Links to Exploration step
Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Induction of Virus-Specific Cytotoxic T Lymphocytes as a Basis for the Development of Broadly Protective Influenza Vaccines</title><author><name sortKey="Hillaire, Marine L B" sort="Hillaire, Marine L B" uniqKey="Hillaire M" first="Marine L. B." last="Hillaire">Marine L. B. Hillaire</name><affiliation><nlm:aff id="I1">Department of Virology, Erasmus Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Osterhaus, Albert D M E" sort="Osterhaus, Albert D M E" uniqKey="Osterhaus A" first="Albert D. M. E." last="Osterhaus">Albert D. M. E. Osterhaus</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Rimmelzwaan, Guus F" sort="Rimmelzwaan, Guus F" uniqKey="Rimmelzwaan G" first="Guus F." last="Rimmelzwaan">Guus F. Rimmelzwaan</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">22007149</idno><idno type="pmc">3189652</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3189652</idno><idno type="RBID">PMC:3189652</idno><idno type="doi">10.1155/2011/939860</idno><date when="2011">2011</date><idno type="wicri:Area/Pmc/Corpus">000D88</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000D88</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Induction of Virus-Specific Cytotoxic T Lymphocytes as a Basis for the Development of Broadly Protective Influenza Vaccines</title><author><name sortKey="Hillaire, Marine L B" sort="Hillaire, Marine L B" uniqKey="Hillaire M" first="Marine L. B." last="Hillaire">Marine L. B. Hillaire</name><affiliation><nlm:aff id="I1">Department of Virology, Erasmus Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Osterhaus, Albert D M E" sort="Osterhaus, Albert D M E" uniqKey="Osterhaus A" first="Albert D. M. E." last="Osterhaus">Albert D. M. E. Osterhaus</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Rimmelzwaan, Guus F" sort="Rimmelzwaan, Guus F" uniqKey="Rimmelzwaan G" first="Guus F." last="Rimmelzwaan">Guus F. Rimmelzwaan</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author></analytic><series><title level="j">Journal of Biomedicine and Biotechnology</title><idno type="ISSN">1110-7243</idno><idno type="eISSN">1110-7251</idno><imprint><date when="2011">2011</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>There is considerable interest in the development of broadly protective influenza vaccines because of the continuous emergence of antigenic drift variants of seasonal influenza viruses and the threat posed by the emergence of antigenically distinct pandemic influenza viruses. It has been recognized more than three decades ago that influenza A virus-specific cytotoxic T lymphocytes recognize epitopes located in the relatively conserved proteins like the nucleoprotein and that they cross-react with various subtypes of influenza A viruses. This implies that these CD8<sup>+</sup> T lymphocytes may contribute to protective heterosubtypic immunity induced by antecedent influenza A virus infections. In the present paper, we review the evidence for the role of virus-specific CD8<sup>+</sup> T lymphocytes in protective immunity against influenza virus infections and discuss vaccination strategies that aim at the induction of cross-reactive virus-specific T-cell responses.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="De Jong, Jc" uniqKey="De Jong J">JC de Jong</name></author><author><name sortKey="Palache, Am" uniqKey="Palache A">AM Palache</name></author><author><name sortKey="Beyer, We" uniqKey="Beyer W">WE Beyer</name></author><author><name sortKey="Rimmelzwaan, Gf" uniqKey="Rimmelzwaan G">GF Rimmelzwaan</name></author><author><name sortKey="Boon, Ac" uniqKey="Boon A">AC Boon</name></author><author><name sortKey="Osterhaus, Ad" uniqKey="Osterhaus A">AD Osterhaus</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Abelin, A" uniqKey="Abelin A">A Abelin</name></author><author><name sortKey="Colegate, T" uniqKey="Colegate T">T Colegate</name></author><author><name sortKey="Gardner, S" uniqKey="Gardner S">S Gardner</name></author><author><name sortKey="Hehme, N" uniqKey="Hehme N">N Hehme</name></author><author><name sortKey="Palache, A" uniqKey="Palache A">A Palache</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Butler, D" uniqKey="Butler D">D Butler</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Epstein, Sl" uniqKey="Epstein S">SL Epstein</name></author><author><name sortKey="Price, Ge" uniqKey="Price G">GE Price</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Stephenson, I" uniqKey="Stephenson I">I Stephenson</name></author><author><name sortKey="Hayden, F" uniqKey="Hayden F">F Hayden</name></author><author><name sortKey="Osterhaus, A" uniqKey="Osterhaus A">A Osterhaus</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Grebe, Km" uniqKey="Grebe K">KM Grebe</name></author><author><name sortKey="Yewdell, Jw" uniqKey="Yewdell J">JW Yewdell</name></author><author><name sortKey="Bennink, Jr" uniqKey="Bennink J">JR Bennink</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Corti, D" uniqKey="Corti D">D Corti</name></author><author><name sortKey="Suguitan, Al" uniqKey="Suguitan A">AL Suguitan</name></author><author><name sortKey="Pinna, D" uniqKey="Pinna D">D Pinna</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ekiert, Dc" uniqKey="Ekiert D">DC Ekiert</name></author><author><name sortKey="Bhabha, G" uniqKey="Bhabha G">G Bhabha</name></author><author><name sortKey="Elsliger, Ma" uniqKey="Elsliger M">MA Elsliger</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Steel, J" uniqKey="Steel J">J Steel</name></author><author><name sortKey="Lowen, Ac" uniqKey="Lowen A">AC Lowen</name></author><author><name sortKey="Wang, Tt" uniqKey="Wang T">TT Wang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wang, Tt" uniqKey="Wang T">TT Wang</name></author><author><name sortKey="Tan, Gs" uniqKey="Tan G">GS Tan</name></author><author><name sortKey="Hai, R" uniqKey="Hai R">R Hai</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wei, Cj" uniqKey="Wei C">CJ Wei</name></author><author><name sortKey="Boyington, Jc" uniqKey="Boyington J">JC Boyington</name></author><author><name sortKey="Mctamney, Pm" uniqKey="Mctamney P">PM McTamney</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Okuno, Y" uniqKey="Okuno Y">Y Okuno</name></author><author><name sortKey="Isegawa, Y" uniqKey="Isegawa Y">Y Isegawa</name></author><author><name sortKey="Sasao, F" uniqKey="Sasao F">F Sasao</name></author><author><name sortKey="Ueda, S" uniqKey="Ueda S">S Ueda</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Smirnov, Ya" uniqKey="Smirnov Y">YA Smirnov</name></author><author><name sortKey="Lipatov, As" uniqKey="Lipatov A">AS Lipatov</name></author><author><name sortKey="Gitelman, Ak" uniqKey="Gitelman A">AK Gitelman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Friesen, Rh" uniqKey="Friesen R">RH Friesen</name></author><author><name sortKey="Koudstaal, W" uniqKey="Koudstaal W">W Koudstaal</name></author><author><name sortKey="Koldijk, Mh" uniqKey="Koldijk M">MH Koldijk</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Fan, J" uniqKey="Fan J">J Fan</name></author><author><name sortKey="Liang, X" uniqKey="Liang X">X Liang</name></author><author><name sortKey="Horton, Ms" uniqKey="Horton M">MS Horton</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Heinen, Pp" uniqKey="Heinen P">PP Heinen</name></author><author><name sortKey="Rijsewijks, Fa" uniqKey="Rijsewijks F">FA Rijsewijks</name></author><author><name sortKey="De Boer Luitjtze, Ea" uniqKey="De Boer Luitjtze E">EA de Boer-Luitjtze</name></author><author><name sortKey="Bianchi, At" uniqKey="Bianchi A">AT Bianchi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Slepushkin, Va" uniqKey="Slepushkin V">VA Slepushkin</name></author><author><name sortKey="Katz, Jm" uniqKey="Katz J">JM Katz</name></author><author><name sortKey="Black, Ra" uniqKey="Black R">RA Black</name></author><author><name sortKey="Gamble, Wc" uniqKey="Gamble W">WC Gamble</name></author><author><name sortKey="Rota, Pa" uniqKey="Rota P">PA Rota</name></author><author><name sortKey="Cox, Nj" uniqKey="Cox N">NJ Cox</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Song, Jm" uniqKey="Song J">JM Song</name></author><author><name sortKey="Wang, Bz" uniqKey="Wang B">BZ Wang</name></author><author><name sortKey="Park, Km" uniqKey="Park K">KM Park</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tompkins, Sm" uniqKey="Tompkins S">SM Tompkins</name></author><author><name sortKey="Zhao, Zs" uniqKey="Zhao Z">ZS Zhao</name></author><author><name sortKey="Lo, Cy" uniqKey="Lo C">CY Lo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hillaire, Mlb" uniqKey="Hillaire M">MLB Hillaire</name></author><author><name sortKey="Van Trierum, Se" uniqKey="Van Trierum S">SE van Trierum</name></author><author><name sortKey="Kreijtz, Jhcm" uniqKey="Kreijtz J">JHCM Kreijtz</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jegerlehner, A" uniqKey="Jegerlehner A">A Jegerlehner</name></author><author><name sortKey="Schmitz, N" uniqKey="Schmitz N">N Schmitz</name></author><author><name sortKey="Storni, T" uniqKey="Storni T">T Storni</name></author><author><name sortKey="Bachmann, Mf" uniqKey="Bachmann M">MF Bachmann</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Effros, Rb" uniqKey="Effros R">RB Effros</name></author><author><name sortKey="Doherty, Pc" uniqKey="Doherty P">PC Doherty</name></author><author><name sortKey="Gerhard, W" uniqKey="Gerhard W">W Gerhard</name></author><author><name sortKey="Bennink, J" uniqKey="Bennink J">J Bennink</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yap, Kl" uniqKey="Yap K">KL Yap</name></author><author><name sortKey="Ada, Gl" uniqKey="Ada G">GL Ada</name></author><author><name sortKey="Mckenzie, If" uniqKey="Mckenzie I">IF McKenzie</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jung, S" uniqKey="Jung S">S Jung</name></author><author><name sortKey="Unutmaz, D" uniqKey="Unutmaz D">D Unutmaz</name></author><author><name sortKey="Wong, P" uniqKey="Wong P">P Wong</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zammit, Dj" uniqKey="Zammit D">DJ Zammit</name></author><author><name sortKey="Cauley, Ls" uniqKey="Cauley L">LS Cauley</name></author><author><name sortKey="Pham, Qm" uniqKey="Pham Q">QM Pham</name></author><author><name sortKey="Lefrancois, L" uniqKey="Lefrancois L">L Lefrançois</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zweerink, Hj" uniqKey="Zweerink H">HJ Zweerink</name></author><author><name sortKey="Courtneidge, Sa" uniqKey="Courtneidge S">SA Courtneidge</name></author><author><name sortKey="Skehel, Jj" uniqKey="Skehel J">JJ Skehel</name></author><author><name sortKey="Crumpton, Mj" uniqKey="Crumpton M">MJ Crumpton</name></author><author><name sortKey="Askonas, Ba" uniqKey="Askonas B">BA Askonas</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yewdell, Jw" uniqKey="Yewdell J">JW Yewdell</name></author><author><name sortKey="Bennink, Jr" uniqKey="Bennink J">JR Bennink</name></author><author><name sortKey="Smith, Gl" uniqKey="Smith G">GL Smith</name></author><author><name sortKey="Moss, B" uniqKey="Moss B">B Moss</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kees, U" uniqKey="Kees U">U Kees</name></author><author><name sortKey="Krammer, Ph" uniqKey="Krammer P">PH Krammer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gotch, F" uniqKey="Gotch F">F Gotch</name></author><author><name sortKey="Mcmichael, A" uniqKey="Mcmichael A">A McMichael</name></author><author><name sortKey="Smith, G" uniqKey="Smith G">G Smith</name></author><author><name sortKey="Moss, B" uniqKey="Moss B">B Moss</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lee, Ly" uniqKey="Lee L">LY Lee</name></author><author><name sortKey="Ha Do, La" uniqKey="Ha Do L">LA Ha Do</name></author><author><name sortKey="Simmons, C" uniqKey="Simmons C">C Simmons</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kreijtz, Jh" uniqKey="Kreijtz J">JH Kreijtz</name></author><author><name sortKey="De Mutsert, G" uniqKey="De Mutsert G">G de Mutsert</name></author><author><name sortKey="Van Baalen, Ca" uniqKey="Van Baalen C">CA van Baalen</name></author><author><name sortKey="Fouchier, Ra" uniqKey="Fouchier R">RA Fouchier</name></author><author><name sortKey="Osterhaus, Ad" uniqKey="Osterhaus A">AD Osterhaus</name></author><author><name sortKey="Rimmelzwaan, Gf" uniqKey="Rimmelzwaan G">GF Rimmelzwaan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jameson, J" uniqKey="Jameson J">J Jameson</name></author><author><name sortKey="Cruz, J" uniqKey="Cruz J">J Cruz</name></author><author><name sortKey="Terajima, M" uniqKey="Terajima M">M Terajima</name></author><author><name sortKey="Ennis, Fa" uniqKey="Ennis F">FA Ennis</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gras, S" uniqKey="Gras S">S Gras</name></author><author><name sortKey="Kedzierski, L" uniqKey="Kedzierski L">L Kedzierski</name></author><author><name sortKey="Valkenburg, Sa" uniqKey="Valkenburg S">SA Valkenburg</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tu, W" uniqKey="Tu W">W Tu</name></author><author><name sortKey="Mao, H" uniqKey="Mao H">H Mao</name></author><author><name sortKey="Zheng, J" uniqKey="Zheng J">J Zheng</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mcmichael, Aj" uniqKey="Mcmichael A">AJ McMichael</name></author><author><name sortKey="Gotch, Fm" uniqKey="Gotch F">FM Gotch</name></author><author><name sortKey="Noble, Gr" uniqKey="Noble G">GR Noble</name></author><author><name sortKey="Beare, Pa" uniqKey="Beare P">PA Beare</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mcmichael, Aj" uniqKey="Mcmichael A">AJ McMichael</name></author><author><name sortKey="Michie, Ca" uniqKey="Michie C">CA Michie</name></author><author><name sortKey="Gotch, Fm" uniqKey="Gotch F">FM