the globu CH7/ B chimeric influenza hemagglutinin polypeptide is the lar head domain of B / seal/Netherlands / 1 /99 HA ( or a B / seal/ globular head domain of A /Netherlands / 219 /03 (H7 ) HA . In Netherlands/ 1 /99 - like influenza virus ) . another specific embodiment, the stem domain of a cH7/ B In another specific embodiment, the stem domain of a chimeric influenza hemagglutinin polypeptide is the stem cB /B chimeric influenza hemagglutinin polypeptide is the domain of B /Brisbane / 60 /2008 HA and the globular head 50 stem domain of B / Wisconsin / 1 / 2010 HA . In another specific domain of the cH7/ B chimeric influenza hemagglutinin embodiment , the stem domain of a B / B chimeric influenza polypeptide is the globular head domain of A /Canada / 504 ) hemagglutinin polypeptide is the stem domain of B /Wis 04 (H7 ) HA . In another specific embodiment, the stem consin / 1 /2010 HA and the globular head domain of the cB /B domain of a cH7/ B chimeric influenza hemagglutinin poly - chimeric influenza hemagglutinin polypeptide is the globu peptide is the stem domain of B /Brisbane /60 / 2008 HA and 55 lar head domain of B /Lee / 1940 HA . In another specific the globular head domain of the cH7/ B chimeric influenza embodiment, the stem domain of a cB / B chimeric influenza hemagglutinin polypeptide is the globular head domain of hemagglutinin polypeptide is the stem domain of B /Wis A / Canada/ 444 / 04 (H7 ) HA . In another specific embodiment, consin /1 /2010 HA and the globular head domain of the cB /B the stem domain of a cH7/ B chimeric influenza hemagglu - chimeric influenza hemagglutinin polypeptide is the globu tinin polypeptide is the stem domain of B / Brisbane /60 /2008 60 lar head domain of B /seal /Netherlands / 1 / 99 HA (or a B /seal / HA and the globular head domain of the cH7/ B chimeric Netherlands /1 /99 -like influenza virus) . influenza hemagglutinin polypeptide is the globular head In another specific embodiment, the stem domain of a domain of A / chicken / Jalisco/ CPA1 /2012 (H7 ) HA . In cB / B chimeric influenza hemagglutinin polypeptide is the another specific embodiment, the stem domain of a cH7 / B stem domain of B / Brisbane/ 60 / 2008 HA . In another specific chimeric influenza hemagglutinin polypeptide is the stem 65 embodiment, the stem domain of a cB / B chimeric influenza domain of B /Brisbane / 60 / 2008 HA and the globular head hemagglutinin polypeptide is the stem domain of B / Bris domain of the cH7/ B chimeric influenza hemagglutinin bane/ 60 / 2008 HA and the globular head domain of the cB / B US 10 , 137 , 189 B2 53 54 chimeric influenza hemagglutinin polypeptide is the globu are from the same hemagglutinin as the stem domain . In lar head domain of B /Lee / 1940 HA . In another specific certain embodiments , the transmembrane domains are from embodiment , the stem domain of a cB / B chimeric influenza influenza virus strain or subtype as the stem domain HA2 hemagglutinin polypeptide is the stem domain of B /Bris subunit . bane /60 / 2008 HA and the globular head domain of the cB / B 5 In certain embodiments , a chimeric influenza virus chimeric influenza hemagglutinin polypeptide is the globu - hemagglutinin polypeptide provided herein comprises a lar head domain of B /seal / Netherlands / 1 / 99 HA ( or a B / seal/ cytoplasmic domain . In embodiments where a chimeric Netherlands / 1 /99 -like influenza virus ). influenza virus hemagglutinin polypeptide provided herein In certain embodiments, a chimeric influenza virus comprises a cytoplasmic domain , the cytoplasmic domain hemagglutinin polypeptide provided herein is monomeric . 10 might be based on any influenza cytoplasmic domain known In certain embodiments , a chimeric influenza virus hemag - to those of skill in the art. In certain embodiments , the glutinin polypeptide provided herein is multimeric . In cer- cytoplasmic domains are based on influenza A cytoplasmic tain embodiments , a chimeric influenza virus hemagglutinin domains . In certain embodiments , the cytoplasmic domains polypeptide provided herein is trimeric . are based on a cytoplasmic domain of an influenza A In certain embodiments, a chimeric influenza virus 15 hemagglutinin selected from the group consisting of H1, H2 , hemagglutinin polypeptide provided herein comprises a H3, H4 , H5, H6 , H7, H8, H9, H10 , H11, H12 , H13 , H14 , signal peptide. Typically , the signal peptide is cleaved during H15 , H16 , and H17 . In certain embodiments , the cytoplas or after polypeptide expression and translation to yield a mic domain might be any cytoplasmic domain deemed mature chimeric influenza virus hemagglutinin polypeptide . useful to one of skill in the art . In certain embodiments, the In certain embodiments , also provided herein are mature 20 cytoplasmic domains are from the same hemagglutinin as chimeric influenza virus hemagglutinin polypeptides that the stem domain . In certain embodiments , the cytoplasmic lack a signal peptide . In embodiments where a chimeric domains are from influenza virus strain or subtype as the influenza virus hemagglutinin polypeptide provided herein stem domain HA2 subunit . comprises a signal peptide, the signal peptide mightbe based In certain embodiments , the chimeric influenza virus on any influenza virus signal peptide known to those of skill 25 hemagglutinin polypeptides provided herein further com in the art . In certain embodiments , the signal peptides are prise one or more polypeptide domains. Useful polypeptide based on influenza A signal peptides . In certain embodi- domains include domains that facilitate purification , folding ments , the signal peptides are based on the signal peptide of and cleavage of portions of a polypeptide . For example , a an influenza A hemagglutinin selected from the group con - His tag (His -His -His -His -His -His , SEQ ID NO : 17 ) , FLAG sisting of H1 , H2 , H3 , H4 , H5 , H6 , H7 , H8 , H9, H10 , H11 , 30 epitope or other purification tag can facilitate purification of H12 , H13 , H14 , H15 , H16 , and H17 . In certain embodi- a chimeric influenza virus hemagglutinin polypeptide pro ments , the signal peptide might be any signal peptide vided herein . In some embodiments , the His tag has the deemed useful to one of skill in the art . sequence , (His ) n , wherein n is 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11, In certain embodiments , a chimeric influenza virus 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 or greater. A foldon , or hemagglutinin polypeptide provided herein comprises a 35 trimerization , domain from bacteriophage T4 fibritin can luminal domain . In embodiments where a chimeric influenza facilitate trimerization of polypeptides provided herein . In virus hemagglutinin polypeptide provided herein comprises some embodiments , the trimerization domain comprises a a luminal domain , the luminal domain might be based on wildtype GCN4pII trimerization heptad repeat or a modified any influenza luminal domain known to those of skill in the GCN4pII trimerization heptad repeat that allows for the art . In certain embodiments , the luminal domains are based 40 formation of trimeric or tetrameric coiled coils . See , e . g . , on influenza Aluminal domains . In certain embodiments , the Weldon et al. , 2010 , PLOSONE 5 ( 9 ) : e12466 . The foldon luminal domains are based on the luminal domain of an domain can have any foldon sequence known to those of influenza A hemagglutinin selected from the group consist - skill in the art (see , e . g . , Papanikolopoulou et al. , 2004 , J . ing of H1, H2 , H3, H4 , H5, H6 , H7, H8 , H9 , H10 , H11 , H12 , Biol. Chem . 279 ( 10 ) : 8991 - 8998 , the contents of which are H13, H14 , H15 , H16 , and H17 . In certain embodiments , the 45 hereby incorporated by reference in their entirety ). luminal domain might be any luminal domain deemed useful Examples include GSGYIPEAPRDGQAYVRKDGEWV to one of skill in the art. In certain embodiments , the luminal LLSTFL (SEQ ID NO : 18 ). A foldon domain can be useful domains are from the same hemagglutinin as the stem to facilitate trimerization of soluble polypeptides provided domain . In certain embodiments, the luminal domains are herein . Cleavage sites can be used to facilitate cleavage of from influenza virus strain or subtype as the stem domain 50 a portion of a polypeptide , for example cleavage of a HA2 subunit . purification tag or foldon domain or both . Useful cleavage In certain embodiments , a chimeric influenza virus sites include a thrombin cleavage site , for example one with hemagglutinin polypeptide provided herein comprises a the sequence LVPRGSP (SEQ ID NO : 19 ) . In certain transmembrane domain . In embodiments where a chimeric embodiments , the cleavage site is a cleavage site recognized influenza virus hemagglutinin polypeptide provided herein 55 by Tobacco Etch Virus ( TEV ) protease ( e . g . , amino acid comprises a transmembrane domain , the transmembrane sequence Glu - Asn -Leu - Tyr- Phe -Gln - (Gly / Ser) (SEQ ID domain might be based on any influenza transmembrane NO : 20 ) ) . domain known to those of skill in the art . In certain In certain embodiments , the chimeric influenza hemag embodiments , the transmembrane domains are based on glutinin polypeptides described herein are soluble polypep influenza A transmembrane domains . In certain embodi- 60 tides . ments , the transmembrane domains are based on a trans- In certain embodiments , the influenza hemagglutinin stem membrane domain of an influenza A hemagglutinin selected domain polypeptides of the chimeric influenza virus hemag from the group consisting of H1, H2, H3, H4, H5, H6 , H7, glutinin polypeptides described herein maintain the cysteine H8 , H9, H10 , H11, H12 , H13, H14 , H15 , H16 , and H17 . In residues identified in influenza hemagglutinin polypeptides certain embodiments , the transmembrane domain might be 65 as A , and A , in FIG . 1 , i. e . , the cysteine residues identified any transmembrane domain deemed useful to one of skill in in influenza hemagglutinin polypeptides as A , and A , in the art. In certain embodiments , the transmembrane domains FIG . 1 are maintained in the chimeric influenza virus hemag US 10 , 137 , 189 B2 55 56 glutinin polypeptides described herein . Thus , in certain minal stem segment and the influenza hemagglutinin head embodiments , in the primary sequence of a chimeric influ - domain polypeptide so that the resulting chimeric influenza enza virus hemagglutinin polypeptide described herein : ( i ) virus hemagglutinin polypeptide is capable of forming a the N - terminal segment of an influenza hemagglutinin stem three - dimensional structure similar to a wild - type influenza domain polypeptide ends at the cysteine residue identified as 5 hemagglutinin . In such embodiments , an influenza hemag A , in FIG . 1 , (ii ) the C -terminal segment of an influenza glutinin head domain polypeptide (which is heterologous to hemagglutinin stem domain polypeptide begins at the cys the influenza hemagglutinin stem domain polypeptide ) is teine residue identified as A , in FIG . 