Gotch</name></author><author><name sortKey="Smith, Gl" uniqKey="Smith G">GL Smith</name></author><author><name sortKey="Moss, B" uniqKey="Moss B">B Moss</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Townsend, Arm" uniqKey="Townsend A">ARM Townsend</name></author><author><name sortKey="Skehel, Jj" uniqKey="Skehel J">JJ Skehel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zweerink, Hj" uniqKey="Zweerink H">HJ Zweerink</name></author><author><name sortKey="Askonas, Ba" uniqKey="Askonas B">BA Askonas</name></author><author><name sortKey="Millican, D" uniqKey="Millican D">D Millican</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Smallman Raynor, M" uniqKey="Smallman Raynor M">M Smallman-Raynor</name></author><author><name sortKey="Cliff, Ad" uniqKey="Cliff A">AD Cliff</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kreijtz, Jh" uniqKey="Kreijtz J">JH Kreijtz</name></author><author><name sortKey="Bodewes, R" uniqKey="Bodewes R">R Bodewes</name></author><author><name sortKey="Van Den Brand, Jm" uniqKey="Van Den Brand J">JM van den Brand</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kreijtz, Jh" uniqKey="Kreijtz J">JH Kreijtz</name></author><author><name sortKey="Bodewes, R" uniqKey="Bodewes R">R Bodewes</name></author><author><name sortKey="Van Amerongen, G" uniqKey="Van Amerongen G">G van Amerongen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Benton, Ka" uniqKey="Benton K">KA Benton</name></author><author><name sortKey="Misplon, Ja" uniqKey="Misplon J">JA Misplon</name></author><author><name sortKey="Lo, Cy" uniqKey="Lo C">CY Lo</name></author><author><name sortKey="Brutkiewicz, Rr" uniqKey="Brutkiewicz R">RR Brutkiewicz</name></author><author><name sortKey="Prasad, Sa" uniqKey="Prasad S">SA Prasad</name></author><author><name sortKey="Epstein, Sl" uniqKey="Epstein S">SL Epstein</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nguyen, Hh" uniqKey="Nguyen H">HH Nguyen</name></author><author><name sortKey="Moldoveanu, Z" uniqKey="Moldoveanu Z">Z Moldoveanu</name></author><author><name sortKey="Novak, Mj" uniqKey="Novak M">MJ Novak</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="O Eill, E" uniqKey="O Eill E">E O’Neill</name></author><author><name sortKey="Krauss, Sl" uniqKey="Krauss S">SL Krauss</name></author><author><name sortKey="Riberdy, Jm" uniqKey="Riberdy J">JM Riberdy</name></author><author><name sortKey="Webster, Rg" uniqKey="Webster R">RG Webster</name></author><author><name sortKey="Woodland, Dl" uniqKey="Woodland D">DL Woodland</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Schulman, Jl" uniqKey="Schulman J">JL Schulman</name></author><author><name sortKey="Kilbourne, Ed" uniqKey="Kilbourne E">ED Kilbourne</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yap, Kl" uniqKey="Yap K">KL Yap</name></author><author><name sortKey="Ada, Gl" uniqKey="Ada G">GL Ada</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wells, Ma" uniqKey="Wells M">MA Wells</name></author><author><name sortKey="Ennis, Fa" uniqKey="Ennis F">FA Ennis</name></author><author><name sortKey="Albrecht, P" uniqKey="Albrecht P">P Albrecht</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Taylor, Pm" uniqKey="Taylor P">PM Taylor</name></author><author><name sortKey="Askonas, Ba" uniqKey="Askonas B">BA Askonas</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wraith, Dc" uniqKey="Wraith D">DC Wraith</name></author><author><name sortKey="Vessey, Ae" uniqKey="Vessey A">AE Vessey</name></author><author><name sortKey="Askonas, Ba" uniqKey="Askonas B">BA Askonas</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lukacher, Ae" uniqKey="Lukacher A">AE Lukacher</name></author><author><name sortKey="Braciale, Vl" uniqKey="Braciale V">VL Braciale</name></author><author><name sortKey="Braciale, Tj" uniqKey="Braciale T">TJ Braciale</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Askonas, Ba" uniqKey="Askonas B">BA Askonas</name></author><author><name sortKey="Taylor, Pm" uniqKey="Taylor P">PM Taylor</name></author><author><name sortKey="Esquivel, F" uniqKey="Esquivel F">F Esquivel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Liang, S" uniqKey="Liang S">S Liang</name></author><author><name sortKey="Mozdzanowska, K" uniqKey="Mozdzanowska K">K Mozdzanowska</name></author><author><name sortKey="Palladino, G" uniqKey="Palladino G">G Palladino</name></author><author><name sortKey="Gerhard, W" uniqKey="Gerhard W">W Gerhard</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Guo, H" uniqKey="Guo H">H Guo</name></author><author><name sortKey="Santiago, F" uniqKey="Santiago F">F Santiago</name></author><author><name sortKey="Lambert, K" uniqKey="Lambert K">K Lambert</name></author><author><name sortKey="Takimoto, T" uniqKey="Takimoto T">T Takimoto</name></author><author><name sortKey="Topham, Dj" uniqKey="Topham D">DJ Topham</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Seo, Sh" uniqKey="Seo S">SH Seo</name></author><author><name sortKey="Webster, Rg" uniqKey="Webster R">RG Webster</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Seo, Sh" uniqKey="Seo S">SH Seo</name></author><author><name sortKey="Peiris, M" uniqKey="Peiris M">M Peiris</name></author><author><name sortKey="Webster, Rg" uniqKey="Webster R">RG Webster</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bodewes, R" uniqKey="Bodewes R">R Bodewes</name></author><author><name sortKey="Kreijtz, Jh" uniqKey="Kreijtz J">JH Kreijtz</name></author><author><name sortKey="Geelhoed Mieras, Mm" uniqKey="Geelhoed Mieras M">MM Geelhoed-Mieras</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Skountzou, I" uniqKey="Skountzou I">I Skountzou</name></author><author><name sortKey="Koutsonanos, Dg" uniqKey="Koutsonanos D">DG Koutsonanos</name></author><author><name sortKey="Kim, Jh" uniqKey="Kim J">JH Kim</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Epstein, Sl" uniqKey="Epstein S">SL Epstein</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Berkhoff, Eg" uniqKey="Berkhoff E">EG Berkhoff</name></author><author><name sortKey="Geelhoed Mieras, Mm" uniqKey="Geelhoed Mieras M">MM Geelhoed-Mieras</name></author><author><name sortKey="Fouchier, Ra" uniqKey="Fouchier R">RA Fouchier</name></author><author><name sortKey="Osterhaus, Ad" uniqKey="Osterhaus A">AD Osterhaus</name></author><author><name sortKey="Rimmelzwaan, Gf" uniqKey="Rimmelzwaan G">GF Rimmelzwaan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Voeten, Jt" uniqKey="Voeten J">JT Voeten</name></author><author><name sortKey="Bestebroer, Tm" uniqKey="Bestebroer T">TM Bestebroer</name></author><author><name sortKey="Nieuwkoop, Nj" uniqKey="Nieuwkoop N">NJ Nieuwkoop</name></author><author><name sortKey="Fouchier, Ra" uniqKey="Fouchier R">RA Fouchier</name></author><author><name sortKey="Osterhaus, Ad" uniqKey="Osterhaus A">AD Osterhaus</name></author><author><name sortKey="Rimmelzwaan, Gf" uniqKey="Rimmelzwaan G">GF Rimmelzwaan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Boon, Acm" uniqKey="Boon A">ACM Boon</name></author><author><name sortKey="De Mutsert, G" uniqKey="De Mutsert G">G de Mutsert</name></author><author><name sortKey="Graus, Ym" uniqKey="Graus Y">YM Graus</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rimmelzwaan, Gf" uniqKey="Rimmelzwaan G">GF Rimmelzwaan</name></author><author><name sortKey="Boon, Ac" uniqKey="Boon A">AC Boon</name></author><author><name sortKey="Voeten, Jt" uniqKey="Voeten J">JT Voeten</name></author><author><name sortKey="Berkhoff, Eg" uniqKey="Berkhoff E">EG Berkhoff</name></author><author><name sortKey="Fouchier, Ra" uniqKey="Fouchier R">RA Fouchier</name></author><author><name sortKey="Osterhaus, Ad" uniqKey="Osterhaus A">AD Osterhaus</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Boon, Ac" uniqKey="Boon A">AC Boon</name></author><author><name sortKey="De Mutsert, G" uniqKey="De Mutsert G">G de Mutsert</name></author><author><name sortKey="Van Baarle, D" uniqKey="Van Baarle D">D Van Baarle</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Berkhoff, Eg" uniqKey="Berkhoff E">EG Berkhoff</name></author><author><name sortKey="Boon, Ac" uniqKey="Boon A">AC Boon</name></author><author><name sortKey="Nieuwkoop, Nj" uniqKey="Nieuwkoop N">NJ Nieuwkoop</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Berkhoff, Eg" uniqKey="Berkhoff E">EG Berkhoff</name></author><author><name sortKey="Geelhoed Mieras, Mm" uniqKey="Geelhoed Mieras M">MM Geelhoed-Mieras</name></author><author><name sortKey="Verschuren, Ej" uniqKey="Verschuren E">EJ Verschuren</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rimmelzwaan, Gf" uniqKey="Rimmelzwaan G">GF Rimmelzwaan</name></author><author><name sortKey="Berkhoff, Eg" uniqKey="Berkhoff E">EG Berkhoff</name></author><author><name sortKey="Nieuwkoop, Nj" uniqKey="Nieuwkoop N">NJ Nieuwkoop</name></author><author><name sortKey="Fouchier, Ra" uniqKey="Fouchier R">RA Fouchier</name></author><author><name sortKey="Osterhaus, Ad" uniqKey="Osterhaus A">AD Osterhaus</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rimmelzwaan, Gf" uniqKey="Rimmelzwaan G">GF Rimmelzwaan</name></author><author><name sortKey="Berkhoff, Eg" uniqKey="Berkhoff E">EG Berkhoff</name></author><author><name sortKey="Nieuwkoop, Nj" uniqKey="Nieuwkoop N">NJ Nieuwkoop</name></author><author><name sortKey="Smith, Dj" uniqKey="Smith D">DJ Smith</name></author><author><name sortKey="Fouchier, Ra" uniqKey="Fouchier R">RA Fouchier</name></author><author><name sortKey="Osterhaus, Ad" uniqKey="Osterhaus A">AD Osterhaus</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gog, Jr" uniqKey="Gog J">JR Gog</name></author><author><name sortKey="Rimmelzwaan, Gf" uniqKey="Rimmelzwaan G">GF Rimmelzwaan</name></author><author><name sortKey="Osterhaus, Ad" uniqKey="Osterhaus A">AD Osterhaus</name></author><author><name sortKey="Grenfell, Bt" uniqKey="Grenfell B">BT Grenfell</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Berkhoff, Eg" uniqKey="Berkhoff E">EG Berkhoff</name></author><author><name sortKey="De Wit, E" uniqKey="De Wit E">E de Wit</name></author><author><name sortKey="Geelhoed Mieras, Mm" uniqKey="Geelhoed Mieras M">MM Geelhoed-Mieras</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Berkhoff, Eg" uniqKey="Berkhoff E">EG Berkhoff</name></author><author><name sortKey="De Wit, E" uniqKey="De Wit E">E de Wit</name></author><author><name sortKey="Geelhoed Mieras, Mm" uniqKey="Geelhoed Mieras M">MM Geelhoed-Mieras</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yewdell, Jw" uniqKey="Yewdell J">JW Yewdell</name></author><author><name sortKey="Bennink, Jr" uniqKey="Bennink J">JR Bennink</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yewdell, Jw" uniqKey="Yewdell J">JW Yewdell</name></author><author><name sortKey="Del Val, M" uniqKey="Del Val M">M Del Val</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yewdell, Jw" uniqKey="Yewdell J">JW Yewdell</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chen, W" uniqKey="Chen W">W Chen</name></author><author><name sortKey="Pang, K" uniqKey="Pang K">K Pang</name></author><author><name sortKey="Masterman, Ka" uniqKey="Masterman K">KA Masterman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Boon, Ac" uniqKey="Boon A">AC Boon</name></author><author><name sortKey="De Mutsert, G" uniqKey="De Mutsert G">G de Mutsert</name></author><author><name sortKey="Graus, Ym" uniqKey="Graus Y">YM Graus</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Belz, Gt" uniqKey="Belz G">GT Belz</name></author><author><name sortKey="Xie, W" uniqKey="Xie W">W Xie</name></author><author><name sortKey="Altman, Jd" uniqKey="Altman J">JD Altman</name></author><author><name sortKey="Doherty, Pc" uniqKey="Doherty P">PC Doherty</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Belz, Gt" uniqKey="Belz G">GT Belz</name></author><author><name sortKey="Stevenson, Pg" uniqKey="Stevenson P">PG Stevenson</name></author><author><name sortKey="Doherty, Pc" uniqKey="Doherty P">PC Doherty</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Boon, Ac" uniqKey="Boon A">AC Boon</name></author><author><name sortKey="De Mutsert, G" uniqKey="De Mutsert G">G de Mutsert</name></author><author><name sortKey="Fouchier, Ra" uniqKey="Fouchier R">RA Fouchier</name></author><author><name sortKey="Sintnicolaas, K" uniqKey="Sintnicolaas K">K Sintnicolaas</name></author><author><name sortKey="Osterhaus, Ad" uniqKey="Osterhaus A">AD Osterhaus</name></author><author><name sortKey="Rimmelzwaan, Gf" uniqKey="Rimmelzwaan G">GF Rimmelzwaan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tussey, Lg" uniqKey="Tussey L">LG Tussey</name></author><author><name sortKey="Rowland Jones, S" uniqKey="Rowland Jones S">S Rowland-Jones</name></author><author><name sortKey="Zheng, Ts" uniqKey="Zheng T">TS Zheng</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cho, Y" uniqKey="Cho Y">Y Cho</name></author><author><name sortKey="Basta, S" uniqKey="Basta S">S Basta</name></author><author><name sortKey="Chen, W" uniqKey="Chen W">W Chen</name></author><author><name sortKey="Bennink, Jr" uniqKey="Bennink J">JR Bennink</name></author><author><name sortKey="Yewdell, Jw" uniqKey="Yewdell J">JW Yewdell</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cui, W" uniqKey="Cui W">W Cui</name></author><author><name sortKey="Kaech, Sm" uniqKey="Kaech S">SM Kaech</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Schanen, Bc" uniqKey="Schanen B">BC Schanen</name></author><author><name sortKey="De Groot, As" uniqKey="De Groot A">AS de Groot</name></author><author><name sortKey="Moise, L" uniqKey="Moise L">L Moise</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Roti, M" uniqKey="Roti M">M Roti</name></author><author><name sortKey="Yang, J" uniqKey="Yang J">J Yang</name></author><author><name sortKey="Berger, D" uniqKey="Berger D">D Berger</name></author><author><name sortKey="Huston, L" uniqKey="Huston L">L Huston</name></author><author><name sortKey="James, Ea" uniqKey="James E">EA James</name></author><author><name sortKey="Kwok, Ww" uniqKey="Kwok W">WW Kwok</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Carragher, Dm" uniqKey="Carragher D">DM Carragher</name></author><author><name sortKey="Kaminski, Da" uniqKey="Kaminski D">DA Kaminski</name></author><author><name sortKey="Moquin, A" uniqKey="Moquin A">A Moquin</name></author><author><name sortKey="Hartson, L" uniqKey="Hartson L">L Hartson</name></author><author><name sortKey="Randall, Td" uniqKey="Randall T">TD Randall</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nguyen, Hh" uniqKey="Nguyen H">HH Nguyen</name></author><author><name sortKey="Van Ginkel, Fw" uniqKey="Van Ginkel F">FW van Ginkel</name></author><author><name sortKey="Vu, Hl" uniqKey="Vu H">HL Vu</name></author><author><name sortKey="Mcghee, Jr" uniqKey="Mcghee J">JR McGhee</name></author><author><name sortKey="Mestecky, J" uniqKey="Mestecky J">J Mestecky</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Epstein, Sl" uniqKey="Epstein S">SL Epstein</name></author><author><name sortKey="Lo, Cy" uniqKey="Lo C">CY Lo</name></author><author><name sortKey="Misplon, Ja" uniqKey="Misplon J">JA Misplon</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Throsby, M" uniqKey="Throsby M">M Throsby</name></author><author><name sortKey="Van Den Brink, E" uniqKey="Van Den Brink E">E van den Brink</name></author><author><name sortKey="Jongeneelen, M" uniqKey="Jongeneelen M">M Jongeneelen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rangel Moreno, J" uniqKey="Rangel Moreno J">J Rangel-Moreno</name></author><author><name sortKey="Carragher, Dm" uniqKey="Carragher D">DM Carragher</name></author><author><name sortKey="Misra, Rs" uniqKey="Misra R">RS Misra</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gorse, Gj" uniqKey="Gorse G">GJ Gorse</name></author><author><name sortKey="Belshe, Rb" uniqKey="Belshe R">RB Belshe</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gorse, Gj" uniqKey="Gorse G">GJ Gorse</name></author><author><name sortKey="Belshe, Rb" uniqKey="Belshe R">RB Belshe</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gorse, Gj" uniqKey="Gorse G">GJ Gorse</name></author><author><name sortKey="Campbell, Mj" uniqKey="Campbell M">MJ Campbell</name></author><author><name sortKey="Otto, Ee" uniqKey="Otto E">EE Otto</name></author><author><name sortKey="Powers, Dc" uniqKey="Powers D">DC Powers</name></author><author><name sortKey="Chambers, Gw" uniqKey="Chambers G">GW Chambers</name></author><author><name sortKey="Newman, Fk" uniqKey="Newman F">FK Newman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Basha, S" uniqKey="Basha S">S Basha</name></author><author><name sortKey="Hazenfeld, S" uniqKey="Hazenfeld S">S Hazenfeld</name></author><author><name sortKey="Brady, Rc" uniqKey="Brady R">RC Brady</name></author><author><name sortKey="Subbramanian, Ra" uniqKey="Subbramanian R">RA Subbramanian</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="He, Xs" uniqKey="He X">XS He</name></author><author><name sortKey="Holmes, Th" uniqKey="Holmes T">TH Holmes</name></author><author><name sortKey="Zhang, C" uniqKey="Zhang C">C Zhang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Powell, Tj" uniqKey="Powell T">TJ Powell</name></author><author><name sortKey="Strutt, T" uniqKey="Strutt T">T Strutt</name></author><author><name sortKey="Reome, J" uniqKey="Reome J">J Reome</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chen, Gl" uniqKey="Chen G">GL Chen</name></author><author><name sortKey="Lau, Yf" uniqKey="Lau Y">YF Lau</name></author><author><name sortKey="Lamirande, Ew" uniqKey="Lamirande E">EW Lamirande</name></author><author><name sortKey="Mccall, Aw" uniqKey="Mccall A">AW McCall</name></author><author><name sortKey="Subbarao, K" uniqKey="Subbarao K">K Subbarao</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sun, K" uniqKey="Sun K">K Sun</name></author><author><name sortKey="Ye, J" uniqKey="Ye J">J Ye</name></author><author><name sortKey="Perez, Dr" uniqKey="Perez D">DR Perez</name></author><author><name sortKey="Metzger, Dw" uniqKey="Metzger D">DW Metzger</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lu, X" uniqKey="Lu X">X Lu</name></author><author><name sortKey="Edwards, Le" uniqKey="Edwards L">LE Edwards</name></author><author><name sortKey="Desheva, Ja" uniqKey="Desheva J">JA Desheva</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Garcia Sastre, A" uniqKey="Garcia Sastre A">A García-Sastre</name></author><author><name sortKey="Egorov, A" uniqKey="Egorov A">A Egorov</name></author><author><name sortKey="Matassov, D" uniqKey="Matassov D">D Matassov</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wang, X" uniqKey="Wang X">X Wang</name></author><author><name sortKey="Li, M" uniqKey="Li M">M Li</name></author><author><name sortKey="Zheng, H" uniqKey="Zheng H">H Zheng</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Donelan, Nr" uniqKey="Donelan N">NR Donelan</name></author><author><name sortKey="Basler, Cf" uniqKey="Basler C">CF Basler</name></author><author><name sortKey="Garcia Sastre, A" uniqKey="Garcia Sastre A">A García-Sastre</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mueller, Sn" uniqKey="Mueller S">SN Mueller</name></author><author><name sortKey="Langley, Wa" uniqKey="Langley W">WA Langley</name></author><author><name sortKey="Carnero, E" uniqKey="Carnero E">E Carnero</name></author><author><name sortKey="Garcia Sastre, A" uniqKey="Garcia Sastre A">A García-Sastre</name></author><author><name sortKey="Ahmed, R" uniqKey="Ahmed R">R Ahmed</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Xie, H" uniqKey="Xie H">H Xie</name></author><author><name sortKey="Liu, Tm" uniqKey="Liu T">TM Liu</name></author><author><name sortKey="Lu, X" uniqKey="Lu X">X Lu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ulmer, Jb" uniqKey="Ulmer J">JB Ulmer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Moss, Rb" uniqKey="Moss R">RB Moss</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Laddy, Dj" uniqKey="Laddy D">DJ Laddy</name></author><author><name sortKey="Weiner, Db" uniqKey="Weiner D">DB Weiner</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ulmer, Jb" uniqKey="Ulmer J">JB Ulmer</name></author><author><name sortKey="Donnelly, Jj" uniqKey="Donnelly J">JJ Donnelly</name></author><author><name sortKey="Parker, Se" uniqKey="Parker S">SE Parker</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tao, P" uniqKey="Tao P">P Tao</name></author><author><name sortKey="Luo, M" uniqKey="Luo M">M Luo</name></author><author><name sortKey="Pan, R" uniqKey="Pan R">R Pan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Donnelly, Jj" uniqKey="Donnelly J">JJ Donnelly</name></author><author><name sortKey="Friedman, A" uniqKey="Friedman A">A Friedman</name></author><author><name sortKey="Ulmer, Jb" uniqKey="Ulmer J">JB Ulmer</name></author><author><name sortKey="Liu, Ma" uniqKey="Liu M">MA Liu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ulmer, Jb" uniqKey="Ulmer J">JB Ulmer</name></author><author><name sortKey="Fu, Tm" uniqKey="Fu T">TM Fu</name></author><author><name sortKey="Deck, Rr" uniqKey="Deck R">RR Deck</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Fu, Tm" uniqKey="Fu T">TM Fu</name></author><author><name sortKey="Guan, L" uniqKey="Guan L">L Guan</name></author><author><name sortKey="Friedman, A" uniqKey="Friedman A">A Friedman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ulmer, Jb" uniqKey="Ulmer J">JB Ulmer</name></author><author><name sortKey="Deck, Rr" uniqKey="Deck R">RR Deck</name></author><author><name sortKey="Dewitt, Cm" uniqKey="Dewitt C">CM Dewitt</name></author><author><name sortKey="Donnelly, Jj" uniqKey="Donnelly J">JJ Donnelly</name></author><author><name sortKey="Liu, Ma" uniqKey="Liu M">MA Liu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Saha, S" uniqKey="Saha S">S Saha</name></author><author><name sortKey="Yoshida, S" uniqKey="Yoshida S">S Yoshida</name></author><author><name sortKey="Ohba, K" uniqKey="Ohba K">K Ohba</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Laddy, Dj" uniqKey="Laddy D">DJ Laddy</name></author><author><name sortKey="Yan, J" uniqKey="Yan J">J Yan</name></author><author><name sortKey="Kutzler, M" uniqKey="Kutzler M">M Kutzler</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Smith, Lr" uniqKey="Smith L">LR Smith</name></author><author><name sortKey="Wloch, Mk" uniqKey="Wloch M">MK Wloch</name></author><author><name sortKey="Ye, M" uniqKey="Ye M">M Ye</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Klinman, Dm" uniqKey="Klinman D">DM Klinman</name></author><author><name sortKey="Takeno, M" uniqKey="Takeno M">M Takeno</name></author><author><name sortKey="Ichino, M" uniqKey="Ichino M">M Ichino</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chen, Cy" uniqKey="Chen C">CY Chen</name></author><author><name sortKey="Liu, Hj" uniqKey="Liu H">HJ Liu</name></author><author><name sortKey="Tsai, Cp" uniqKey="Tsai C">CP Tsai</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Barefoot, Be" uniqKey="Barefoot B">BE Barefoot</name></author><author><name sortKey="Sample, Cj" uniqKey="Sample C">CJ Sample</name></author><author><name sortKey="Ramsburg, Ea" uniqKey="Ramsburg E">EA Ramsburg</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Barefoot, Be" uniqKey="Barefoot B">BE Barefoot</name></author><author><name sortKey="Athearn, K" uniqKey="Athearn K">K Athearn</name></author><author><name sortKey="Sample, Cj" uniqKey="Sample C">CJ Sample</name></author><author><name sortKey="Ramsburg, Ea" uniqKey="Ramsburg E">EA Ramsburg</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Berglund, P" uniqKey="Berglund P">P Berglund</name></author><author><name sortKey="Fleeton, Mn" uniqKey="Fleeton M">MN Fleeton</name></author><author><name sortKey="Smerdou, C" uniqKey="Smerdou C">C Smerdou</name></author><author><name sortKey="Liljestrom, P" uniqKey="Liljestrom P">P Liljeström</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Vemula, Sv" uniqKey="Vemula S">SV Vemula</name></author><author><name sortKey="Mittal, Sk" uniqKey="Mittal S">SK Mittal</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="He, F" uniqKey="He F">F He</name></author><author><name sortKey="Madhan, S" uniqKey="Madhan S">S Madhan</name></author><author><name sortKey="Kwang, J" uniqKey="Kwang J">J Kwang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rimmelzwaan, Gf" uniqKey="Rimmelzwaan G">GF Rimmelzwaan</name></author><author><name sortKey="Sutter, G" uniqKey="Sutter G">G Sutter</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hoelscher, Ma" uniqKey="Hoelscher M">MA Hoelscher</name></author><author><name sortKey="Singh, N" uniqKey="Singh N">N Singh</name></author><author><name sortKey="Garg, S" uniqKey="Garg S">S Garg</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Holman, Dh" uniqKey="Holman D">DH Holman</name></author><author><name sortKey="Wang, D" uniqKey="Wang D">D Wang</name></author><author><name sortKey="Raja, Nu" uniqKey="Raja N">NU Raja</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Prasad, Sa" uniqKey="Prasad S">SA Prasad</name></author><author><name sortKey="Norbury, Cc" uniqKey="Norbury C">CC Norbury</name></author><author><name sortKey="Chen, W" uniqKey="Chen W">W Chen</name></author><author><name sortKey="Bennink, Jr" uniqKey="Bennink J">JR Bennink</name></author><author><name sortKey="Yewdell, Jw" uniqKey="Yewdell J">JW Yewdell</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Roy, S" uniqKey="Roy S">S Roy</name></author><author><name sortKey="Kobinger, Gp" uniqKey="Kobinger G">GP Kobinger</name></author><author><name sortKey="Lin, J" uniqKey="Lin J">J Lin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Steitz, J" uniqKey="Steitz J">J Steitz</name></author><author><name sortKey="Barlow, Pg" uniqKey="Barlow P">PG Barlow</name></author><author><name sortKey="Hossain, J" uniqKey="Hossain J">J Hossain</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hoelscher, Ma" uniqKey="Hoelscher M">MA Hoelscher</name></author><author><name sortKey="Jayashankar, L" uniqKey="Jayashankar L">L Jayashankar</name></author><author><name sortKey="Garg, S" uniqKey="Garg S">S Garg</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hoelscher, Ma" uniqKey="Hoelscher M">MA Hoelscher</name></author><author><name sortKey="Garg, S" uniqKey="Garg S">S Garg</name></author><author><name sortKey="Bangari, Ds" uniqKey="Bangari D">DS Bangari</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gao, W" uniqKey="Gao W">W Gao</name></author><author><name sortKey="Soloff, Ac" uniqKey="Soloff A">AC Soloff</name></author><author><name sortKey="Lu, X" uniqKey="Lu X">X Lu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Singh, S" uniqKey="Singh S">S Singh</name></author><author><name sortKey="Toro, H" uniqKey="Toro H">H Toro</name></author><author><name sortKey="Tang, Dc" uniqKey="Tang D">DC Tang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sipo, I" uniqKey="Sipo I">I Sipo</name></author><author><name sortKey="Knauf, M" uniqKey="Knauf M">M Knauf</name></author><author><name sortKey="Fechner, H" uniqKey="Fechner H">H Fechner</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kreijtz, Jh" uniqKey="Kreijtz J">JH Kreijtz</name></author><author><name sortKey="Suezer, Y" uniqKey="Suezer Y">Y Suezer</name></author><author><name sortKey="De Mutsert, G" uniqKey="De Mutsert G">G de Mutsert</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kreijtz, Jh" uniqKey="Kreijtz J">JH Kreijtz</name></author><author><name sortKey="Suezer, Y" uniqKey="Suezer Y">Y Suezer</name></author><author><name sortKey="De Mutsert, G" uniqKey="De Mutsert G">G de Mutsert</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kreijtz, Jh" uniqKey="Kreijtz