1 ; and ( iii ) the influenza hemagglutinin head domain polypeptide (which is heterolo located , in primary sequence , between the N - terminal and gous to the influenza hemagglutinin stem domain polypep - 10 Cdo -terminal segments of the influenza hemagglutinin stem tide ) is between the N -terminal and C -terminal segments of domain polypeptide. the influenza hemagglutinin stem domain polypeptidede . In one example , an HA1 N - terminal stem segment of a In certain embodiments , the HA1 N - terminal stem seg chimeric influenza virus hemagglutinin polypeptide ment of the chimeric influenza virus hemagglutinin poly described herein may end at any one of hemagglutinin peptides described herein does not end exactly at A , ( e . g . , 15 aminoa acid positions 45 -48 (using H3 numbering ) and an Cys32 of an HA1 subunit from an H3 hemagglutinin ) , but at HA1 C - terminal stem segment of the chimeric influenza a residue in sequence and structural vicinity to Am . For virus hemagglutinin polypeptide may start at any one of example , in certain embodiments , the HA1 N -terminal stem hemagglutinin amino acid positions 282 - 287 ( using H3 segment of the chimeric influenza virus hemagglutinin poly numbering) ; and the heterologous head domain may begin at peptides described herein ends at Ap _ 1 , A2 - 2 , A2 - 3, A , - 4 , 20 any one of amino acid positions 46 - 49 and end at any one of Ap - 5 , A2 - 6 , A2 -79 Ap - 8 , Ap - 9 , An - 10 . In certain embodiments, amino acid position 284 - 289 (using H3 numbering ) . the HA1 N - terminal stem segment of the chimeric influenza In certain embodiments , when the stem domain of the virus hemagglutinin polypeptides described herein ends in chimeric influenza virus hemagglutinin polypeptides the range of Ap- 1 to Ap- 3, A2- 3 to Ap -5 , Ap -5 to Ap- 8, A2 - 8 described herein is derived from an influenza B virus , the to An- 10 . For example , an HA1 N - terminal stem segment 25 HA1 N -terminal stem segment may end at, e . g ., amino acid ending at Ap- 10 would end at Leu42 of an H3 hemagglutinin . 35 , 36 , 37 , 38 , 39, 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49, or In certain embodiments , the HA1 N - terminal stem segment 50 of the HA ( in primary amino acid sequence ) , and the HA1 of the chimeric influenza virus hemagglutinin polypeptides C -terminal stem segment may begin at, e . g . , amino amino described herein ends at Ap + 1 , Ap + 2 , Ap+ 3 , Ap+ 4 , Ap + 5 , A2 + 62 acid 280 , 281, 282 , 283 , 284 , 285 , 286 , 287 , 288 , 289, 290 , Ap + 7, Ap + 8, A2+ 9 , Ap + 10 . In certain embodiments , the HA1 30 291, 292 , 293 , 294 , 295 , 296 , 297 , 298 , 299, or 300 of the N - terminal stem segment of the chimeric influenza virus HA ( in primary amino acid sequence ). The globular head hemagglutinin polypeptides described herein ends in the domain of the chimeric influenza virus hemagglutinin poly range of Ap + 1 to Ap + 5 , Ap + 5 to Ap + 10 The end of an HA1 peptide thus would be inserted between the HA1 N - terminal N - terminal stem segment should be selected in conjunction stem segment and the HA1 C - terminal stem segment of the with the end of the HA1 C - terminal stem segment and the 35 influenza B virus stem domain . For example , in the HA of influenza hemagglutinin head domain polypeptide so that influenza virus B /Hong Kong/ 8 /73 (PDB :2RFT : GenBank : the resulting chimeric influenza virus hemagglutinin poly - M10298 . 1 ) , the HA1 N -terminal stem segmentwould begin peptide is capable of forming a three -dimensional structure with amino acids DRICT (SEQ ID NO : 22 ) , with “ D ” being similar to a wild - type influenza hemagglutinin . In such position 1 , and would end at amino acid position 42 ( in embodiments , an influenza hemagglutinin head domain 40 primary sequence ) ; and the HA1 C -terminal stem segment polypeptide (which is heterologous to the influenza hemag - would begin at amino acid position 288 ( in primary glutinin stem domain polypeptide ) is located , in primary sequence ) and continue to the end of the C -terminus of the sequence , between the N - terminal and C - terminal segments HA . of the influenza hemagglutinin stem domain polypeptide. In certain embodiments , a chimeric influenza hemagglu In certain embodiments , the HA1 C - terminal stem seg - 45 tinin (HA ) polypeptide described herein may be conjugated ment of the chimeric influenza virus hemagglutinin poly - to heterologous proteins, e . g . , a major histocompatibility peptides described herein does not start exactly at A , ( e . g ., complex (MHC ) with or without heat shock proteins ( e . g . , Cys277 of an HA1 subunit from an H3 hemagglutinin ), but Hsp10 , Hsp20 , Hsp30 , Hsp40 , Hsp60 , Hsp70 , Hsp90 , or at a residue in sequence and structural vicinity to A , . For Hsp100 ) . In certain embodiments, a chimeric influenza example , in certain embodiments , the HA1 C -terminal stem 50 hemagglutinin (HA ) polypeptide described herein may be segment of the chimeric influenza virus hemagglutinin poly - conjugated to immunomodulatory molecules , such as pro peptides described herein starts at about Ag- 1 , Ag- 2 , Ag - 3 , teins which would target the chimeric influenza hemagglu Ag- 4, Ag- 5, Ag -6 ,Ag - 7, Ag- 8, Ag -9 ,Ag - 10 . In certain embodi tinin (HA ) polypeptide to immune cells such as B cells ( e . g ., ments , the HA1 C - terminal stem segment of the chimeric C3d ) or T cells . In certain embodiments , chimeric influenza influenza virus hemagglutinin polypeptides described herein 55 hemagglutinin (HA ) polypeptide described herein may be starts in the range of Ag- 1 to Ag - 5 , Ag- 5 to Ag - 10 . For conjugated to proteins which stimulate the innate immune example , an HA1 C - terminal stem segment ending at Ag - 10 system such as interferon type 1 , alpha, beta , or gamma would start at Isoleucine267 of an H3 hemagglutinin . In interferon , colony stimulating factors such as granulocyte certain embodiments , the HA1 C - terminal stem segment of macrophage colony - stimulating factor (GM - CSF ) , interleu the chimeric influenza virus hemagglutinin polypeptides 60 kin ( IL ) - 1 , IL - 2 , IL - 4 , IL - 5 , IL - 6 , IL - 7 , IL - 12 , IL - 15 , IL - 18 , described herein starts at Ag + 1 , Ag + 2, A , + 3 , Ag + 4 , Ag+ 5 , Ag + 63 IL - 21 , IL - 23 , tumor necrosis factor ( TNF ) - B , TNFC , B7. 1 , Ag+ 7 , Ag + 8, Ag+ 9 , Ag + 10 . In certain embodiments , the HA1 B 7 . 2 , 4 - 1BB , CD40 ligand (CD40L ), and drug- inducible C - terminal stem segment of the chimeric influenza virus CD40 ( iCD40 ). hemagglutinin polypeptides described herein starts in the It will be understood by those of skill in the art that the range of Ag + 1 to Ag+ 3 , Ag + 3 to Ag+ 5 , Ag+ 5 to Ag+ 8 , Ag+ 8 to 65 chimeric influenza virus hemagglutinin polypeptides pro Ag + 10 . The end of an HA1 N - terminal stem segment should vided herein can be prepared according to any technique be selected in conjunction with the start of the HA1 C -ter - known by and deemed suitable to those of skill in the art , US 10 , 137 , 189 B2 57 58 including the techniques described herein . In certain tially free of cellular material includes preparations of embodiments , the chimeric influenza virus hemagglutinin nucleic acid having less than about 30 % , 20 % , 10 % , or 5 % polypeptides are isolated . (by dry weight) of other nucleic acids . The term " substan 5 . 2 Nucleic Acids Encoding Chimeric Influenza Virus tially free of culture medium ” includes preparations of Hemagglutinin (HA ) Polypeptides nucleic acid in which the culture medium represents less Provided herein are nucleic acids that encode the chimeric than about 50 % , 20 % , 10 % , or 5 % of the volume of the influenza hemagglutinin (HA ) polypeptides described herein preparation . The term " substantially free of chemical pre (e .g ., the chimeric influenza hemagglutinin (HA ) polypep cursors or other chemicals” includes preparations in which tides described in Section 5 . 1 ) . Due to the degeneracy of the the nucleic acid is separated from chemical precursors or genetic code , any nucleic acid that encodes a chimeric 10 other chemicals which are involved in the synthesis of the influenza hemagglutinin (HA ) polypeptide described herein nucleic acid . In specific embodiments , such preparations of is encompassed herein . In certain embodiments , nucleic the nucleic acid have less than about 50 % , 30 % , 20 % , 10 % , acids corresponding to , or capable of hybridizing with , 5 % (by dry weight ) of chemical precursors or compounds naturally occurring influenza virus nucleic acids encoding an other than the nucleic acid of interest. HA1 N -terminal stem segment, an HA1 C -terminal stem 15 In addition , provided herein are nucleic acids encoding segment , HA2 domain , luminal domain , transmembrane the individual components of a chimeric influenza hemag domain , and /or cytoplasmic domain are used to produce a glutinin ( HA ) polypeptide described herein , e . g . , nucleic chimeric influenza hemagglutinin (HA ) polypeptide acids encoding the globular head domain , the HA1 N - ter described herein . minal stem segment, the HA1 C -terminal stem segment Also provided herein are nucleic acids capable of hybrid - 20 and /or the HA2 domain a chimeric influenza hemagglutinin izing to a nucleic acid encoding a chimeric influenza hemag - (HA ) polypeptide described herein are provided herein . glutinin (HA ) polypeptide described herein ( e. g . , the chi- Nucleic acids encoding components of a chimeric influenza meric influenza hemagglutinin (HA ) polypeptides described hemagglutinin (HA ) polypeptide described herein may be in Section 5 . 1 ) . In certain embodiments , provided herein are assembled using standard molecular biology techniques nucleic acids capable of hybridizing to a fragment of a 25 known to the one of skill in the art so as to yield a chimeric nucleic acid encoding a chimeric influenza hemagglutinin influenza hemagglutinin (HA ) polypeptide described herein . (HA ) polypeptide described herein . In other embodiments, 5 . 3 Expression of Chimeric Influenza Virus Hemaggluti provided herein are nucleic acids capable of hybridizing to nin (HA ) Polypeptides the full length nucleic acid encoding a chimeric influenza Provided herein are vectors , including expression vectors , hemagglutinin (HA ) polypeptide described herein . General 30 containing a nucleic acid encoding a chimeric influenza parameters for hybridization conditions for nucleic acids are hemagglutinin (HA ) polypeptide described herein ( e . g . , the described in Sambrook et al. , Molecular Cloning — A Labo - chimeric influenza hemagglutinin (HA ) polypeptides ratory Manual ( 2nd Ed. ) , Vols. 1 - 3 , Cold Spring Harbor described in Section 5 . 