J">JH Kreijtz</name></author><author><name sortKey="Suzer, Y" uniqKey="Suzer Y">Y Suzer</name></author><author><name sortKey="Bodewes, R" uniqKey="Bodewes R">R Bodewes</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sutter, G" uniqKey="Sutter G">G Sutter</name></author><author><name sortKey="Wyatt, Ls" uniqKey="Wyatt L">LS Wyatt</name></author><author><name sortKey="Foley, Pl" uniqKey="Foley P">PL Foley</name></author><author><name sortKey="Bennink, Jr" uniqKey="Bennink J">JR Bennink</name></author><author><name sortKey="Moss, B" uniqKey="Moss B">B Moss</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hessel, A" uniqKey="Hessel A">A Hessel</name></author><author><name sortKey="Schwendinger, M" uniqKey="Schwendinger M">M Schwendinger</name></author><author><name sortKey="Holzer, Gw" uniqKey="Holzer G">GW Holzer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Breathnach, Cc" uniqKey="Breathnach C">CC Breathnach</name></author><author><name sortKey="Clark, Hj" uniqKey="Clark H">HJ Clark</name></author><author><name sortKey="Clark, Rc" uniqKey="Clark R">RC Clark</name></author><author><name sortKey="Olsen, Cw" uniqKey="Olsen C">CW Olsen</name></author><author><name sortKey="Townsend, Hg" uniqKey="Townsend H">HG Townsend</name></author><author><name sortKey="Lunn, Dp" uniqKey="Lunn D">DP Lunn</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Berthoud, Tk" uniqKey="Berthoud T">TK Berthoud</name></author><author><name sortKey="Hamill, M" uniqKey="Hamill M">M Hamill</name></author><author><name sortKey="Lillie, Pj" uniqKey="Lillie P">PJ Lillie</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Galarza, Jm" uniqKey="Galarza J">JM Galarza</name></author><author><name sortKey="Latham, T" uniqKey="Latham T">T Latham</name></author><author><name sortKey="Cupo, A" uniqKey="Cupo A">A Cupo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Layton, Gt" uniqKey="Layton G">GT Layton</name></author><author><name sortKey="Harris, Sj" uniqKey="Harris S">SJ Harris</name></author><author><name sortKey="Myhan, J" uniqKey="Myhan J">J Myhan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ross, Tm" uniqKey="Ross T">TM Ross</name></author><author><name sortKey="Mahmood, K" uniqKey="Mahmood K">K Mahmood</name></author><author><name sortKey="Crevar, Cj" uniqKey="Crevar C">CJ Crevar</name></author><author><name sortKey="Schneider Ohrum, K" uniqKey="Schneider Ohrum K">K Schneider-Ohrum</name></author><author><name sortKey="Heaton, Pm" uniqKey="Heaton P">PM Heaton</name></author><author><name sortKey="Bright, Ra" uniqKey="Bright R">RA Bright</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lee, Dh" uniqKey="Lee D">DH Lee</name></author><author><name sortKey="Park, Jk" uniqKey="Park J">JK Park</name></author><author><name sortKey="Lee, Yn" uniqKey="Lee Y">YN Lee</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Furuya, Y" uniqKey="Furuya Y">Y Furuya</name></author><author><name sortKey="Chan, J" uniqKey="Chan J">J Chan</name></author><author><name sortKey="Regner, M" uniqKey="Regner M">M Regner</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Morein, B" uniqKey="Morein B">B Morein</name></author><author><name sortKey="Sundquist, B" uniqKey="Sundquist B">B Sundquist</name></author><author><name sortKey="Hoglund, S" uniqKey="Hoglund S">S Hoglund</name></author><author><name sortKey="Dalsgaard, K" uniqKey="Dalsgaard K">K Dalsgaard</name></author><author><name sortKey="Osterhaus, A" uniqKey="Osterhaus A">A Osterhaus</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Voeten, Jt" uniqKey="Voeten J">JT Voeten</name></author><author><name sortKey="Rimmelzwaan, Gf" uniqKey="Rimmelzwaan G">GF Rimmelzwaan</name></author><author><name sortKey="Nieuwkoop, Nj" uniqKey="Nieuwkoop N">NJ Nieuwkoop</name></author><author><name sortKey="Lovgren Bengtsson, K" uniqKey="Lovgren Bengtsson K">K Lövgren-Bengtsson</name></author><author><name sortKey="Osterhaus, Ad" uniqKey="Osterhaus A">AD Osterhaus</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sambhara, S" uniqKey="Sambhara S">S Sambhara</name></author><author><name sortKey="Kurichh, A" uniqKey="Kurichh A">A Kurichh</name></author><author><name sortKey="Miranda, R" uniqKey="Miranda R">R Miranda</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gluck, R" uniqKey="Gluck R">R Glück</name></author><author><name sortKey="Mischler, R" uniqKey="Mischler R">R Mischler</name></author><author><name sortKey="Finkel, B" uniqKey="Finkel B">B Finkel</name></author><author><name sortKey="Que, Ju" uniqKey="Que J">JU Que</name></author><author><name sortKey="Scarpa, B" uniqKey="Scarpa B">B Scarpa</name></author><author><name sortKey="Cryz, Sj" uniqKey="Cryz S">SJ Cryz</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rimmelzwaan, Gf" uniqKey="Rimmelzwaan G">GF Rimmelzwaan</name></author><author><name sortKey="Nieuwkoop, N" uniqKey="Nieuwkoop N">N Nieuwkoop</name></author><author><name sortKey="Brandenburg, A" uniqKey="Brandenburg A">A Brandenburg</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ennis, Fa" uniqKey="Ennis F">FA Ennis</name></author><author><name sortKey="Cruz, J" uniqKey="Cruz J">J Cruz</name></author><author><name sortKey="Jameson, J" uniqKey="Jameson J">J Jameson</name></author><author><name sortKey="Klein, M" uniqKey="Klein M">M Klein</name></author><author><name sortKey="Burt, D" uniqKey="Burt D">D Burt</name></author><author><name sortKey="Thipphawong, J" uniqKey="Thipphawong J">J Thipphawong</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wilschut, J" uniqKey="Wilschut J">J Wilschut</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bungener, L" uniqKey="Bungener L">L Bungener</name></author><author><name sortKey="Huckriede, A" uniqKey="Huckriede A">A Huckriede</name></author><author><name sortKey="De Mare, A" uniqKey="De Mare A">A de Mare</name></author><author><name sortKey="De Vries Idema, J" uniqKey="De Vries Idema J">J de Vries-Idema</name></author><author><name sortKey="Wilschut, J" uniqKey="Wilschut J">J Wilschut</name></author><author><name sortKey="Daemen, T" uniqKey="Daemen T">T Daemen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bungener, L" uniqKey="Bungener L">L Bungener</name></author><author><name sortKey="Serre, K" uniqKey="Serre K">K Serre</name></author><author><name sortKey="Bijl, L" uniqKey="Bijl L">L Bijl</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Conne, P" uniqKey="Conne P">P Conne</name></author><author><name sortKey="Gauthey, L" uniqKey="Gauthey L">L Gauthey</name></author><author><name sortKey="Vernet, P" uniqKey="Vernet P">P Vernet</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pregliasco, F" uniqKey="Pregliasco F">F Pregliasco</name></author><author><name sortKey="Mensi, C" uniqKey="Mensi C">C Mensi</name></author><author><name sortKey="Serpilli, W" uniqKey="Serpilli W">W Serpilli</name></author><author><name sortKey="Speccher, L" uniqKey="Speccher L">L Speccher</name></author><author><name sortKey="Masella, P" uniqKey="Masella P">P Masella</name></author><author><name sortKey="Belloni, A" uniqKey="Belloni A">A Belloni</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="De Bruijn, Ia" uniqKey="De Bruijn I">IA de Bruijn</name></author><author><name sortKey="Nauta, J" uniqKey="Nauta J">J Nauta</name></author><author><name sortKey="Gerez, L" uniqKey="Gerez L">L Gerez</name></author><author><name sortKey="Palache, Am" uniqKey="Palache A">AM Palache</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="review-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">J Biomed Biotechnol</journal-id><journal-id journal-id-type="publisher-id">JBB</journal-id><journal-title-group><journal-title>Journal of Biomedicine and Biotechnology</journal-title></journal-title-group><issn pub-type="ppub">1110-7243</issn><issn pub-type="epub">1110-7251</issn><publisher><publisher-name>Hindawi Publishing Corporation</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">22007149</article-id><article-id pub-id-type="pmc">3189652</article-id><article-id pub-id-type="doi">10.1155/2011/939860</article-id><article-categories><subj-group subj-group-type="heading"><subject>Review Article</subject></subj-group></article-categories><title-group><article-title>Induction of Virus-Specific Cytotoxic T Lymphocytes as a Basis for the Development of Broadly Protective Influenza Vaccines</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Hillaire</surname><given-names>Marine L. B.</given-names></name><xref ref-type="aff" rid="I1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Osterhaus</surname><given-names>Albert D. M. E.</given-names></name><xref ref-type="aff" rid="I1"><sup>1, 2</sup></xref><xref ref-type="aff" rid="I2"></xref></contrib><contrib contrib-type="author"><name><surname>Rimmelzwaan</surname><given-names>Guus F.</given-names></name><xref ref-type="aff" rid="I1"><sup>1, 2</sup></xref><xref ref-type="aff" rid="I2"></xref><xref ref-type="corresp" rid="cor1">*</xref></contrib></contrib-group><aff id="I1"><sup>1</sup>Department of Virology, Erasmus Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands</aff><aff id="I2"><sup>2</sup>Viroclinics Biosciences BV, Parklaan 44, 3016 BC Rotterdam, Rotterdam, The Netherlands</aff><author-notes><corresp id="cor1">*Guus F. Rimmelzwaan: <email>g.rimmelzwaan@erasmusmc.nl</email></corresp><fn fn-type="other"><p>Academic Editor: Zhengguo Xiao</p></fn></author-notes><pub-date pub-type="ppub"><year>2011</year></pub-date><pub-date pub-type="epub"><day>5</day><month>10</month><year>2011</year></pub-date><volume>2011</volume><elocation-id>939860</elocation-id><history><date date-type="received"><day>3</day><month>6</month><year>2011</year></date><date date-type="rev-recd"><day>1</day><month>7</month><year>2011</year></date><date date-type="accepted"><day>2</day><month>8</month><year>2011</year></date></history><permissions><copyright-statement>Copyright © 2011 Marine L. B. Hillaire et al.</copyright-statement><copyright-year>2011</copyright-year><license license-type="open-access"><license-p>This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</license-p></license></permissions><abstract><p>There is considerable interest in the development of broadly protective influenza vaccines because of the continuous emergence of antigenic drift variants of seasonal influenza viruses and the threat posed by the emergence of antigenically distinct pandemic influenza viruses. It has been recognized more than three decades ago that influenza A virus-specific cytotoxic T lymphocytes recognize epitopes located in the relatively conserved proteins like the nucleoprotein and that they cross-react with various subtypes of influenza A viruses. This implies that these CD8<sup>+</sup> T lymphocytes may contribute to protective heterosubtypic immunity induced by antecedent influenza A virus infections. In the present paper, we review the evidence for the role of virus-specific CD8<sup>+</sup> T lymphocytes in protective immunity against influenza virus infections and discuss vaccination strategies that aim at the induction of cross-reactive virus-specific T-cell responses.</p></abstract></article-meta></front><body><sec id="sec1"><title>1. Introduction</title><p>Every year, influenza A viruses (IAVs) cause epidemic outbreaks of respiratory tract infection resulting in excess morbidity and mortality. Especially individuals with certain underlying medical conditions and the elderly are at risk for complications of influenza.Therefore, it is recommended to vaccinate these individuals against influenza annually.</p><p>Currently used vaccines largely aim at the induction of antibodies directed to viral glycoproteins, in particular the hemagglutinin (HA). These antibodies neutralize the virus by preventing viral attachment to host cells and are generally considered the main correlate of protection against influenza virus infection [<xref ref-type="bibr" rid="B1">1</xref>]. Therefore, assessing postvaccination HA-specific antibody titers is used as surrogate marker for vaccine efficacy compliant with EMEA and FDA guidelines [<xref ref-type="bibr" rid="B2">2</xref>, <xref ref-type="bibr" rid="B3">3</xref>].</p><p>However, seasonal influenza viruses continuously accumulate amino acid substitutions in the antigenic sites of the HA molecules and consequently display considerable antigenic drift.</p><p>This allows currently circulating influenza viruses to escape from the neutralizing activity of antibodies induced by previous infections or vaccination and necessitates updating the vaccine regularly to match recent epidemic strains.</p><p>Occasionally, novel strains of influenza A viruses are introduced with HA molecules that are antigenically distinct from seasonal influenza A viruses including those of a novel subtype. Seasonal influenza vaccines are not protective against these new viruses, which may spark a pandemic outbreak of influenza and against which specific vaccines need to be developed. The pandemic of 2009 caused by influenza A/H1N1 viruses of swine origin painfully highlighted that the development of a matching vaccine is a time consuming process, and, in many countries, vaccines became available after the peak of pandemic [<xref ref-type="bibr" rid="B4">4</xref>, <xref ref-type="bibr" rid="B5">5</xref>].</p><p>For these reasons, there is considerable interest in the development of more broadly protective influenza vaccines that ideally would afford broad protection against various subtypes of influenza A viruses [<xref ref-type="bibr" rid="B6">6</xref>, <xref ref-type="bibr" rid="B7">7</xref>] and/or antigenic drift variants within a subtype.</p><p>It has been well established that infection with influenza A virus can induce a certain degree of protective immunity to infection with other influenza A viruses of unrelated subtypes (heterosubtypic immunity) (for review see [<xref ref-type="bibr" rid="B8">8</xref>]). Elucidation of the correlates of protection of this type of immunity may aid the development of more universal vaccines. Since different subtypes of influenza A virus are defined by the absence of serological cross-reactivity, it is unlikely that antibodies to HA or neuraminidase (NA) contribute to this type of infection-induced immunity to a great extent. However, recently antibodies have been identified specific for epitopes located in the stem region of the HA molecule, displaying broad reactivity and broad neutralizing activity against several different influenza A viruses of different HA subtypes [<xref ref-type="bibr" rid="B9">9</xref>–<xref ref-type="bibr" rid="B16">16</xref>]. HA-stem-based vaccines may be a promising venue for the development of broadly protective vaccines. Other vaccine candidates aiming at the induction of cross-protective antibodies may include those based on the M2 protein [<xref ref-type="bibr" rid="B17">17</xref>–<xref ref-type="bibr" rid="B21">21</xref>]. The induction of M2-specific antibodies after infection is rather inefficient. Furthermore, several studies have shown that postinfection serum does not afford protection against a heterosubtypic strain of influenza A virus, whereas virus-specific T cells do [<xref ref-type="bibr" rid="B22">22</xref>]. Nevertheless, induction of M2-specific antibodies after M2 hyperimmunization does afford heterosubtypic immunity. However, it was shown that the protection mediated by vaccine-induced M2 antibodies was weak and could not prevent infection of mice. The mechanism of protection was based on antibody-dependent cell cytotoxicity (ADCC) [<xref ref-type="bibr" rid="B23">23</xref>].</p><p>Since the majority of virus-specific T cells, and in particular CD8<sup>+</sup> cytotoxic T lymphocytes (CTL), are directed against relatively conserved viral proteins like the nucleoprotein (NP) and the matrix 1 protein (M1), it was already suggested three decades ago that virus-specific CTLs contribute to heterosubtypic immunity [<xref ref-type="bibr" rid="B24">24</xref>, <xref ref-type="bibr" rid="B25">25</xref>]. In the present paper, we review the evidence that influenza virus-specific T cells contribute to (cross-)protective immunity and discuss vaccine formulation that can induce virus-specific CTL.</p></sec><sec id="sec2"><title>2. CTLs Contribute to Heterosubtypic Immunity</title><p>The most important mode of action of virus-specific CTL is recognition and elimination of virus-infected cells. This way, the production of progeny virus is prevented. Thus, the presence of preexisting T-cell immunity results in more rapid clearance of virus infections. Key for heterosubtypic immunity is that CTLs are cross-reactive and recognize epitopes shared by influenza A viruses of different subtypes. The effectors functions of CTLs that are responsible for the elimination of virus-infected cells include the release of perforin and granzyme from their granules and Fas/FasL interactions with infected target cells. In addition, upon activation virus-specific CD8<sup>+</sup> T cells can produce a variety of different cytokines including IFN-<italic>γ</italic> and TNF-<italic>α</italic>. It was shown that virus-specific CTLs, through their receptor recognize viral peptides, which are generated by the endogenous route of antigen processing and that are ultimately presented by MHC class I molecules on the surface of antigen-presenting cells or virus-infected cells [<xref ref-type="bibr" rid="B26">26</xref>, <xref ref-type="bibr" rid="B27">27</xref>]. For the efficient induction of virus-specific CTLs, it is required that the antigen is present in the cytosol of antigen-presenting cells where antigen processing takes place. </p><p>Influenza virus-specific CTL can recognize epitopes that are shared by different subtypes of influenza A virus. Indeed, it was shown that a large proportion of mouse and human CTLs induced after infection with influenza A virus were directed against the relatively conserved NP and M1 protein [<xref ref-type="bibr" rid="B32">29</xref>, <xref ref-type="bibr" rid="B31">31</xref>, <xref ref-type="bibr" rid="B28">37</xref>–<xref ref-type="bibr" rid="B30">39</xref>]. This raised the expectation that these cells contribute to cross-protection against viruses of different subtypes.</p><p>Many studies have been performed to demonstrate the cross-reactivity of influenza virus-specific CTLs and their role in heterosubtypic immunity. The outcomes of these studies are summarized in <xref ref-type="table" rid="tab1">Table 1</xref>. </p><sec sec-type="subsection" id="sec2.1"><title>2.1. Evidence for Cross-Reactivity of CTL In Vitro</title><p>Early evidence for the intersubtypic cross-reactivity of CTL was described by Zweerink et al. [<xref ref-type="bibr" rid="B34">28</xref>, <xref ref-type="bibr" rid="B33">40</xref>], who demonstrated that mouse CTL specific for influenza virus of the H2N1 subtype could lyse target cells infected with virus of the H3N2 subtype. </p><p>Also with other combinations of subtypes, the cross-reactive nature of virus-specific CTL was confirmed (<xref ref-type="table" rid="tab1">Table 1</xref>). For example, it was shown that in healthy individuals, with a history of infection with seasonal influenza virus, memory CD8<sup>+</sup> T cells were present in the blood that cross-reacted with highly pathogenic H5N1 virus [<xref ref-type="bibr" rid="B35">32</xref>–<xref ref-type="bibr" rid="B37">34</xref>]. The presence of cross-reactive CTL may afford a certain degree of protection against infection with these viruses, which still constitute a pandemic threat. It is of interest to note that especially younger individuals are at risk for severe disease and fatal outcome of influenza H5N1 infection [<xref ref-type="bibr" rid="B38">41</xref>]. It is tempting to speculate that younger individuals less likely have been exposed to seasonal influenza A viruses of the H3N2 or H1N1 subtype and, thus, have not mounted a CTL response to these viruses. Therefore, they may be more susceptible to infection with a virus of an alternative subtype. However, it cannot be ruled out that other factors play a role in the observed disproportionate age distribution of severe H5N1 cases. Furthermore, CTL obtained from healthy subjects before the pandemic of 2009 displayed cross-reactivity with the pandemic 2009 pH1N1 virus [<xref ref-type="bibr" rid="B40">35</xref>, <xref ref-type="bibr" rid="B39">36</xref>], which may have afforded a certain degree of protection against this virus.</p></sec><sec sec-type="subsection" id="sec2.2"><title>2.2. Evidence for the Role of CTL in Protection against Infection</title><p>Evidence for the role of virus-specific CTL in protection against influenza virus infection predominantly stems from animal models (<xref ref-type="table" rid="tab2">Table 2</xref>). Using various combinations of influenza A virus subtypes, it was demonstrated that CTL responses induced after a primary infection with influenza virus either correlated with protection against challenge infection with a virus of another subtype or were responsible for protective immunity [<xref ref-type="bibr" rid="B8">8</xref>, <xref ref-type="bibr" rid="B41">42</xref>–<xref ref-type="bibr" rid="B46">47</xref>]. The full extent of cross-reactivity of human CTL is not known. However, since the conserved proteins like the NP, M1, and the polymerase proteins display a high degree of sequence homology, it is assumed that the extent of cross-reactivity between different subtypes of influenza A virus is substantial. This is exemplified by demonstrating that human CTLs directed to human influenza A viruses of the H3N2 subtype cross-react considerably with avian influenza A viruses of the H5N1 subtype [<xref ref-type="bibr" rid="B41">42</xref>].</p><p>By adoptive transfer or depletion of virus-specific CD8<sup>+</sup> T cells, it was confirmed that these cells contributed to protective heterosubtypic immunity [<xref ref-type="bibr" rid="B22">22</xref>, <xref ref-type="bibr" rid="B50">48</xref>–<xref ref-type="bibr" rid="B49">50</xref>, <xref ref-type="bibr" rid="B48">52</xref>]. Indeed, the adoptive transfer of virus-specific CTLs to naïve recipient mice had a beneficial effect on the course of subsequent challenge infections. It was shown that transfer of CTL from mice infected with seasonal H3N2 virus protected recipient mice against challenge infection with 2009 pH1N1 virus [<xref ref-type="bibr" rid="B22">22</xref>]. Also chickens that received CTL from chickens infected with H9N2 virus were protected against subsequent challenge infection with highly pathogenic H5N1 virus [<xref ref-type="bibr" rid="B51">56</xref>]. Also, depletion of CD8<sup>+</sup> T cells prior to challenge infection confirmed that these cells contribute to heterosubtypic immunity. Primed mice or chickens, from which CTL were depleted, had higher lung virus titer, developed more severe disease, and displayed higher mortality rates after challenge infection than control animals [<xref ref-type="bibr" rid="B53">54</xref>, <xref ref-type="bibr" rid="B52">55</xref>, <xref ref-type="bibr" rid="B55">57</xref>, <xref ref-type="bibr" rid="B54">59</xref>].</p><p>There is little evidence that CTLs contribute to heterosubtypic immunity in humans. The first and, to our knowledge, the only evidence for this was described by McMichael et al. They demonstrated that in experimentally infected individuals, virus-specific cytotoxicity inversely correlated with the extent of virus shedding in the absence of antibodies specific for the H1N1 strain that was used for infection [<xref ref-type="bibr" rid="B29">38</xref>]. </p><p>There is, however, epidemiological evidence that indicate that prior exposure to influenza viruses is inducing protective immunity against a heterosubtypic strain of influenza [<xref ref-type="bibr" rid="B56">60</xref>]. People, who experienced symptomatic influenza caused by infection with influenza viruses of the H1N1 subtype, were partially protected from infection with the pandemic H2N2 viruses in 1957 [<xref ref-type="bibr" rid="B56">60</xref>]. A possible correlation with the presence of virus-specific CTL-mediated immunity was not studied. More circumstantial evidence is based on the observation that the ratio between synonymous and nonsynonymous (Ds/Dn) mutations in the NP gene is lower in CTL epitope sequences than in the rest of the protein. This also provides indirect evidence that CTLs exert antiviral activity in humans at the population level [<xref ref-type="bibr" rid="B57">61</xref>] and indicates that CTL epitopes are under selective pressure. Indeed, a number of amino acid substitutions that were observed in CTL epitopes during the evolution of influenza A/H3N2 viruses were associated with escape from recognition by virus-specific CTL [<xref ref-type="bibr" rid="B57">61</xref>–<xref ref-type="bibr" rid="B61">65</xref>]. Examples include the R384G substitution at the anchor residue of the HLA-B∗2705 restricted NP<sub>383–391</sub> epitope and amino acid substitutions at T-cell receptor contact residues of the HLA-B∗3501 restricted NP<sub>418–426</sub> epitope. In both cases, the amino acid substitutions affected the <italic>in vitro </italic>human influenza virus-specific CTL response significantly [<xref ref-type="bibr" rid="B62">66</xref>, <xref ref-type="bibr" rid="B63">67</xref>].</p><p>Of interest, the R384G substitution alone was detrimental to viral fitness and was only tolerated in the presence of two functionally compensating comutations [<xref ref-type="bibr" rid="B64">68</xref>, <xref ref-type="bibr" rid="B65">69</xref>].</p><p>Thus, apparently, the virus has the capacity to overcome functional constraints in order to evade T-cell immunity. The rapid fixation of the R384G substitution could be explained by strong bottle-neck and founder effects at the population level in a theoretical model [<xref ref-type="bibr" rid="B66">70</xref>]. Although CTL epitopes, can thus display variability allowing the virus to escape from recognition by CTL specific for these epitopes, other epitopes remain fully conserved including the immunodominant M1<sub>58–66</sub> epitope that is restricted by HLA-A∗0201, which has a high prevalence in most countries. For this and some other conserved epitopes it was demonstrated that also functional constraints may play a role in limiting the virus to escape efficiently from recognition by CTL to these highly conserved epitopes [<xref ref-type="bibr" rid="B67">71</xref>, <xref ref-type="bibr" rid="B68">72</xref>]. Thus, influenza virus CTL epitopes are either conserved, display variation at non-anchor residues, or loose their anchor residues at the cost of viral fitness, which need to be functionally compensated by the accumulation of comutations.</p></sec></sec><sec id="sec3"><title>3. Considerations for Vaccine Development</title><p>A large number of peptides are generated during processing of viral proteins in infected cells, but only some of these peptides are ultimately presented by major histocompatibility complex class I molecules and recognized by specific CTL. The hierarchy of CTL responses is called immunodominance [<xref ref-type="bibr" rid="B69">73</xref>–<xref ref-type="bibr" rid="B71">75</xref>] and has been demonstrated in animal models [<xref ref-type="bibr" rid="B72">76</xref>] and humans [<xref ref-type="bibr" rid="B73">77</xref>].