1 ) . In a specific embodiment, the Laboratory , Cold Spring Harbor, N . Y . (1989 ) , and in vector is an expression vector that is capable of directing the Ausubel et al. , Current Protocols in Molecular Biology, vol. 35 expression of a nucleic acid encoding a chimeric influenza 2 , Current Protocols Publishing , New York ( 1994 ) . Hybrid - hemagglutinin (HA ) polypeptide described herein . Non ization may be performed under high stringency conditions, limiting examples of expression vectors include , but are not medium stringency conditions , or low stringency conditions . limited to , plasmids and viral vectors , such as replication Those of skill in the art will understand that low , medium defective retroviruses, adenoviruses , adeno -associated and high stringency conditions are contingent upon multiple 40 viruses and baculoviruses . Expression vectors also may factors all of which interact and are also dependent upon the include , without limitation , transgenic animals and non nucleic acids in question . For example , high stringency mammalian cells / organisms, e . g . , mammalian cells / organ conditions may include temperatures within 5° C . melting isms that have been engineered to perform mammalian temperature of the nucleic acid ( s ) , a low salt concentration N -linked glycosylation . ( e . g ., less than 250 mM ) , and a high co -solvent concentra - 45 In some embodiments , provided herein are expression tion (e . g ., 1 - 20 % of co -solvent , e .g . , DMSO ) . Low strin - vectors encoding components of a chimeric influenza gency conditions , on the other hand , may include tempera - hemagglutinin (HA ) polypeptide described herein . Such tures greater than 10° C . below the melting temperature of vectors may be used to express the components in one or the nucleic acid ( s ), a high salt concentration ( e . g . , greater more host cells and the components may be isolated and than 1000 mM ) and the absence of co - solvents . 50 conjugated together with a linker using techniques known to In some embodiments , a nucleic acid encoding a chimeric one of skill in the art . influenza hemagglutinin (HA ) polypeptide described herein An expression vector comprises a nucleic acid encoding is isolated . In certain embodiments , an “ isolated " nucleic a chimeric influenza hemagglutinin (HA ) polypeptide acid refers to a nucleic acid molecule which is separated described herein in a form suitable for expression of the from other nucleic acid molecules which are present in the 55 nucleic acid in a host cell . In a specific embodiment, an natural source of the nucleic acid . In other words, the expression vector includes one or more regulatory isolated nucleic acid can comprise heterologous nucleic sequences, selected on the basis of the host cells to be used acids that are not associated with it in nature . In other for expression , which is operably linked to the nucleic acid embodiments , an “ isolated ” nucleic acid , such as a cDNA to be expressed . Within an expression vector , “ operably molecule, can be substantially free of other cellular material, 60 linked ” is intended to mean that a nucleic acid of interest is or culture medium when produced by recombinant tech - linked to the regulatory sequence ( s ) in a manner which niques , or substantially free of chemical precursors or other allows for expression of the nucleic acid ( e . g . , in an in vitro chemicals when chemically synthesized . The term “ substan - transcription / translation system or in a host cell when the tially free of cellular material” includes preparations of vector is introduced into the host cell ) . Regulatory nucleic acid in which the nucleic acid is separated from 65 sequences include promoters , enhancers and other expres cellular components of the cells from which it is isolated or sion control elements ( e . g . , polyadenylation signals ) . Regu recombinantly produced . Thus, nucleic acid that is substan - latory sequences include those which direct constitutive US 10 , 137 , 189 B2 59 60 expression of a nucleic acid in many types of host cells , into a buffer solution . The plants are then exposed ( e . g . , via those which direct expression of the nucleic acid only in injection or submersion ) to the Agrobacterium that com certain host cells ( e . g ., tissue - specific regulatory sequences ) , prises the nucleic acids encoding a fl chimeric influenza and those which direct the expression of the nucleic acid hemagglutinin (HA ) polypeptide described herein such that upon stimulation with a particular agent (e . g ., inducible 5 the Agrobacterium transforms the gene of interest to a regulatory sequences ) . It will be appreciated by those skilled portion of the plant cells . The chimeric influenza hemag in the art that the design of the expression vector can depend glutinin (HA ) polypeptide is then transiently expressed by on such factors as the choice of the host cell to be trans the plant and can isolated using methods known in the art formed , the level of expression of protein desired , etc . The and described herein . ( For specific examples see Shoji et al. , term " host cell ” is intended to include a particular subject 10 2008 , Vaccine , 26 (23 ) : 2930 - 2934 ; and D ' Aoust et al. , 2008 , cell transformed or transfected with a nucleic acid and the J . Plant Biotechnology , 6 ( 9 ) : 930 - 940 ) . In a specific embodi progeny or potential progeny of such a cell. Progeny of such ment, the plant is a tobacco plant ( e . g ., Nicotiana tabacum ) . a cell may not be identical to the parent cell transformed or In another specific embodiment, the plant is a relative of the transfected with the nucleic acid due to mutations or envi- tobacco plant ( e . g ., Nicotiana benthamiana ) . In another ronmental influences that may occur in succeeding genera - 15 specific embodiment, the chimeric influenza hemagglutinin tions or integration of the nucleic acid into the host cell (HA ) polypeptides described herein are expressed in a genome. species of soy. In another specific embodiment, the chimeric Expression vectors can be designed for expression of a influenza hemagglutinin (HA ) polypeptides described herein chimeric influenza hemagglutinin (HA ) polypeptide are expressed in a species of corn . In another specific described herein using prokaryotic ( e g ., E . coli ) or eukary - 20 embodiment, the chimeric influenza hemagglutinin (HA ) otic cells ( e . g . , insect cells (using baculovirus expression polypeptides described herein are expressed in a species of vectors, see , e . g . , Treanor et al. , 2007, JAMA , 297 ( 14 ) : rice 1577 - 1582 incorporated by reference herein in its entirety ) , In other embodiments , algae ( e . g ., Chlamydomonas rein yeast cells , plant cells, algae or mammalian cells ). Examples hardtii ) may be engineered to express a chimeric influenza of yeast host cells include , but are not limited to S . pombe 25 hemagglutinin (HA ) polypeptide described herein , e . g ., a and S . cerevisiae and examples, infra . Examples of mam - chimeric influenza hemagglutinin (HA ) polypeptide malian host cells include , but are not limited to , Crucell described in Section 5 . 1 ( see , e . g . , Rasala et al. , 2010 , Plant Per .C6 cells , Vero cells , CHO cells , VERY cells , BHK cells , Biotechnology Journal (Published online Mar . 7 , 2010 )) . HeLa cells , COS cells , MDCK cells , 293 cells , 3T3 cells or In certain embodiments , the plants used to express the W138 cells . In certain embodiments , the hosts cells are 30 chimeric influenza hemagglutinin (HA ) polypeptides myeloma cells , e . g ., NSO cells , 45 .6 TG1. 7 cells , AF - 2 clone described herein are engineered to express components of an 9B5 cells, AF - 2 clone 9B5 cells , 1558L cells , MOPC 315 N - glycosylation system ( e . g ., a bacterial or mammalian cells , MPC - 11 cells , NCI- H929 cells , NP cells , NS0 / 1 cells , N - glycosylation system ), i. e ., the plants can perform N - gly P3 NS1 Ag4 cells , P3 /NS1 / 1 -Ag4 - 1 cells , P3U1 cells , cosylation . P3X63Ag8 cells , P3X63A98 .653 cells , P3X63Ag8U . 1 cells , 35 Plant cells that can be used to express the chimeric RPMI 8226 cells , Sp20 - Ag14 cells , U266B1 cells , influenza hemagglutinin (HA ) polypeptides described herein X63AG8. 653 cells , Y3. Ag . 1 . 2 . 3 cells, and YO cells . Non and methods for the production of proteins utilizing plant limiting examples of insect cells include Sf9 , Sf21, cell culture systems are described in , e .g ., U . S . Pat. Nos. Trichoplusia ni, Spodoptera frupperda and Bombyx mori . In 5 ,929 , 304 ; 7 ,504 ,560 ; 6 , 770 ,799 ; 6 , 551, 820 ; 6 , 136 ,320 ; a particular embodiment, a mammalian cell culture system 40 6 ,034 , 298 ; 5 , 914 , 935 ; 5 ,612 ,487 ; and 5 , 484 ,719 , U . S . patent ( e . g . Chinese hamster ovary or baby hamster kidney cells ) is application publication Nos. 2009 /0208477 , 2009 /0082548 , used for expression of a chimeric influenza hemagglutinin 2009 /0053762 , 2008 /0038232 , 2007/ 0275014 and 2006 / (HA ) polypeptide. In another embodiment, a plant cell 0204487 , and Shoji et al. , 2008 , Vaccine, 26 ( 23 ) :2930 - 2934 , culture system is used for expression of a chimeric influenza and D ' Aoust et al. , 2008, J . Plant Biotechnology, 6 ( 9 ) : 930 hemagglutinin (HA ) polypeptide . See , e . g ., U . S . Pat. Nos. 45 940 (which are incorporated herein by reference in their 7 ,504 , 560 ; 6 , 770 ,799 ; 6 ,551 , 820 ; 6 , 136 ,320 ; 6 , 034 , 298 ; entirety ) . 5 , 914 , 935 ; 5 ,612 ,487 ; and 5 , 484 , 719 , and U . S . patent appli - The host cells comprising the nucleic acids that encode cation publication Nos. 2009/ 0208477 , 2009/ 0082548 , the chimeric influenza hemagglutinin (HA ) polypeptide 2009 /0053762 , 2008 /0038232 , 2007 /0275014 and 2006 / described herein can be isolated , e . g . , the cells are outside of 0204487 for plant cells and methods for the production of 50 the body of a subject or are isolated (i . e ., separated from ) proteins utilizing plant cell culture systems. In specific untransfected /untransformed host cells . In certain embodi embodiments , plant cell culture systems are not used for ments, the cells are engineered to express nucleic acids that expression of a chimeric influenza hemagglutinin (HA ) encode the chimeric influenza hemagglutinin (HA ) polypep polypeptide described herein . tides described herein . In certain embodiments , plants ( e . g . , plants of the genus 55 An expression vector can be introduced into host cells via Nicotiana ) may be engineered to express a chimeric influ - conventional transformation or transfection techniques . enza hemagglutinin (HA ) polypeptide described herein ( e. g ., Such techniques include, but are not limited to , calcium a chimeric influenza hemagglutinin (HA ) polypeptide phosphate or calcium chloride co -precipitation , DEAE -dex described in Section 5 . 