</p><p>In mice it was shown that the hierarchy of primary and secondary CTL responses differ [<xref ref-type="bibr" rid="B72">76</xref>, <xref ref-type="bibr" rid="B74">78</xref>, <xref ref-type="bibr" rid="B75">79</xref>]. Since some CTL epitopes are more dominant than others, also the HLA usage of the CTL response is dependent on the repertoire of viral epitopes. For this reason, the HLA usage of the CTL response to influenza A virus is different from that to influenza B virus [<xref ref-type="bibr" rid="B76">80</xref>]. Immunodominance also complicates the analysis of CTL responses induced by vaccination or infection. Assessing the response to a single epitope is not fully informative without knowing it is relative immunodominance. In addition, it has been shown that the response to a single epitope can be influenced by other non-corresponding HLA alleles [<xref ref-type="bibr" rid="B73">77</xref>, <xref ref-type="bibr" rid="B77">81</xref>].</p><p>The HLA haplotype dictates which epitopes can be presented and recognized and determines the magnitude of the virus-specific CTL response. For example, the immunodominant M1<sub>58–66</sub> epitope is only recognized in HLA-A∗0201 positive subjects, and, in these individuals, the overall CTL response to influenza A virus is higher than in HLA-A∗0201 negative subjects that are matched for the remaining HLA alleles [<xref ref-type="bibr" rid="B73">77</xref>]. </p><p>Thus, both immunodominance and HLA restriction of CTL responses should be taken into account when assessing the ability of candidate vaccines to induce virus-specific CTL responses. </p><p>For the efficient induction of CTL responses, it is critical that viral antigens enter the endogenous route of antigen processing. To achieve this, viral proteins need to be delivered in the cytosol of antigen presenting-cells, where degradation of these proteins by the proteasome takes place. The peptides that are generated are then transported by the transporter associated with antigen processing (TAP) into the endoplasmic reticulum where binding of antigenic peptides with their corresponding MHC class I molecules can take place. These MHC class I/peptide complexes are subsequently transported to the cell membrane for recognition by virus-specific CD8<sup>+</sup> T lymphocytes. The cytosolic delivery of viral proteins by vaccine preparations can be achieved by using live (attenuated) virus, viral vectors, or expression from plasmid DNA, which allow de novo synthesis of viral proteins in the infected cells. Alternatively, particulate antigen presentation forms can be used which can translocate viral proteins into the cytosol directly or through endosomal degradation of the exogenous viral proteins [<xref ref-type="bibr" rid="B78">82</xref>].</p><p>In addition to CD8<sup>+</sup> T cells, CD4<sup>+</sup> T cells have been shown to contribute to heterosubtypic immunity [<xref ref-type="bibr" rid="B53">54</xref>, <xref ref-type="bibr" rid="B52">55</xref>]. The relationship between CD4<sup>+</sup> and CD8<sup>+</sup> T cells has been studied extensively, and it seems that memory CD8<sup>+</sup> T cells are impaired in the absence of memory CD4<sup>+</sup> T cells leading to increased cell death and decreased secondary T-cell response [<xref ref-type="bibr" rid="B79">83</xref>]. Thus, it is imperative that vaccines also induce adequate virus-specific CD4<sup>+</sup> T-helper cell responses in addition to CD8<sup>+</sup> T-cell responses. Of interest, also CD4<sup>+</sup> T cells specific for seasonal influenza A viruses display cross-reactivity with influenza A viruses of different subtypes including 2009 pH1N1 [<xref ref-type="bibr" rid="B80">84</xref>] and H5N1 [<xref ref-type="bibr" rid="B35">32</xref>, <xref ref-type="bibr" rid="B37">34</xref>, <xref ref-type="bibr" rid="B81">85</xref>]. </p><p>Other cells of the adaptive immune system may play a role in heterosubtypic immunity against influenza A viruses. Some studies have indicated that B cells and mucosal antibodies play a role in heterosubtypic immunity [<xref ref-type="bibr" rid="B23">23</xref>, <xref ref-type="bibr" rid="B43">44</xref>, <xref ref-type="bibr" rid="B82">86</xref>–<xref ref-type="bibr" rid="B86">90</xref>]. However, we and others were able to adoptively transfer heterosubtypic immunity with T cells but not with B cells to naïve recipient mice (<xref ref-type="table" rid="tab2">Table 2</xref>). Of interest, CD4<sup>+</sup> T cells are necessary to promote the protective effect of virus-specific CD8<sup>+</sup> T cells [<xref ref-type="bibr" rid="B22">22</xref>]. However, since this special issue focusrs on CD8<sup>+</sup> T, cells we did not discuss the role of other immune cells extensively. Also cells of the innate immune system (like NK cells and macrophages) have protective efficacy; however, since these cells do not develop memory against pathogens, they cannot be at the basis of vaccination strategies which aim at the induction of immunological memory against these pathogens.</p></sec><sec id="sec4"><title>4. Live Attenuated Vaccines</title><p>The use of live attenuated influenza vaccines (LAIVs) is of interest since it results in viral protein synthesis in infected antigen-presenting cells which is a prerequisite for the efficient induction of virus-specific CTL responses [<xref ref-type="bibr" rid="B87">91</xref>–<xref ref-type="bibr" rid="B90">94</xref>]. LAIVs also induce antibody responses and, thus, have the capacity to induce both virus-specific CTL and B cells which both contribute to protective immunity. They are currently used in the United States and in Russia, and request of approval for their use in Europe has been submitted. </p><p>LAIVs have been obtained by adaptation to replicate at low temperatures (25–33°C). The use of these cold-adapted viruses results in mild infections of the upper respiratory tract only. It has been shown in humans that LAIVs induce stronger virus-specific T-cell responses than inactivated vaccines [<xref ref-type="bibr" rid="B90">94</xref>, <xref ref-type="bibr" rid="B91">95</xref>]. Intranasal administration of H3N2 LAIV-afforded mice partial protection against infection with H1N1 virus. LAIV-vaccinated mice that were depleted of CD8<sup>+</sup> T cells were not protected and did not survive H1N1 challenge infection [<xref ref-type="bibr" rid="B92">96</xref>]. Furthermore, seasonal LAIV induced strong CTL response in mice and afforded protection against 2009 pH1N1 virus whereas an inactivated vaccine did not [<xref ref-type="bibr" rid="B93">97</xref>]. Similar findings were observed by others, and the contribution of T cells in protection against 2009 pH1N1 was confirmed after depletion of these cells [<xref ref-type="bibr" rid="B94">98</xref>].</p><p>LAIVs based on nonpathogenic H5N2 viruses also provided protection against challenge with highly pathogenic H5N1 in mice, which correlated with the induction of cross-reactive antibodies but also with cross-reactive T cells [<xref ref-type="bibr" rid="B95">99</xref>]. </p><p>Another strategy to attenuate influenza viruses is to delete part of the nonstructural protein 1 (NS1) [<xref ref-type="bibr" rid="B96">100</xref>–<xref ref-type="bibr" rid="B98">102</xref>]. This protein is known to be an antagonist of IFN<italic>α</italic>. Truncation of NS1 renders this protein nonfunctional causing attenuation of the virus [<xref ref-type="bibr" rid="B98">102</xref>]. It has been shown in mice that influenza virus, with altered NS1 genes induce potent and protective memory T-cell responses [<xref ref-type="bibr" rid="B99">103</xref>].</p><p>Also a live attenuated M1 mutant H1N1 virus with an attenuated phenotype <italic>in vivo </italic>was generated [<xref ref-type="bibr" rid="B100">104</xref>]. This live attenuated mutant virus also induced broadly cross-reactive immunity against H3N2 and H5N1 viruses, which was shown to be based on both humoral and cellular responses by adoptive transfer experiments.</p></sec><sec id="sec5"><title>5. DNA Vaccines</title><p>DNA vaccines have the advantage that they can be produced rapidly and at low cost. DNA vaccines encode for one or several proteins of influenza viruses and induce an immune response targeting the encoded protein [<xref ref-type="bibr" rid="B101">105</xref>].</p><p>Typically, plasmids are constructed with the gene of interest, for example, the NP gene, under control of a strong eukaryotic promoter, for example, the CMV promoter. Upon immunization of the plasmid by injection, electroporation, or gene gun delivery, the gene is expressed in cells that have taken up the plasmid (e.g., myocytes or dendritic cells). Then, the proteins are synthesized in the cytosol of these cells. After processing of these proteins, immunogenic peptides will be generated and presented by MHC class I molecules to virus-specific T cells [<xref ref-type="bibr" rid="B102">106</xref>].</p><p> The design of DNA vaccine is complex. Over the years, it has been shown that numerous factors play a role in the efficiency of expression such as the promoter, the G/C content (sequences rich in C/G are likely to form secondary structure that inhibit translation), supercoiling that increase transfection efficiency, polyadenylation that enhance stability of mRNA, and codon optimization (for review see [<xref ref-type="bibr" rid="B103">107</xref>]).</p><p> It has been shown in mice that the administration of DNA vaccine encoding the NP protein of influenza induced a strong CTL response which correlated with protection against challenge infection with homologous or heterologous virus [<xref ref-type="bibr" rid="B104">108</xref>]. Numerous studies have confirmed these results with DNA vaccines expressing NP, M1, or HA proteins in various animal models [<xref ref-type="bibr" rid="B105">109</xref>–<xref ref-type="bibr" rid="B110">114</xref>]. One study evaluated the delivery of the vaccine by <italic>in vivo</italic> electroporation instead of the classical epidermal route. They showed that, in mice, ferrets, and nonhuman primates, this route of delivery induce protective humoral and cellular immunity [<xref ref-type="bibr" rid="B111">115</xref>]. </p><p>Recently, a phase I clinical trial was performed with a candidate influenza DNA vaccine. The vaxfectin-adjuvanted plasmid DNA vaccines encoding influenza H5 HA, NP, and M2 were able to elicit T-cell responses against HA in most of the subjects and against NP and M2 in some of them [<xref ref-type="bibr" rid="B112">116</xref>]. </p><p>Safety remains a concern for DNA vaccination. There might be a risk of integration into the host genome, which may increase the risk of malignancies or tolerance induction [<xref ref-type="bibr" rid="B113">117</xref>].</p></sec><sec id="sec6"><title>6. Vectored Vaccines</title><p>Various viruses can be used as viral vectors to deliver foreign antigens. As for LAIV, the use of viral vectors caused infection of cells, which would allow endogenous antigen processing and MHC class I restricted presentation. Several viruses have been considered as potential vector vaccine candidates and were able to induce CTL response such as baculovirus [<xref ref-type="bibr" rid="B114">118</xref>], vesicular stomatitis virus [<xref ref-type="bibr" rid="B115">119</xref>, <xref ref-type="bibr" rid="B116">120</xref>], and Semliki Forest virus [<xref ref-type="bibr" rid="B117">121</xref>]. Adenovirus and poxviruses, like modified vaccinia virus Ankara (MVA), have been studied extensively for the delivery of influenza antigens. The design and production of such vaccines have been reviewed elsewhere [<xref ref-type="bibr" rid="B118">122</xref>–<xref ref-type="bibr" rid="B120">124</xref>]. </p><p>Recombinant adenoviruses that are unable to replicate in human cells and that encode one or more genes of interest such as the HA, NP, and M1 genes, can be produced. Using such recombinant, viruses protective T-cell responses were induced in mice [<xref ref-type="bibr" rid="B21">21</xref>, <xref ref-type="bibr" rid="B121">125</xref>–<xref ref-type="bibr" rid="B128">132</xref>] and chickens [<xref ref-type="bibr" rid="B128">132</xref>, <xref ref-type="bibr" rid="B129">133</xref>]. Recently, it was also demonstrated that an adenovirus-based vaccine expressing HA, NP, and M1 of the 2009 pH1N1 virus induced protective humoral and cellular immunity against homologous challenge and partial protection against challenge with a heterologous virus [<xref ref-type="bibr" rid="B130">134</xref>].</p><p>MVA-based influenza vaccines have been studied in various animal models extensively [<xref ref-type="bibr" rid="B120">124</xref>, <xref ref-type="bibr" rid="B131">135</xref>–<xref ref-type="bibr" rid="B133">137</xref>]. These vector vaccines conferred protection and induced virus-specific CTL responses [<xref ref-type="bibr" rid="B134">138</xref>–<xref ref-type="bibr" rid="B136">140</xref>].</p><p>Recently, MVA vectors encoding the NP and M1 genes were evaluated in a phase I clinical trial and were shown to be safe and immunogenic. These candidate vaccines also induced virus-specific CD8<sup>+</sup> T-cell responses more efficiently compared to other vaccination strategies [<xref ref-type="bibr" rid="B137">141</xref>].</p></sec><sec id="sec7"><title>7. Other Vaccines and Adjuvants</title><p>In addition to the vaccine formulation described above, other vaccine formulations have been described able to induce virus-specific CD8<sup>+</sup> T-cell responses. For example, virus-like particles, which can be produced after expressing influenza virus antigens in (insect) cells [<xref ref-type="bibr" rid="B138">142</xref>], have been shown to induce CTL responses in mice [<xref ref-type="bibr" rid="B139">143</xref>, <xref ref-type="bibr" rid="B140">144</xref>] and in chickens [<xref ref-type="bibr" rid="B141">145</xref>]. Also, with gamma-irradiated influenza A virus preparations, protective immunity was induced in mice against infection with homologous and heterologous influenza A viruses. Adoptive transfer experiments showed that protective immunity was mediated by virus-specific T cells [<xref ref-type="bibr" rid="B142">146</xref>].