1 ) . In specific embodiments , plants tran -mediated transfection , lipofection , and electroporation . are engineered to express a chimeric influenza hemaggluti - 60 Suitable methods for transforming or transfecting host cells nin (HA ) polypeptide described herein via an agroinfiltration can be found in Sambrook et al. , 1989 , Molecular Clon procedure using methods known in the art . For example , ing - A Laboratory Manual , 2nd Edition , Cold Spring Har nucleic acids encoding a gene of interest , e . g ., a gene bor Press , New York , and other laboratory manuals . In encoding a chimeric influenza hemagglutinin (HA ) polypep - certain embodiments , a host cell is transiently transfected tide described herein , is introduced into a strain of Agro - 65 with an expression vector containing a nucleic acid encoding bacterium . Subsequently the strain is grown in a liquid chimeric influenza hemagglutinin (HA ) polypeptide . In culture and the resulting bacteria are washed and suspended other embodiments , a host cell is stably transfected with an US 10 , 137 , 189 B2 62 expression vector containing a nucleic acid encoding a The heterologous polypeptide may be a polypeptide that has chimeric influenza hemagglutinin (HA ) polypeptide . immunopotentiating activity , or that targets the influenza For stable transfection of mammalian cells , it is known virus to a particular cell type , such as an antibody that binds that, depending upon the expression vector and transfection to an antigen on a specific cell type or a ligand that binds a technique used , only a small fraction of cells may integrate 5 specific receptor on a specific cell type . the foreign DNA into their genome. In order to identify and Influenza viruses containing a chimeric influenza hemag select these integrants , a nucleic acid that encodes a select - glutinin (HA ) polypeptide described herein may be pro able marker ( e . g . , for resistance to antibiotics ) is generally duced by supplying in trans the chimeric influenza hemag introduced into the host cells along with the nucleic acid of glutinin (HA ) polypeptide during production of virions interest . Examples of selectable markers include those 10 using techniques known to one skilled in the art, such as which confer resistance to drugs , such as G418 , hygromycin reverse genetics and helper - free plasmid rescue . Alterna and methotrexate . Cells stably transfected with the intro - tively , the replication of a parental influenza virus compris duced nucleic acid can be identified by drug selection ( e . g ., ing a genome engineered to express a chimeric influenza cells that have incorporated the selectable marker gene will hemagglutinin (HA ) polypeptide described herein in cells survive , while the other cells die ) . 15 susceptible to infection with the virus wherein hemaggluti As an alternative to recombinant expression of a chimeric nin function is provided in trans will produce progeny influenza hemagglutinin (HA ) polypeptide described herein influenza viruses containing the chimeric influenza hemag using a host cell, an expression vector containing a nucleic glutinin (HA ) polypeptide. acid encoding a chimeric influenza hemagglutinin (HA ) In another aspect , provided herein are influenza viruses polypeptide can be transcribed and translated in vitro using , 20 comprising a genome engineered to express a chimeric e . g ., T7 promoter regulatory sequences and T7 polymerase . influenza hemagglutinin (HA ) polypeptide described herein In a specific embodiment, a coupled transcription / translation ( e .g . , a chimeric influenza hemagglutinin (HA ) polypeptide system , such as Promega TNT® , or a cell lysate or cell described in Section 5. 1 ). In a specific embodiment, the extract comprising the components necessary for transcrip - genome of a parental influenza virus is engineered to encode tion and translation may be used to produce a chimeric 25 a chimeric influenza hemagglutinin (HA ) polypeptide influenza hemagglutinin (HA ) polypeptide described herein . described herein , which is expressed by progeny influenza Once a chimeric influenza hemagglutinin (HA ) polypep - virus. In another specific embodiment, the genome of a tide described herein has been produced , it may be isolated parental influenza virus is engineered to encode a chimeric or purified by any method known in the art for isolation or influenza hemagglutinin (HA ) polypeptide described herein , purification of a protein , for example , by chromatography 30 which is expressed and incorporated into the virions of ( e . g ., ion exchange , affinity , particularly by affinity for the progeny influenza virus. Thus , the progeny influenza virus specific antigen or a " tag " associated with the antigen ( e . g ., resulting from the replication of the parental influenza virus a HIS tag , strep tag / strep II tag , a maltose binding protein , contain a chimeric influenza hemagglutinin (HA ) polypep a glutatione S - transferase tag , myc tag, HA tag) , by Protein tide described herein . The virions of the parental influenza A , and chromatography ( e . g . , sizing column chromatogra - 35 virus may have incorporated into them a chimeric influenza phy, hydrophopic interaction chromatography (HIC ), hemagglutinin (HA ) polypeptide that contains a stem or reversed phase chromatography, simulated moving bed head domain from the same or a different type , subtype or chromatography , size eclusion chromatography, monolith strain of influenza virus. Alternatively, the virions of the chromatography, convective interaction media chromatog parental influenza virus may have incorporated into them a raphy, lectin chromatography ) ), centrifugation , differential 40 moiety that is capable of functionally replacing one or more solubility , ultrafiltration , precipitation , or by any other stan - of the activities of influenza virus hemagglutinin polypep dard technique for the isolation or purification of proteins. In tide (e . g. , the receptor binding and /or fusogenic activities of specific embodiments , the isolated /purified chimeric influ - influenza virus hemagglutinin ). In certain embodiments , one enza hemagglutinin (HA ) polypeptides described herein are or more of the activities of the influenza virus hemagglutinin soluble , e . g . , made soluble using any method known to those 45 polypeptide is provided by a fusion protein comprising ( i ) an of skill in the art , e . g ., the methods described herein (see , ectodomain of a polypeptide heterologous to influenza virus e . g ., Section 6 .6 . 1 . 2 ) . fused to ( ii ) a transmembrane domain , or a transmembrane Provided herein are methods for producing a chimeric domain and a cytoplasmic domain of an influenza virus influenza hemagglutinin (HA ) polypeptide described herein . hemagglutinin polypeptide . In a specific embodiment, the In one embodiment, the method comprises culturing a host 50 virions of the parental influenza virus may have incorporated cell containing a nucleic acid encoding the polypeptide in a into them a fusion protein comprising ( i ) an ectodomain of suitable medium such that the polypeptide is produced . In a receptor binding / fusogenic polypeptide of an infectious some embodiments , the method further comprises isolating agent other than influenza virus fused to ( ii ) a transmem the polypeptide from the medium or the host cell . brane domain , or a transmembrane domain and a cytoplas 5 . 4 Influenza Virus Vectors 55 mic domain of an influenza virus hemagglutinin . For a In one aspect , provided herein are influenza viruses con - description of fusion proteins that provide one or more taining a chimeric influenza hemagglutinin (HA ) polypep - activities of an influenza virus hemagglutinin polypeptide tide described herein ( e . g ., a chimeric influenza hemagglu - and methods for the production of influenza viruses engi tinin (HA ) polypeptide described in Section 5 . 1 ) . In a neered to express such fusion proteins, see, e . g . , Interna specific embodiment, the chimeric influenza hemagglutinin 60 tional patent application Publication No . WO 2007 /064802 , (HA ) polypeptide described herein is incorporated into the published Jun . 7 , 2007 and U .S . patent application publica virions of the influenza virus. The influenza viruses may be tion no . 2012 /0122185 ; each ofwhich is incorporated herein conjugated to moieties that target the viruses to particular b y reference in its entirety . cell types , such as immune cells . In some embodiments , the In certain embodiments, the influenza viruses engineered virions of the influenza virus have incorporated into them or 65 to express one or more of the chimeric influenza hemagglu express a heterologous polypeptide in addition to a chimeric tinin (HA ) polypeptides described herein comprise a influenza hemagglutinin (HA ) polypeptide described herein . neuraminidase (NA ), or fragment thereof, that is from the US 10 , 137 , 189 B2 63 64 same source ( e . g . , influenza virus strain or subtype ) as that proteins such as E1, E2, and E3 ) , Borna disease virus, from which the globular head domain of the chimeric Hantaan virus, foamyvirus, and SARS - CoV virus . influenza hemagglutinin (HA ) polypeptide is derived . In In one embodiment, a flavivirus surface glycoprotein may certain embodiments , the influenza viruses engineered to be used , such as Dengue virus (DV ) E protein . In some express one ormore of the chimeric influenza hemagglutinin 5 embodiments , a Sindbis virus glycoprotein from the alphavi polypeptides described herein comprise a neuraminidase rus family is used ( K . S . Wang , R . J . Kuhn , E . G . Strauss , S . (NA ), or fragment thereof, that is from the same source ( e. g ., Ou , J. H . Strauss , J. Virol. 66 , 4992 (1992 )) . In certain influenza virus strain or subtype ) as that from which the embodiments , the heterologous polypeptide is derived from globular head domain of the chimeric influenza hemagglu - an NDV HN or F protein ; a human immunodeficiency virus tinin polypeptide is derived , wherein the globular head 10 (HIV ) gp160 (or a product thereof, such as gp41 or gp120 ); domain is heterologous to the stem domain of the HA1 a hepatitis B virus surface antigen (HBsAg ) ; a glycoprotein and / or HA2 subunits of the chimeric influenza hemaggluti - of herpesvirus ( e . g . , gD , gE ); or VP1 of poliovirus . nin polypeptide . In certain embodiments , the influenza In another embodiment , the heterologous polypeptide is viruses engineered to express one or more of the chimeric derived from any non -viral targeting system known in the influenza hemagglutinin polypeptides described herein com - 15 art . In certain embodiments , a protein of a nonviral pathogen prise a neuraminidase (NA ) , or fragment thereof, that is such as an intracellular bacteria or protozoa is used . In some from the same source ( e . g . , influenza virus strain or subtype ) embodiments , the bacterial polypeptide is provided by, e . g . , as that from which the HA stem domain of the chimeric Chlamydia , Rikettsia , Coxelia , Listeria , Brucella , or Legio influenza hemagglutinin polypeptide is derived . nella . In some embodiments , protozoan polypeptide is pro In some embodiments , the virions of the parental influ - 20 vided by, e . g ., Plasmodia species, Leishmania spp. , Toxo enza virus have incorporated into them a heterologous plasma gondii, or Trypanosoma cruzi. Other exemplary polypeptide . In certain embodiments , the genome of a targeting systems are described in Waehler et al ., 2007 , parental influenza virus is engineered to encode a heterolo - “ Engineering targeted viral vectors for gene therapy, ” gous polypeptide and a chimeric influenza hemagglutinin Nature Reviews Genetics 8 : 573 - 587 , which is incorporated (HA ) polypeptide , which are expressed by progeny influ - 25 herein in its entirety . enza virus. In specific embodiments , the chimeric influenza In certain embodiments, the heterologous polypeptide hemagglutinin (HA ) polypeptide, the heterologous polypep - expressed by an influenza virus has immunopotentiating tide, or both are incorporated into virions of the progeny (immune stimulating ) activity . Non - limiting examples of influenza virus. immunopotentiating polypeptides include , but are not lim The heterologous polypeptide may be a polypeptide that 30 ited to , stimulation molecules, cytokines, chemokines, anti targets the influenza virus to a particular cell type , such as an bodies and other agents such as Flt - 3 ligands . Specific antibody that recognizes an antigen on a specific cell type or examples of polypeptides with immunopotentiating activity a ligand that binds a specific receptor on a specific cell type . include : interferon type 1 , alpha , beta , or gamma interferon , In some embodiments , the targeting polypeptide replaces the colony stimulating factors such as granulocyte -macrophage target cell recognition function of the virus. In a specific 35 colony - stimulating factor (GM - CSF ) , interleukin ( IL ) - 1 , embodiment, the heterologous polypeptide targets the influ - IL - 2 , IL - 4 , IL - 5 , IL - 6 , IL - 7 , IL - 12 , IL - 15 , IL - 18 , IL -21 , enza virus to the same cell types that influenza virus infects IL - 23 , tumor necrosis factor ( TNF ) - B , TNFa , B7. 1 , B7. 2 , in nature . In other specific embodiments, the heterologous 4 - 1BB , CD40 ligand (CD40L ) , and drug - inducible CD40 polypeptide targets the progeny influenza virus to immune ( iCD40 ) (see , e . g . , Hanks, B . A ., et al. 2005 . Nat Med cells , such as B cells , T cells , macrophages or dendritic cells . 40 11 : 130 - 137, which is incorporated herein by reference in its In some embodiments , the heterologous polypeptide recog - entirety . ) nizes and binds to cell - specific markers of antigen present . Since the genome of influenza A and B viruses consist of ing cells , such as dendritic cells ( e . g . , such as CD44 ) . In one eight ( 8 ) single - stranded , negative sense segments ( influenza embodiment, the heterologous polypeptide is DC -SIGN C viruses consist of seven ( 7 ) single - stranded , negative which targets the virus to dendritic cells . In another embodi- 45 sense segments ), the genome of a parental influenza virus ment, the heterologous polypeptide is an antibody ( e . g ., a may be engineered to express a chimeric influenza hemag single -chain antibody ) that targets the virus to an immune glutinin (HA ) polypeptide described herein (and any other cell, which may be fused with a transmembrane domain polypeptide , such as a heterologous polypeptide ) using a from another polypeptide so that it is incorporated into the recombinant segment and techniques known to one skilled influenza virus virion . In some embodiments , the antibody is 50 in the art, such a reverse genetics and helper- free plasmid a CD20 antibody , a CD34 antibody , or an antibody against rescue . In one embodiment, the recombinant segment com DEC - 205 . Techniques for engineering viruses to express prises a nucleic acid encoding the chimeric influenza hemag polypeptides with targeting functions are known in the art. glutinin (HA ) polypeptide as well as the 3 ' and 5 ' incorpo See , e .g . , Yang et al ., 2006 , PNAS 103 : 11479 - 11484 and ration signals which are required for proper replication , United States patent application Publication No. 55 transcription and packaging of the RNAs (Fujii et al ., 2003 , 20080019998 , published Jan . 24 , 2008 , and No . Proc. Natl . Acad . Sci. USA 100 :2002 - 2007 ; Zheng , et al. , 20070020238 , published Jan . 25 , 2007 , the contents of each 1996 , Virology 217 : 242 - 251, both ofwhich are incorporated of which are incorporated herein in their entirety . by reference herein in their entireties ). In a specific embodi In another embodiment, the heterologous polypeptide is a ment, the recombinant segment uses the 3 ' and 5 ' noncoding viral attachment protein . Non - limiting examples of viruses 60 and / or nontranslated sequences of segments of influenza whose attachment protein ( s ) can be used in this aspect are viruses that are from a different or the same type , subtype or viruses selected from the group of: Lassa fever virus , strain as the parental influenza virus . In some embodiments , Hepatitis B virus, Rabies virus, Newcastle disease virus the recombinant segment comprises the 3 ' noncoding region (NDV ), a retrovirus such as human immunodeficiency virus, of an influenza virus hemagglutinin polypeptide , the tick - borne encephalitis virus , vaccinia virus , herpesvirus , 65 untranslated regions of an influenza virus hemagglutinin poliovirus , alphaviruses such as Semliki Forest virus, Ross p olypeptide , and the 5 ' non - coding region of an influenza River virus , and Aura virus ( which comprise surface glyco virus hemagglutinin polypeptide. In specific embodiments , US 10 , 137 , 189 B2 65 66 the recombinant segment comprises the 3 ' and 5 ' noncoding tal influenza virus . In some embodiments , the parental and/ or nontranslated sequences of the HA segment of an influenza virus gene is the HA gene . In some embodiments , influenza virus that is the same type , subtype or strain as the the parental influenza virus gene is the NA gene . In some influenza virus type, subtype or strain as the HA1 N - terminal embodiments , the parental influenza virus gene is the NS1 stem segment, the HA1 C - terminal stem segment , the globu - 5 gene . lar head domain , and / or the HA2 of a chimeric influenza Techniques known to one skilled in the art may be used hemagglutinin (HA ) polypeptide . In certain embodiments, to produce an influenza virus containing a chimeric influ the recombinant segment encoding the chimeric influenza e nza hemagglutinin (HA ) polypeptide described herein and hemagglutinin (HA ) polypeptide may replace the HA seg - an influenza virus comprising a genome engineered to ment of a parental influenza virus . In some embodiments , 10 express a chimeric influenza hemagglutinin (HA ) polypep the recombinant segment encoding the chimeric influenza tide described herein . For example , reverse genetics tech hemagglutinin (HA ) polypeptide may replace the NS1 gene niques may be used to generate such an influenza virus. of the parental influenza virus . In some embodiments , the Briefly , reverse genetics techniques generally involve the recombinant segment encoding the chimeric influenza preparation of synthetic recombinant viral RNAs that con hemagglutinin (HA ) polypeptide may replace the NA gene 15 tain the non - coding regions of the negative - strand , viral of the parental influenza virus . Exemplary influenza virus RNA which are essential for the recognition by viral poly strains that can be used to express the chimeric influenza merases and for packaging signals necessary to generate a hemagglutinin (HA ) polypeptides described herein include mature virion . The recombinant RNAs are synthesized from Ann Arbor/ 1 /50 , A / Ann Arbor/ 6 /60 , A / Puerto Rico / 8 / 34 , a recombinant DNA template and reconstituted in vitro with A / South Dakota /6 / 2007 , A /Uruguay /716 / 2007, A / Califor - 20 purified viral polymerase complex to form recombinant nia /07 /2009 , A /Perth / 16 /2009 , A /Brisbane /59 / 2007 , A /Bris ribonucleoproteins (RNPs ) which can be used to transfect bane / 10 / 2007 , A / Leningrad / 134 / 47 / 57 , B / Brisbane /60 / cells . A more efficient transfection is achieved if the viral 2008 , B / Yamagata/ 1 /88 , A /Panama / 2007 / 99 , A /Wyoming / 3 / polymerase proteins are present during transcription of the 03 , and A /WSN / 33 . synthetic RNAs either in vitro or in vivo . The synthetic In some embodiments , an influenza virus hemagglutinin 25 recombinant RNPs can be rescued into infectious virus gene segment encodes a chimeric influenza hemagglutinin particles . The foregoing techniques are described in U . S . (HA ) polypeptide described herein . In specific embodi- Pat. No. 5 , 166 ,057 issued Nov . 24 , 1992 ; in U . S . Pat. No . ments , the influenza virus hemagglutinin gene segment and 5 ,854 ,037 issued Dec. 29, 1998 ; in European Patent Publi at least one other influenza virus gene segment comprise cation EP 0702085A1, published Feb . 20 , 1996 ; in U . S . packaging signals that enable the influenza virus hemagglu - 30 patent application Ser. No. 09 /152 , 845; in International tinin gene segment and the at least one other gene segment Patent Publications PCT WO 97/ 12032 published Apr . 3, to segregate together during replication of a recombinant 1997 ; WO 96 / 34625 published Nov. 7 , 1996 ; in European influenza virus ( see , Gao & Palese 2009 , PNAS 106 : 15891 - Patent Publication EP A780475 ; WO 99 /02657 published 15896 ; International Application Publication No . W011/ Jan . 21, 1999; WO 98 /53078 published Nov. 26 , 1998 ; WO 014645 ; and U . S . Patent Application Publication No . 2012 / 35 98/ 02530 published Jan . 22 , 1998 ; WO 99/ 15672 published 0244183 ) . Apr. 1 , 1999 ; WO 98 / 13501 published Apr. 2 , 1998 ; WO In some embodiments , the genome of a parental influenza 97 /06270 published Feb . 20 , 1997; and EPO 780 475A1 virus may be engineered to express a chimeric influenza published Jun . 25 , 1997 , each of which is incorporated by hemagglutinin (HA ) polypeptide described herein using a reference herein in its entirety. recombinant segment that is bicistronic . Bicistronic tech - 40 Alternatively , helper- free plasmid technology may be niques allow the engineering of coding sequences of mul- used to produce an influenza virus containing chimeric tiple proteins into a single mRNA through the use of internal influenza hemagglutinin (HA ) polypeptide described herein ribosome entry site ( IRES ) sequences . IRES sequences and an influenza virus comprising a genome engineered to direct the internal recruitment of ribosomes to the RNA express a chimeric influenza hemagglutinin (HA ) polypep molecule and allow downstream translation in a cap inde - 45 tide described herein . Briefly , full length cDNAs of viral pendent manner. Briefly , a coding region of one protein is segments are amplified using PCR with primers that include inserted into the open reading frame (ORF ) of a second unique restriction sites, which allow the insertion of the PCR protein . The insertion is flanked by an IRES and any product into the plasmid vector (Flandorfer et al. , 2003 , J. untranslated signal sequences necessary for proper expres Virol. 77 : 9116 - 9123 ; Nakaya et al. , 2001, J . Virol . 75 : 11868 sion and /or function . The insertion must not disrupt the ORF , 50 11873 ; both of which are incorporated herein by reference in polyadenylation or transcriptional promoters of the second their entireties ) . The plasmid vector is designed so that an protein (see , e . g ., Garcia - Sastre et al. , 1994 , J . Virol. exact negative ( VRNA sense ) transcript is expressed . For 68 :6254 -6261 and Garcia - Sastre et al. , 1994 Dev . Biol. example , the plasmid vector may be designed to position the Stand . 