</p><p>Specific adjuvant systems like immune-stimulating complexes (ISCOMs) can be used for the induction of virus-specific CTL responses. ISCOMs consist of cholesterol, phospholipids, viral proteins, and glycosides of the adjuvant Quil A [<xref ref-type="bibr" rid="B143">147</xref>]. In addition to enhancing B-cell responses, the use of ISCOMs also induces strong T-cell responses. Since ISCOMs also facilitate transport of viral protein into the cytoplasm of antigen-presenting cells, it also induces CTL responses [<xref ref-type="bibr" rid="B144">148</xref>]. It has been demonstrated in mice that, with ISCOM-based vaccines, heterosubtypic immunity can be induced, which correlated with the induction of the virus-specific T-cell responses [<xref ref-type="bibr" rid="B145">149</xref>, <xref ref-type="bibr" rid="B146">150</xref>]. Also, in humans, virus-specific CTL responses could be induced with ISCOM-based vaccines in addition to antibody responses [<xref ref-type="bibr" rid="B147">151</xref>, <xref ref-type="bibr" rid="B148">152</xref>]. For the formulation of virosomes, the membrane glycoproteins of influenza viruses are incorporated into a lipid bilayer containing phospholipids resulting in vesicles of +/−150 nm in diameter [<xref ref-type="bibr" rid="B149">153</xref>]. Since the fusion activity of the HA molecules is retained, it would allow delivery of antigens (or plasmid DNA) from the endosomes into the cytosol, allowing the induction of CTL responses [<xref ref-type="bibr" rid="B150">154</xref>, <xref ref-type="bibr" rid="B151">155</xref>]. </p><p>In clinical trials, virosome-based vaccines were more immunogenic in the elderly than conventional vaccines [<xref ref-type="bibr" rid="B146">150</xref>, <xref ref-type="bibr" rid="B152">156</xref>–<xref ref-type="bibr" rid="B154">158</xref>].</p></sec><sec id="sec8"><title>8. Conclusions</title><p>There is ample evidence that virus-specific CTLs contribute to protective immunity against influenza virus infections. Because of their cross-reactive nature, virus-specific CTLs afford protection against influenza A viruses of various subtypes.</p><p>It should be realized that antibodies, directed against the viral envelope proteins HA and NA, are the primary correlates of protection against infection with influenza A viruses provided that they match the strain causing the infection.</p><p>The presence of sufficiently high titers of specific serum antibodies, induced by vaccination or infection, will protect individuals from a subsequent infection. Under these circumstances, the induction or presence of virus-specific CD8<sup>+</sup> T lymphocytes may be redundant. Therefore, the induction of these antibodies should be the strategy of choice. However, in the case of the emergence of drift variants of seasonal viruses, the available vaccines may not be as efficacious due to a poor antigenic match. In the case of the introduction of a novel pandemic strain, the seasonal vaccines will be poorly protective, and novel pandemic vaccines need to be produced, which is a time-consuming process. Under these circumstances, in which humoral immunity fails to afford protection, the presence of cross-reactive CTL will not prevent infection but will contribute to more rapid clearance of infection and reduce disease severity and mortality. Various vaccination formulations aiming at the induction of virus-specific CTL are currently under development. Future preclinical and clinical testing need to provide information on the effectiveness of these vaccines. In a pandemic scenario, vaccines that induce cross-protective CTL could be used for emergency vaccination until vaccines become available that induce antibodies of the proper specificity. Especially, immunogenically naïve subjects, like young children, that have not previously experienced influenza virus infection may benefit from such a strategy.</p></sec></body><back><ref-list><ref id="B1"><label>1</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>de Jong</surname><given-names>JC</given-names></name><name><surname>Palache</surname><given-names>AM</given-names></name><name><surname>Beyer</surname><given-names>WE</given-names></name><name><surname>Rimmelzwaan</surname><given-names>GF</given-names></name><name><surname>Boon</surname><given-names>AC</given-names></name><name><surname>Osterhaus</surname><given-names>AD</given-names></name></person-group><article-title>Haemagglutination-inhibiting antibody to influenza virus</article-title><source><italic>Developments in Biologicals</italic></source><year>2003</year><volume>115</volume><fpage>63</fpage><lpage>73</lpage><pub-id pub-id-type="pmid">15088777</pub-id></element-citation></ref><ref id="B2"><label>2</label><element-citation publication-type="other"><comment>Food and Drug Administration guidance for industry, <ext-link ext-link-type="uri" xlink:href="http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Vaccines/ucm092272.pdf">http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Vaccines/ucm092272.pdf</ext-link></comment></element-citation></ref><ref id="B3"><label>3</label><element-citation publication-type="other"><collab>The European Agency for the Evaluation of Medical Products</collab><article-title>Note for guidance on harmonisation of requirements for influenza vaccines</article-title><year>1997</year></element-citation></ref><ref id="B4"><label>4</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Abelin</surname><given-names>A</given-names></name><name><surname>Colegate</surname><given-names>T</given-names></name><name><surname>Gardner</surname><given-names>S</given-names></name><name><surname>Hehme</surname><given-names>N</given-names></name><name><surname>Palache</surname><given-names>A</given-names></name></person-group><article-title>Lessons from pandemic influenza A(H1N1): the research-based vaccine industry’s perspective</article-title><source><italic>Vaccine</italic></source><year>2010</year><volume>29</volume><issue>6</issue><fpage>1135</fpage><lpage>1138</lpage><pub-id pub-id-type="pmid">21115061</pub-id></element-citation></ref><ref id="B5"><label>5</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Butler</surname><given-names>D</given-names></name></person-group><article-title>Portrait of a year-old pandemic</article-title><source><italic>Nature</italic></source><year>2010</year><volume>464</volume><issue>7292</issue><fpage>1112</fpage><lpage>1113</lpage><pub-id pub-id-type="pmid">20414281</pub-id></element-citation></ref><ref id="B6"><label>6</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Epstein</surname><given-names>SL</given-names></name><name><surname>Price</surname><given-names>GE</given-names></name></person-group><article-title>Cross-protective immunity to influenza A viruses</article-title><source><italic>Expert Review of Vaccines</italic></source><year>2010</year><volume>9</volume><issue>11</issue><fpage>1325</fpage><lpage>1341</lpage><pub-id pub-id-type="pmid">21087110</pub-id></element-citation></ref><ref id="B7"><label>7</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Stephenson</surname><given-names>I</given-names></name><name><surname>Hayden</surname><given-names>F</given-names></name><name><surname>Osterhaus</surname><given-names>A</given-names></name><etal></etal></person-group><article-title>Report of the fourth meeting on ’Influenza vaccines that induce broad spectrum and long-lasting immune responses’, World Health Organization and Wellcome Trust, London, United Kingdom, 9-10 november 2009</article-title><source><italic>Vaccine</italic></source><year>2010</year><volume>28</volume><issue>23</issue><fpage>3875</fpage><lpage>3882</lpage><pub-id pub-id-type="pmid">20398616</pub-id></element-citation></ref><ref id="B8"><label>8</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Grebe</surname><given-names>KM</given-names></name><name><surname>Yewdell</surname><given-names>JW</given-names></name><name><surname>Bennink</surname><given-names>JR</given-names></name></person-group><article-title>Heterosubtypic immunity to influenza A virus: where do we stand?</article-title><source><italic>Microbes and Infection</italic></source><year>2008</year><volume>10</volume><issue>9</issue><fpage>1024</fpage><lpage>1029</lpage><pub-id pub-id-type="pmid">18662798</pub-id></element-citation></ref><ref id="B9"><label>9</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Corti</surname><given-names>D</given-names></name><name><surname>Suguitan</surname><given-names>AL</given-names><suffix>Jr.</suffix></name><name><surname>Pinna</surname><given-names>D</given-names></name><etal></etal></person-group><article-title>Heterosubtypic neutralizing antibodies are produced by individuals immunized with a seasonal influenza vaccine</article-title><source><italic>Journal of Clinical Investigation</italic></source><year>2010</year><volume>120</volume><issue>5</issue><fpage>1663</fpage><lpage>1673</lpage><pub-id pub-id-type="pmid">20389023</pub-id></element-citation></ref><ref id="B10"><label>10</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ekiert</surname><given-names>DC</given-names></name><name><surname>Bhabha</surname><given-names>G</given-names></name><name><surname>Elsliger</surname><given-names>MA</given-names></name><etal></etal></person-group><article-title>Antibody recognition of a highly conserved influenza virus epitope</article-title><source><italic>Science</italic></source><year>2009</year><volume>324</volume><issue>5924</issue><fpage>246</fpage><lpage>251</lpage><pub-id pub-id-type="pmid">19251591</pub-id></element-citation></ref><ref id="B11"><label>11</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Steel</surname><given-names>J</given-names></name><name><surname>Lowen</surname><given-names>AC</given-names></name><name><surname>Wang</surname><given-names>TT</given-names></name><etal></etal></person-group><article-title>Influenza virus vaccine based on the conserved hemagglutinin stalk domain</article-title><source><italic>MBio</italic></source><year>2010</year><volume>1</volume><issue>1</issue></element-citation></ref><ref id="B12"><label>12</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wang</surname><given-names>TT</given-names></name><name><surname>Tan</surname><given-names>GS</given-names></name><name><surname>Hai</surname><given-names>R</given-names></name><etal></etal></person-group><article-title>Vaccination with a synthetic peptide from the influenza virus hemagglutinin provides protection against distinct viral subtypes</article-title><source><italic>Proceedings of the National Academy of Sciences of the United States of America</italic></source><year>2010</year><volume>107</volume><issue>44</issue><fpage>18979</fpage><lpage>18984</lpage><pub-id pub-id-type="pmid">20956293</pub-id></element-citation></ref><ref id="B13"><label>13</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wei</surname><given-names>CJ</given-names></name><name><surname>Boyington</surname><given-names>JC</given-names></name><name><surname>McTamney</surname><given-names>PM</given-names></name><etal></etal></person-group><article-title>Induction of broadly neutralizing H1N1 influenza antibodies by vaccination</article-title><source><italic>Science</italic></source><year>2010</year><volume>329</volume><issue>5995</issue><fpage>1060</fpage><lpage>1064</lpage><pub-id pub-id-type="pmid">20647428</pub-id></element-citation></ref><ref id="B14"><label>14</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Okuno</surname><given-names>Y</given-names></name><name><surname>Isegawa</surname><given-names>Y</given-names></name><name><surname>Sasao</surname><given-names>F</given-names></name><name><surname>Ueda</surname><given-names>S</given-names></name></person-group><article-title>A common neutralizing epitope conserved between the hemagglutinins of influenza A virus H1 and H2 strains</article-title><source><italic>Journal of Virology</italic></source><year>1993</year><volume>67</volume><issue>5</issue><fpage>2552</fpage><lpage>2558</lpage><pub-id pub-id-type="pmid">7682624</pub-id></element-citation></ref><ref id="B15"><label>15</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Smirnov</surname><given-names>YA</given-names></name><name><surname>Lipatov</surname><given-names>AS</given-names></name><name><surname>Gitelman</surname><given-names>AK</given-names></name><etal></etal></person-group><article-title>An epitope shared by the hemagglutinins of H1, H2, H5, and H6 subtypes of influenza A virus</article-title><source><italic>Acta Virologica</italic></source><year>1999</year><volume>43</volume><issue>4</issue><fpage>237</fpage><lpage>244</lpage><pub-id pub-id-type="pmid">10749369</pub-id></element-citation></ref><ref id="B16"><label>16</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Friesen</surname><given-names>RH</given-names></name><name><surname>Koudstaal</surname><given-names>W</given-names></name><name><surname>Koldijk</surname><given-names>MH</given-names></name><etal></etal></person-group><article-title>New class of monoclonal antibodies against severe influenza: prophylactic and therapeutic efficacy in ferrets</article-title><source><italic>PLoS ONE</italic></source><year>2010</year><volume>5</volume><issue>2</issue><comment>Article ID e9106.