82 :237 - 246 , each of which is hereby incorporated by PCR product between a truncated human RNA polymerase reference in its entirety ). See also , e . g ., U . S . Pat. No. 55 I promoter and a hepatitis delta virus ribozyme sequence 6 ,887 , 699 , U . S . Pat . No. 6 ,001 , 634 , U . S . Pat. No. 5 , 854 , 037 such that an exact negative ( vRNA sense) transcript is and U . S . Pat . No. 5 ,820 ,871 , each of which is incorporated produced from the polymerase I promoter . Separate plasmid herein by reference in its entirety . Any IRES known in the vectors comprising each viral segment as well as expression art or described herein may be used in accordance with the vectors comprising necessary viral proteins may be trans invention ( e . g ., the IRES of BiP gene , nucleotides 372 to 592 60 fected into cells leading to production of recombinant viral of GenBank database entry HUMGRP78 ; or the IRES of particles . In another example , plasmid vectors from which encephalomyocarditis virus ( EMCV ) , nucleotides 1430 - both the viral genomic RNA and mRNA encoding the 2115 of GenBank database entry CQ867238 .) . Thus, in necessary viral proteins are expressed may be used . For a certain embodiments , a parental influenza virus is engi- detailed description of helper - free plasmid technology see , neered to contain a bicistronic RNA segment that expresses 65 e. g. , International Publication No . WO 01 /04333 ; U . S . Pat . the chimeric influenza hemagglutinin (HA ) polypeptide and Nos . 6 , 951, 754 , 7 , 384 ,774 , 6 ,649 ,372 , and 7 , 312 , 064; Fodor another polypeptide , such as a gene expressed by the paren - et al. , 1999 , J . Virol. 73: 9679- 9682 ; Quinlivan et al. , 2005, US 10 , 137 , 189 B2 68 J. Virol. 79 :8431 - 8439; Hoffmann et al. , 2000 , Proc . Natl . ments , the influenza viruses, or influenza virus polypeptides , Acad . Sci. USA 97 :6108 -6113 ; Neumann et al. , 1999 , Proc . genes or genome segments for use as described herein are Natl . Acad . Sci . USA 96 : 9345 - 9350 ; Enami and Enami, obtained or derived from a combination of influenza C virus 2000 , J . Virol. 74 ( 12 ) :5556 - 5561; and Pleschka et al ., 1996 , and influenza A virus and / or influenza B virus subtypes or J . Virol. 70 ( 6 ): 4188 -4192 , which are incorporated herein by 5 strains. reference in their entireties . In certain embodiments , the influenza viruses provided The influenza viruses described herein may be propagated herein have an attenuated phenotype . In specific embodi in any substrate that allows the virus to grow to titers that ments , the attenuated influenza virus is based on influenza A permit their use in accordance with the methods described virus . In other embodiments , the attenuated influenza virus herein . In one embodiment, the substrate allows the viruses 10 is based on influenza B virus . In yet other embodiments , the to grow to titers comparable to those determined for the attenuated influenza virus is based on influenza C virus . In corresponding wild - type viruses . In certain embodiments , other embodiments , the attenuated influenza virus may the substrate is one which is biologically relevant to the comprise genes or genome segments from one or more influenza virus or to the virus from which the HA function strains or subtypes of influenza A , influenza B , and /or is derived . In a specific embodiment, an attenuated influenza 15 influenza C virus . In some embodiments , the attenuated virus by virtue of , e . g ., a mutation in the NS1 gene , may be backbone virus comprises genes from an influenza A virus propagated in an IFN - deficient substrate . For example , a and an influenza B virus . suitable IFN - deficient substrate may be one that is defective In specific embodiments , attenuation of influenza virus is in its ability to produce or respond to interferon , or is one desired such that the virus remains , at least partially , infec which an IFN - deficient substrate may be used for the growth 20 tious and can replicate in vivo , but only generate low titers of any number of viruses which may require interferon - resulting in subclinical levels of infection that are non deficient growth environment. See, for example , U . S . Pat. pathogenic . Such attenuated viruses are especially suited for Nos. 6 ,573 , 079 , issued Jun . 3 , 2003 , 6 , 852 , 522, issued Feb . embodiments described herein wherein the virus or an 8 , 2005 , and 7 ,494 , 808 , issued Feb . 24 , 2009, the entire immunogenic composition thereof is administered to a sub contents of each of which is incorporated herein by refer - 25 ject to induce an immune response . Attenuation of the ence in its entirety . In a specific embodiment, the virus is influenza virus can be accomplished according to any propagated in embryonated eggs ( e . g ., chicken eggs) . In a method known in the art , such as, e . g . , selecting viral specific embodiment, the virus is propagated in 8 day old , mutants generated by chemicalmutagenesis , mutation of the 9 - day old , 8 - 10 day old , 10 day old , 11 - day old , 10 - 12 day genomeby genetic engineering , selecting reassortant viruses old , or 12 -day old embryonated eggs ( e . g . , chicken eggs ) . In 30 that contain segments with attenuated function , or selecting certain embodiments , the virus is propagated in MDCK for conditional virus mutants ( e . g . , cold - adapted viruses ) . cells , Vero cells, 293T cells , or other cell lines known in the Alternatively , naturally occurring attenuated influenza art . In certain embodiments , the virus is propagated in cells viruses may be used as influenza virus backbones for the derived from embryonated eggs. influenza virus vectors . The influenza viruses described herein may be isolated 35 In one embodiment, an influenza virus may be attenuated , and purified by any method known to those of skill in the art. at least in part, by virtue of substituting the HA gene of the In one embodiment, the virus is removed from cell culture parental influenza virus with a chimeric influenza hemag and separated from cellular components , typically by well glutinin (HA ) polypeptide described herein . In some known clarification procedures , e . g ., such as gradient cen embodiments , an influenza virus may be attenuated , at least trifugation and column chromatography, and may be further 40 in part, by engineering the influenza virus to express a purified as desired using procedures well known to those mutated NS1 gene that impairs the ability of the virus to skilled in the art , e . g ., plaque assays . antagonize the cellular interferon (IFN ) response . Examples In certain embodiments , the influenza viruses, or influ - of the types of mutations that can be introduced into the enza virus polypeptides, genes or genome segments for use influenza virus NS1 gene include deletions, substitutions, as described herein are obtained or derived from an influ - 45 insertions and combinations thereof. One or more mutations enza A virus. In certain embodiments , the influenza viruses, can be introduced anywhere throughout the NS1 gene ( e . g . , or influenza virus polypeptides , genes or genome segments the N -terminus , the C - terminus or somewhere in between ) for use as described herein are obtained or derived from two and / or the regulatory element of the NS1 gene . In one or more influenza A virus subtypes or strains. embodiment, an attenuated influenza virus comprises a In some embodiments , the influenza viruses , or influenza 50 genome having a mutation in an influenza virus NS1 gene virus polypeptides, genes or genome segments for use as resulting in a deletion consisting of 5 , preferably 10 , 15 , 20 , described herein are obtained or derived from an influenza 25 , 30 , 35 , 40 , 45 , 50 , 55 , 60 , 65 , 75 , 80 , 85 , 90 , 95 , 99 , 100 , B virus. In certain embodiments , the influenza viruses , or 105 , 110 , 115 , 120 , 125 , 126 , 130 , 135 , 140 , 145 , 150 , 155 , influenza virus polypeptides , genes or genome segments for 160 , 165 , 170 or 175 amino acid residues from the C -ter use as described herein are obtained or derived from two or 55 minus of NS1, or a deletion of between 5 - 170 , 25 - 170 , more influenza B virus subtypes or strains. In other embodi 50 - 170 , 100 - 170 , 100 - 160 , or 105 - 160 amino acid residues ments , the influenza viruses , or influenza virus polypeptides , from the C - terminus . In another embodiment, an attenuated genes or genome segments for use as described herein are influenza virus comprises a genome having a mutation in an obtained or derived from a combination of influenza A and influenza virus NS1 gene such that it encodes an NS1 protein influenza B virus subtypes or strains . 60 of amino acid residues 1 - 130 , amino acid residues 1 - 126 , In some embodiments, the influenza viruses , or influenza amino acid residues 1 - 120 , amino acid residues 1 - 115 , virus polypeptides , genes or genome segments for use as amino acid residues 1 -110 , amino acid residues 1 - 100 , described herein are obtained or derived from an influenza amino acid residues 1 - 99 , amino acid residues 1 - 95 , amino C virus . In certain embodiments , the influenza viruses , or acid residues 1 - 85 , amino acid residues 1 - 83 , amino acid influenza virus polypeptides , genes or genome segments for 65 residues 1 - 80 , amino acid residues 1 - 75 , amino acid residues use as described herein are obtained or derived from two or 1 - 73 , amino acid residues 1 - 70 , amino acid residues 1 -65 , or more influenza C virus subtypes or strains . In other embodi- amino acid residues 1 -60 , wherein the N - terminus amino US 10 , 137 , 189 B2 69 70 acid is number 1 . For examples of NS1 mutations and virus ), a rhabdovirus ( such as vesicular stomatitis virus influenza viruses comprising a mutated NS1, see , e. g. , U . S . (VSV ) or papillomaviruses ) , poxvirus (such as , e . g . , vac Pat. Nos. 6 , 468 ,544 and 6 ,669 ,943 ; and Li et al. , 1999 , J . cinia virus, a MVA - T7 vector , or fowlpox ) , metapneumovi Infect. Dis . 179 : 1132 - 1138 , each of which is incorporated by rus , measles virus, herpesvirus (such as herpes simplex reference herein in its entirety . 5 virus) , or foamyvirus. See , e .g ., Lawrie and Tumin , 1993 , In another embodiment, an influenza virus may be attenu - Cur. Opin . Genet. Develop . 3 , 102 - 109 (retroviral vectors ) ; ated , at least in part, by mutating an NA or M gene of the Bett et al ., 1993 , J . Virol. 67 , 5911 (adenoviral vectors ) ; virus as described in the literature . Zhou et al. , 1994 , J . Exp . Med . 179 , 1867 ( adeno -associated 5 . 5 Non - Influenza Virus Vectors virus vectors ) ; Dubensky et al. , 1996 , J . Virol. 70 , 508 -519 In one aspect , provided herein are non - influenza viruses 10 ( viral vectors from the pox family including vaccinia virus containing a chimeric influenza hemagglutinin (HA ) poly - and the avian pox viruses and viral vectors from the alpha peptide described herein ( e . g . , a chimeric influenza hemag virus genus such as those derived from Sindbis and Semliki glutinin (HA ) polypeptide described in Section 5. 1 ). In a Forest Viruses ) ; U .S . Pat . No . 5 ,643 ,576 (Venezuelan equine specific embodiment, the chimeric influenza hemagglutinin encephalitis virus ); WO 96 /34625 ( VSV ) ; Ohe et al. , 1995 , (HA ) polypeptide described herein is incorporated into the 15 Human Gene Therapy 6 , 325 - 333 ; Woo et al ., WO virions of the non - influenza virus . In a specific embodiment, 94 / 12629; Xiao & Brandsma, 1996 , Nucleic Acids. Res. 24 , the chimeric influenza hemagglutinin (HA ) polypeptide 2630 -2622 (papillomaviruses ) ; and Bukreyev and Collins, described herein is contained in /expressed by a purified 2008 , Curr Opin Mol Ther . 10 : 46 - 55 (NDV ) , each of which ( e . g . , plaque purified ) or isolated virus. The non - influenza is incorporated by reference herein in its entirety . viruses may be conjugated to moieties that target the viruses 20 In a specific embodiment, the non - influenza virus vector to particular cell types , such as immune cells . In some is NDV . Any NDV type , subtype or strain may serve as the embodiments , the virions of the non - influenza virus have backbone that is engineered to express a chimeric influenza incorporated into them or express a heterologous polypep - hemagglutinin (HA ) polypeptide described herein , includ tide in addition to a chimeric influenza hemagglutinin (HA ) ing, but not limited to , naturally occurring strains, variants polypeptide described herein . The heterologous polypeptide 25 or mutants , mutagenized viruses, reassortants and/ or geneti may be a polypeptide that has immunopotentiating activity , cally engineered viruses. In a specific embodiment, the NDV or that targets the non - influenza virus to a particular cell that serves as the backbone for genetic engineering is a type, such as an antibody that recognizes an antigen on a naturally - occurring strain . In certain embodiments , the NDV specific cell type or a ligand that binds a specific receptor on that serves as the backbone for genetic engineering is a lytic a specific cell type . See Section 5 . 4 supra for examples of 30 strain . In other embodiments , the NDV that serves as the such heterologous polypeptides. backbone for genetic engineering is a non - lytic strain . In Non - influenza viruses containing / expressing a chimeric certain embodiments , the NDV that serves as the backbone influenza hemagglutinin (HA ) polypeptide described herein for genetic engineering is lentogenic strain . In some embodi can be produced using techniques known to those skilled in ments, the NDV that serves as the backbone for genetic the art. Non - influenza viruses containing a chimeric influ - 35 engineering is a mesogenic strain . In other embodiments , the enza hemagglutinin (HA ) polypeptide described herein may NDV that serves as the backbone for genetic engineering is be produced by supplying in trans the chimeric influenza a velogenic strain . Specific examples of NDV strains hemagglutinin (HA ) polypeptide during production of viri - include, but are not limited to , the 73 - T strain , Ulster strain , ons using techniques known to one skilled in the art. MTH - 68 strain , Italien strain , Hickman strain , PV701 strain , Alternatively , the replication of a parental non - influenza 40 Hitchner B1 strain , La Sota strain , YG97 strain , MET95 virus comprising a genome engineered to express a chimeric strain , and F48E9 strain . In a specific embodiment, the NDV influenza hemagglutinin (HA ) polypeptide described herein that serves as the backbone for genetic engineering is the in cells susceptible to infection with the virus wherein Hitchner B1 strain . In another specific embodiment, the hemagglutinin function is provided in trans will produce NDV that serves as the backbone for genetic engineering is progeny viruses containing the chimeric influenza hemag - 45 the La Sota strain . glutinin (HA ) polypeptide . In one embodiment, the NDV used as the backbone for a Any virus type, subtype or strain including , but not non - influenza virus vector is engineered to express a modi limited to , naturally occurring strains, variants or mutants , fied F protein in which the cleavage site of the F protein is mutagenized viruses, reassortants and /or genetically modi- replaced with one containing one or two extra arginine fied viruses may be used as a non - influenza virus vector. In 50 residues , allowing the mutant cleavage site to be activated a specific embodiment, the parental non - influenza virus is by ubiquitously expressed proteases of the furin family . not a naturally occurring virus . In another specific embodi- Specific examples of NDVs that express such a modified F ment, the parental non - influenza virus is a genetically engi - protein include , but are not limited to , rNDV /F2aa and neered virus . In certain embodiments , an enveloped virus is rNDV /F3aa . For a description of mutations introduced into preferred for the expression of a membrane bound chimeric 55 a NDV F protein to produce a modified F protein with a influenza hemagglutinin (HA ) polypeptide described herein . mutated cleavage site , see, e . g . , Park et al . ( 2006 ) “ Engi In an exemplary embodiment, the non - influenza virus neered viral vaccine constructs with dual specificity : Avian vector is a Newcastle disease virus (NDV ) . In another influenza and Newcastle disease .” PNAS USA 103 : 8203 embodiment, the non - influenza virus vector is a vaccinia 2808 , which is incorporated herein by reference in its virus. In another embodiment, the non - influenza virus vector 60 entirety . is a baculovirus . In other exemplary , non - limiting, embodi In one embodiment, the non - influenza virus vector is a ments, the non - influenza virus vector is adenovirus , adeno - poxvirus. A poxvirus vector may be based on any member associated virus (AAV ) , hepatitis B virus, retrovirus ( such of the poxviridae , in particular, a vaccinia virus or an avipox as, e . g . , a gammaretrovirus such as Mouse Stem Cell Virus virus ( e . g . , such as canarypox , fowlpox , etc . ) that provides (MSCV ) genome or Murine Leukemia Virus (MLV ) , e . g ., 65 suitable sequences for vaccine vectors . In a specific embodi Moloney murine leukemia virus , oncoretrovirus, or lentivi- ment, the poxviral vector is a vaccinia virus vector. Suitable rus ), an alphavirus ( e . g ., Venezuelan equine encephalitis vaccinia viruses include, but are not limited to , the Copen US 10 , 137 , 189 B2 71 72 hagen (VC - 2) strain (Goebel , et al. , Virol 179 : 247 - 266 , J. Virol. 80 : 11062 -11073 , and in United States patent appli 1990 ; Johnson , et al. , Virol. 196 : 381 - 401 , 1993 ) , modified cation Publication No. 20090068221 , published Mar. 12 , Copenhagen strain (NYVAC ) ( U . S . Pat. No. 6 , 265 ,189 ) , the 2009, each of which is incorporated in its entirety herein . In WYETH strain and the modified Ankara (MVA ) strain a specific embodiment, the VLPs comprising chimeric influ ( Antoine , et al . , Virol. 244 : 365 - 396 , 1998 ) . Other suitable 5 enza hemagglutinin (HA ) polypeptides described herein are poxviruses include fowlpox strains such as ALVAC and generated using baculovirus . In other embodiments , the TROVAC vectors that provide desirable properties and are VLPs comprising chimeric influenza hemagglutinin (HA ) highly attenuated (see , e. g ., U . S . Pat . No . 6 , 265 , 189 ; Tarta - polypeptide described herein are generated using 293T cells . glia et al. , In AIDS Research Reviews, Koff, et al. , eds. , Vol. In specific embodiments , VLPs , e .g . , VLPs comprising a 3 , Marcel Dekker, N . Y ., 1993 ; and Tartaglia et al. , 1990 , 10 chimeric influenza hemagglutinin (HA ) polypeptide Reviews in Immunology 10 : 13 - 30 , 1990 ) . described herein , are expressed in cells ( e . g . , 293T cells ) . In Methods of engineering non - influenza viruses to express certain embodiments , the VLPs are expressed in cells that influenza polypeptides are well known in the art , as are express surface glycoproteins that comprise sialic acid . In methods for attenuating, propagating , and isolating and accordance with such embodiments , the cells are cultured in purifying such viruses. For such techniques with respect to 15 the presence of neuraminidase ( e . g ., viral of bacterial NDV vectors , see , e . g . , International Publication No . WO neuraminidase ) . In certain embodiments , VLPs , e . g . , VLPs 01/ 04333 ; U . S . Pat . Nos. 7 , 442 , 379 , 6 , 146 ,642 , 6 ,649 , 372 , comprising a chimeric influenza hemagglutinin (HA ) poly 6 ,544 ,785 and 7, 384 ,774 ; Swayne et al . ( 2003 ) . Avian Dis . peptide described herein , are expressed in cells that do not 47 : 1047 - 1050 ; and Swayne et al. ( 2001 ) . J . Virol. 11868 express surface glycoproteins that comprise sialic acid . 11873 , each of which is incorporated by reference in its 20 In a specific embodiment, a chimeric influenza hemag entirety. For such techniques with respect to poxviruses , see , glutinin (HA ) polypeptide described herein may be incor e . g ., Piccini, et al. , Methods of Enzymology 153 : 545 -563 , porated into a virosome . A virosome containing a chimeric 1987 ; International Publication No. WO 96 / 11279; U . S . Pat. influenza hemagglutinin (HA ) polypeptide described herein No. 4 , 769, 330 ; U . S . Pat . No . 4 ,722 ,848 ; U . S . Pat . No. may be produced using techniques known to those skilled in 4 , 769, 330 ; U . S . Pat. No . 4 ,603 , 112 ; U . S . Pat. No . 5 , 110 ,587 ; 25 the art. For example , a virosome may be produced by U . S . Pat. No . 5 , 174 ,993 ; EP 83 286 ; EP 206 920 ; Mayr et al. , disrupting a purified virus , extracting the genome , and Infection 3 : 6 - 14 , 1975 ; and Sutter and Moss , Proc . Natl. reassembling particles with the viral proteins ( e . g . , a chi Acad . Sci. USA 89 : 10847 - 10851, 1992 . In certain embodi - meric influenza hemagglutinin (HA ) polypeptide described ments , the non - influenza virus is attenuated . herein ) and lipids to form lipid particles containing viral Exemplary considerations for the selection of a non - 30 proteins . influenza virus vector, particularly for use in compositions 5 . 7 Bacterial Vectors for administration to a subject , are safety , low toxicity , In a specific embodiment, bacteria may be engineered to stability , cell type specificity , and immunogenicity , particu - express a chimeric influenza hemagglutinin (HA ) polypep larly , antigenicity of the chimeric influenza hemagglutinin tide described herein ( e . g . , a chimeric influenza hemagglu (HA ) polypeptide described herein expressed by the non - 35 tinin (HA ) polypeptide described in Section 5 . 1 ) . Suitable influenza virus vector. bacteria for expression of a chimeric influenza hemaggluti 5 . 6 Virus- Like Particles and Virosomes nin (HA ) polypeptide described herein include , but are not The chimeric influenza hemagglutinin (HA ) polypeptides limited to , Listeria , Salmonella , Shigella sp ., Mycobacte described herein ( e . g ., the chimeric influenza hemagglutinin rium tuberculosis, E . coli, Neisseria meningitides, Brucella (HA ) polypeptides described in Section 5 . 1 ) can be incor- 40 abortus, Brucella melitensis , Borrelia burgdorferi, Lacto porated into virus - like particle (VLP ) vectors , e . g ., purified / bacillus, Campylobacter, Lactococcus , Bifidobacterium , and isolated VLPs. VLPs generally comprise a viral Francisella tularensis . In a specific embodiment, the bacte polypeptide ( s ) typically derived from a structural protein ( s ) ria engineered to express a chimeric influenza hemagglutinin of a virus. In some embodiments , the VLPs are not capable (HA ) polypeptide described herein are attenuated . Tech of replicating . In certain embodiments , the VLPs may lack 45 niques for the production of bacteria engineered to express the complete genome of a virus or comprise a portion of the a heterologous polypeptide are known in the art and can be genome of a virus . In some embodiments , the VLPs are not applied to the expression of a chimeric influenza hemagglu capable of infecting a cell. In some embodiments , the VLPs tinin (HA ) polypeptide described herein . See, e. g ., United express on their surface one or more of viral ( e . g ., virus States Patent Application Publication No . 20080248066 , surface glycoprotein ) or non - viral ( e . g . , antibody or protein ) 50 published Oct. 9 , 2008 , and United States Patent Application targeting moieties known to one skilled in the art or Publication No . 20070207171 , published Sep . 6 , 2007 , each described herein . In some embodiments, the VLPs comprise of which are incorporated by reference herein in their a chimeric influenza hemagglutinin (HA ) polypeptide entirety . In certain embodiments , the bacterial vectors used described herein and a viral structural protein , such as HIV herein possess the ability to perform N -linked glycosylation , gag. In a specific embodiment, the VLPs comprise a chi- 55 e .g ., such bacteria naturally possess N - glycosylation meric influenza hemagglutinin (HA ) polypeptide described machinery ( e .g ., Campylobacter ) or have been genetically herein and an HIV gag polypeptide . engineered to possess N - glycosylation machinery . Methods for producing and characterizing recombinantly 5 . 8 Generation of Antibodies Against Chimeric Influenza produced VLPs have been described based on several Hemagglutinin (HA ) Polypeptides viruses, including influenza virus (Bright et al. (2007 ) Vac - 60 The chimeric influenza hemagglutinin (HA ) polypeptides cine. 25 : 3871) , human papilloma virus type 1 (Hagnesee et described herein ( e . g . , the chimeric influenza hemagglutinin al . ( 1991 ) J . Virol. 67 : 315 ) , human papilloma virus type 16 (HA ) polypeptides described in Section 5 . 1 ) , nucleic acids (Kirnbauer et al. Proc . Natl. Acad . Sci. ( 1992 )89 : 12180 ), encoding such polypeptides, or vectors comprising such HIV - 1 (Haffer et al. , ( 1990 ) J. Virol. 64 :2653 ), and hepatitis nucleic acids or polypeptides described herein may be used A (Winokur ( 1991 ) 65 : 5029 ) , each of which is incorporated 65 to elicit neutralizing antibodies against influenza , for herein in its entirety . Methods for expressing VLPs that example , against the stalk region of an influenza virus contain NDV proteins are provided by Pantua et al . (2006 ) hemagglutinin polypeptide. In a specific embodiment, the US 10 , 137 , 189 B2 73 74 chimeric influenza hemagglutinin (HA ) polypeptides, assay , such as a panning assay, ELISA , surface plasmon nucleic acids encoding such polypeptides , or vectors com resonance , or other antibody screening assay known in the prising such nucleic acids or polypeptides described herein art may be used to screen for antibodies that bind to the may be administered to a non -human subject ( e. g ., a mouse , chimeric influenza hemagglutinin (HA ) polypeptide. The rabbit , rat , guinea pig , etc . ) to induce an immune response 5 antibody library screened may be a commercially available that includes the production of antibodies which may be antibody library, an in vitro generated library , or a library isolated using techniques known to one of skill in the art ( e . g ., immunoaffinity chromatography, centrifugation , pre obtained by identifying and cloning or isolating antibodies cipitation , etc . ) . from an individual infected with influenza . In particular In certain embodiments , human antibodies directed 10 embodiments , the antibody library is generated from a against the chimeric influenza hemagglutinin (HA ) polypep survivor of an influenza virus outbreak . Antibody libraries tides described herein can be generated using non -human may be generated in accordance with methods known in the subjects ( e . g ., transgenic mice ) that are capable of producing art. In a particular embodiment, the antibody library is human antibodies . For example , human antibodies can be generated by cloning the antibodies and using them in phage produced using transgenic mice which are incapable of 15 display libraries or a phagemid display library . expressing functional endogenous immunoglobulins, but Antibodies identified in the methods described herein may which can express human immunoglobulin genes. For be tested for neutralizing activity and lack of autoreactivity example , the human heavy and light chain immunoglobulin using the biological assays known in the art or described gene complexes may be introduced randomly or by homolo - herein . In one embodiment, an antibody isolated from a gous recombination into mouse embryonic stem cells . Alter - 20 non - human animal or an antibody library neutralizes a natively , the human variable region , constant region , and hemagglutinin polypeptide from more than one influenza diversity region may be introduced into mouse embryonic subtype . In some embodiments , an antibody elicited or stem cells in addition to the human heavy and light chain identified using a chimeric influenza hemagglutinin (HA ) genes. The mouse heavy and light chain immunoglobulin polypeptide described herein , a nucleic acid encoding such genes may be rendered non - functional separately or simul- 25 a polypeptide, or a vector encoding such a nucleic acid or taneously with the introduction of human immunoglobulin polypeptide neutralizes an influenza H3 virus . In some loci by homologous recombination . In particular , homozy - embodiments , an antibody elicited or identified using a gous deletion of the JH region prevents endogenous anti chimeric influenza hemagglutinin (HA ) polypeptide body production . The modified embryonic stem cells are described herein , a nucleic acid encoding such a polypep expanded and microinjected into blastocysts to produce 30 tide , or a vector comprising such a nucleic acid or polypep chimeric mice . The chimeric mice are then bred to produce tide neutralizes 1, 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11, 12 , 13 , 14 , 15 , homozygous offspring which express human antibodies. The or 16 or more subtypes or strains of influenza virus . In one human immunoglobulin transgenes harbored by the trans - embodiment, the neutralizing antibody neutralizes one or genic mice rearrange during B cell differentiation , and more influenza A viruses and one or more influenza B subsequently undergo class switching and somatic mutation . 35 viruses . In particular embodiments , the neutralizing anti Thus , using such a technique , it is possible to produce body is not, or does not bind the same epitope as CR6261, therapeutically useful IgG , IgA , IgM and IgE antibodies . For CR6325 , CR6329 , CR6307 , CR6323 , 2A , D7, D8 , F10 , an overview of this technology for producing human anti G17, H40 , A66 , D80 , E88 , E90 , H98 , C179 (produced by bodies , see Lonberg and Huszar, Int. Rev . Immunol. 13 :65 - hybridoma FERM BP -4517 ; clones sold by Takara Bio , Inc . 93 (1995 ) . For a detailed discussion of this technology for 40 ( Otsu , Shiga , Japan ) ) , and / or AI3C (FERM BP -4516 ) ; or producing human antibodies and human monoclonal anti - any other antibody described in Ekiert DC et al. ( 2009 ) bodies and protocols for producing such antibodies , see , Antibody Recognition of a Highly Conserved Influenza e .g ., PCT publications WO 98 /24893 ; WO 92 /01047 ; WO Virus Epitope. Science (published in Science Express Feb . 96 /34096 ; WO 96 / 33735 ; European Patent No . 0 598 877 ; 26 , 2009 ) ; Kashyap et al. ( 2008 ) Combinatorial antibody U . S . Pat . Nos . 5 , 413 , 923 ; 5 ,625 , 126 ; 5 ,633 ,425 ; 5 , 569, 825 ; 45 libraries from survivors of the Turkish H5N1 avian influenza 5 ,661 ,016 ; 5 ,545 ,806 ; 5 , 814 ,318 ; 5 ,885 , 793 ; 5 ,916 ,771 ; and outbreak reveal virus neutralization strategies. Proc Natl 5 , 939 ,598 , which are incorporated by reference herein in Acad Sci USA 105 : 5986 - 5991 ; Sui et al . ( 2009 ) Structural their entirety . Companies such as Abgenix , Inc . ( Freemont, and functional bases for broad -spectrum neutralization of Calif . ) , Genpharm (San Jose , Calif . ) , and Medarex , Inc . avian and human influenza A viruses. Nat Struct Mol Biol ( Princeton , N . J .) can be engaged to provide human antibod - 50 16 : 265 - 273 ; U . S . Pat . Nos . 5 , 589 ,174 , 5 , 631, 350 , 6 , 337, ies directed against a selected antigen . In addition , non - 070 , and 6 ,720 , 409 ; International Application No. PCT/ human subjects may be transplanted with human peripheral US2007/ 068983 published as International Publication No . blood leukocytes , splenocytes, or bonemarrow ( e .g ., Trioma WO 2007 / 134237 ; International Application No . PCT/ Techniques XTL ) so that human antibodies that bind to a US2008 /075998 published as International Publication No . chimeric influenza hemagglutinin (HA ) polypeptide 55 WO 2009/ 036157 ; International Application No. PCT/ described herein are generated . EP2007 /059356 published as International Publication No . Alternatively , the chimeric influenza hemagglutinin (HA ) WO 2008 / 028946 ; and International Application No. PCT/ polypeptides described herein may be used to screen for US2008 / 085876 published as International Publication No. antibodies from antibody libraries . For example , an isolated WO 2009 /079259 . In other embodiments , the neutralizing chimeric influenza hemagglutinin (HA ) polypeptide may be 60 antibody is not an antibody described in Wang et al . ( 2010 ) immobilized to a solid support ( e . g . , a silica gel, a resin , a “ Broadly Protective Monoclonal Antibodies against H3 derivatized plastic film , a glass bead , cotton , a plastic bead , Influenza Viruses following Sequential Immunization with a polystyrene bead , an alumina gel , or a polysaccharide, a Different Hemagglutinins, ” PLOS Pathogens 6 ( 2 ) : 1 - 9 . In magnetic bead ) , and screened for binding to antibodies . As particular embodiments , the neutralizing antibody does not an alternative, the antibodies may be immobilized to a solid 65 use the lg VH1- 69 segment. In some embodiments , the support and screened for binding to the isolated chimeric interaction of the neutralizing antibody with the antigen is influenza hemagglutinin (HA ) polypeptide. Any screening not mediated exclusively by the heavy chain .