</comment></element-citation></ref><ref id="B17"><label>17</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Fan</surname><given-names>J</given-names></name><name><surname>Liang</surname><given-names>X</given-names></name><name><surname>Horton</surname><given-names>MS</given-names></name><etal></etal></person-group><article-title>Preclinical study of influenza virus A M2 peptide conjugate vaccines in mice, ferrets, and rhesus monkeys</article-title><source><italic>Vaccine</italic></source><year>2004</year><volume>22</volume><issue>23-24</issue><fpage>2993</fpage><lpage>3003</lpage><pub-id pub-id-type="pmid">15297047</pub-id></element-citation></ref><ref id="B18"><label>18</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Heinen</surname><given-names>PP</given-names></name><name><surname>Rijsewijks</surname><given-names>FA</given-names></name><name><surname>de Boer-Luitjtze</surname><given-names>EA</given-names></name><name><surname>Bianchi</surname><given-names>AT</given-names></name></person-group><article-title>Vaccination of pigs with a DNA construct expressing an influenza virus M2-nucleoprotein fusion protein exacerbates disease after challenge with influenza A virus</article-title><source><italic>Journal of General Virology</italic></source><year>2002</year><volume>83</volume><issue>8</issue><fpage>1851</fpage><lpage>1859</lpage><pub-id pub-id-type="pmid">12124449</pub-id></element-citation></ref><ref id="B19"><label>19</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Slepushkin</surname><given-names>VA</given-names></name><name><surname>Katz</surname><given-names>JM</given-names></name><name><surname>Black</surname><given-names>RA</given-names></name><name><surname>Gamble</surname><given-names>WC</given-names></name><name><surname>Rota</surname><given-names>PA</given-names></name><name><surname>Cox</surname><given-names>NJ</given-names></name></person-group><article-title>Protection of mice against influenza A virus challenge by vaccination with baculovirus-expressed M2 protein</article-title><source><italic>Vaccine</italic></source><year>1995</year><volume>13</volume><issue>15</issue><fpage>1399</fpage><lpage>1402</lpage><pub-id pub-id-type="pmid">8578816</pub-id></element-citation></ref><ref id="B20"><label>20</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Song</surname><given-names>JM</given-names></name><name><surname>Wang</surname><given-names>BZ</given-names></name><name><surname>Park</surname><given-names>KM</given-names></name><etal></etal></person-group><article-title>Influenza virus-like particles containing M2 induce broadly cross protective immunity</article-title><source><italic>PLoS ONE</italic></source><year>2011</year><volume>6</volume><issue>1</issue><comment>Article ID e14538.</comment></element-citation></ref><ref id="B21"><label>21</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Tompkins</surname><given-names>SM</given-names></name><name><surname>Zhao</surname><given-names>ZS</given-names></name><name><surname>Lo</surname><given-names>CY</given-names></name><etal></etal></person-group><article-title>Matrix protein 2 vaccination and protection against influenza viruses, including subtype H5N1</article-title><source><italic>Emerging Infectious Diseases</italic></source><year>2007</year><volume>13</volume><issue>3</issue><fpage>426</fpage><lpage>435</lpage><pub-id pub-id-type="pmid">17552096</pub-id></element-citation></ref><ref id="B22"><label>22</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hillaire</surname><given-names>MLB</given-names></name><name><surname>van Trierum</surname><given-names>SE</given-names></name><name><surname>Kreijtz</surname><given-names>JHCM</given-names></name><etal></etal></person-group><article-title>Cross-protective immunity against influenza pH<sub>1</sub>N<sub>1</sub> 2009 viruses induced by seasonal influenza A (H<sub>3</sub>N<sub>2</sub>) virus is mediated by virus-specific T-cells</article-title><source><italic>Journal of General Virology</italic></source><year>2011</year><volume>92</volume><issue>10</issue><fpage>2339</fpage><lpage>2349</lpage><pub-id pub-id-type="pmid">21653752</pub-id></element-citation></ref><ref id="B23"><label>23</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Jegerlehner</surname><given-names>A</given-names></name><name><surname>Schmitz</surname><given-names>N</given-names></name><name><surname>Storni</surname><given-names>T</given-names></name><name><surname>Bachmann</surname><given-names>MF</given-names></name></person-group><article-title>Influenza A vaccine based on the extracellular domain of M2: weak protection mediated via antibody-dependent NK cell activity</article-title><source><italic>Journal of Immunology</italic></source><year>2004</year><volume>172</volume><issue>9</issue><fpage>5598</fpage><lpage>5605</lpage></element-citation></ref><ref id="B24"><label>24</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Effros</surname><given-names>RB</given-names></name><name><surname>Doherty</surname><given-names>PC</given-names></name><name><surname>Gerhard</surname><given-names>W</given-names></name><name><surname>Bennink</surname><given-names>J</given-names></name></person-group><article-title>Generation of both cross reactive and virus specific T-cell populations after immunization with serologically distinct influenza A viruses</article-title><source><italic>Journal of Experimental Medicine</italic></source><year>1977</year><volume>145</volume><issue>3</issue><fpage>557</fpage><lpage>568</lpage><pub-id pub-id-type="pmid">233901</pub-id></element-citation></ref><ref id="B25"><label>25</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Yap</surname><given-names>KL</given-names></name><name><surname>Ada</surname><given-names>GL</given-names></name><name><surname>McKenzie</surname><given-names>IF</given-names></name></person-group><article-title>Transfer of specific cytotoxic T lymphocytes protects mice inoculated with influenza virus</article-title><source><italic>Nature</italic></source><year>1978</year><volume>273</volume><issue>5659</issue><fpage>238</fpage><lpage>239</lpage><pub-id pub-id-type="pmid">306072</pub-id></element-citation></ref><ref id="B26"><label>26</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Jung</surname><given-names>S</given-names></name><name><surname>Unutmaz</surname><given-names>D</given-names></name><name><surname>Wong</surname><given-names>P</given-names></name><etal></etal></person-group><article-title>In Vivo depletion of CD11c<sup>+</sup> dendritic cells abrogates priming of CD8<sup>+</sup> T cells by exogenous cell-associated antigens</article-title><source><italic>Immunity</italic></source><year>2002</year><volume>17</volume><issue>2</issue><fpage>211</fpage><lpage>220</lpage><pub-id pub-id-type="pmid">12196292</pub-id></element-citation></ref><ref id="B27"><label>27</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zammit</surname><given-names>DJ</given-names></name><name><surname>Cauley</surname><given-names>LS</given-names></name><name><surname>Pham</surname><given-names>QM</given-names></name><name><surname>Lefrançois</surname><given-names>L</given-names></name></person-group><article-title>Dendritic cells maximize the memory CD8 T cell response to infection</article-title><source><italic>Immunity</italic></source><year>2005</year><volume>22</volume><issue>5</issue><fpage>561</fpage><lpage>570</lpage><pub-id pub-id-type="pmid">15894274</pub-id></element-citation></ref><ref id="B34"><label>28</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zweerink</surname><given-names>HJ</given-names></name><name><surname>Courtneidge</surname><given-names>SA</given-names></name><name><surname>Skehel</surname><given-names>JJ</given-names></name><name><surname>Crumpton</surname><given-names>MJ</given-names></name><name><surname>Askonas</surname><given-names>BA</given-names></name></person-group><article-title>Cytotoxic T cells kill influenza virus infected cells but do not distinguish between serologically distinct type A viruses</article-title><source><italic>Nature</italic></source><year>1977</year><volume>267</volume><issue>5609</issue><fpage>354</fpage><lpage>356</lpage><pub-id pub-id-type="pmid">194164</pub-id></element-citation></ref><ref id="B32"><label>29</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Yewdell</surname><given-names>JW</given-names></name><name><surname>Bennink</surname><given-names>JR</given-names></name><name><surname>Smith</surname><given-names>GL</given-names></name><name><surname>Moss</surname><given-names>B</given-names></name></person-group><article-title>Influenza A virus nucleoprotein is a major target antigen for cross-reactive anti-influenza A virus cytotoxic T lymphocytes</article-title><source><italic>Proceedings of the National Academy of Sciences of the United States of America</italic></source><year>1985</year><volume>82</volume><issue>6</issue><fpage>1785</fpage><lpage>1789</lpage><pub-id pub-id-type="pmid">3872457</pub-id></element-citation></ref><ref id="B155"><label>30</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kees</surname><given-names>U</given-names></name><name><surname>Krammer</surname><given-names>PH</given-names></name></person-group><article-title>Most influenza A virus-specific memory cytotoxic T lymphocytes react with antigenic epitopes associated with internal virus determinants</article-title><source><italic>Journal of Experimental Medicine</italic></source><year>1984</year><volume>159</volume><issue>2</issue><fpage>365</fpage><lpage>377</lpage><pub-id pub-id-type="pmid">6198430</pub-id></element-citation></ref><ref id="B31"><label>31</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gotch</surname><given-names>F</given-names></name><name><surname>McMichael</surname><given-names>A</given-names></name><name><surname>Smith</surname><given-names>G</given-names></name><name><surname>Moss</surname><given-names>B</given-names></name></person-group><article-title>Identification of viral molecules recognized by influenza-specific human cytotoxic T lymphocytes</article-title><source><italic>Journal of Experimental Medicine</italic></source><year>1987</year><volume>165</volume><issue>2</issue><fpage>408</fpage><lpage>416</lpage><pub-id pub-id-type="pmid">3029268</pub-id></element-citation></ref><ref id="B35"><label>32</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lee</surname><given-names>LY</given-names></name><name><surname>Ha Do</surname><given-names>LA</given-names></name><name><surname>Simmons</surname><given-names>C</given-names></name><etal></etal></person-group><article-title>Memory T cells established by seasonal human influenza A infection cross-react with avian influenza A (H5N1) in healthy individuals</article-title><source><italic>Journal of Clinical Investigation</italic></source><year>2008</year><volume>118</volume><issue>10</issue><fpage>3478</fpage><lpage>3490</lpage><pub-id pub-id-type="pmid">18802496</pub-id></element-citation></ref><ref id="B36"><label>33</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kreijtz</surname><given-names>JH</given-names></name><name><surname>de Mutsert</surname><given-names>G</given-names></name><name><surname>van Baalen</surname><given-names>CA</given-names></name><name><surname>Fouchier</surname><given-names>RA</given-names></name><name><surname>Osterhaus</surname><given-names>AD</given-names></name><name><surname>Rimmelzwaan</surname><given-names>GF</given-names></name></person-group><article-title>Cross-recognition of avian H5N1 influenza virus by human cytotoxic T-lymphocyte populations directed to human influenza A virus</article-title><source><italic>Journal of Virology</italic></source><year>2008</year><volume>82</volume><issue>11</issue><fpage>5161</fpage><lpage>5166</lpage><pub-id pub-id-type="pmid">18353950</pub-id></element-citation></ref><ref id="B37"><label>34</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Jameson</surname><given-names>J</given-names></name><name><surname>Cruz</surname><given-names>J</given-names></name><name><surname>Terajima</surname><given-names>M</given-names></name><name><surname>Ennis</surname><given-names>FA</given-names></name></person-group><article-title>Human CD8<sup>+</sup> and CD4<sup>+</sup> T lymphocyte memory to influenza a viruses of swine and avian species</article-title><source><italic>Journal of Immunology</italic></source><year>1999</year><volume>162</volume><issue>12</issue><fpage>7578</fpage><lpage>7583</lpage></element-citation></ref><ref id="B40"><label>35</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gras</surname><given-names>S</given-names></name><name><surname>Kedzierski</surname><given-names>L</given-names></name><name><surname>Valkenburg</surname><given-names>SA</given-names></name><etal></etal></person-group><article-title>Cross-reactive CD8<sup>+</sup> T-cell immunity between the pandemic H1N1-2009 and H1N1-1918 influenza A viruses</article-title><source><italic>Proceedings of the National Academy of Sciences of the United States of America</italic></source><year>2010</year><volume>107</volume><issue>28</issue><fpage>12599</fpage><lpage>12604</lpage><pub-id pub-id-type="pmid">20616031</pub-id></element-citation></ref><ref id="B39"><label>36</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Tu</surname><given-names>W</given-names></name><name><surname>Mao</surname><given-names>H</given-names></name><name><surname>Zheng</surname><given-names>J</given-names></name><etal></etal></person-group><article-title>Cytotoxic T lymphocytes established by seasonal human influenza cross-react against 2009 pandemic H1N1 influenza virus</article-title><source><italic>Journal of Virology</italic></source><year>2010</year><volume>84</volume><issue>13</issue><fpage>6527</fpage><lpage>6535</lpage><pub-id pub-id-type="pmid">20410263</pub-id></element-citation></ref><ref id="B28"><label>37</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>McMichael</surname><given-names>AJ</given-names></name><name><surname>Gotch</surname><given-names>FM</given-names></name><name><surname>Noble</surname><given-names>GR</given-names></name><name><surname>Beare</surname><given-names>PA</given-names></name></person-group><article-title>Cytotoxic T-cell immunity to influenza</article-title><source><italic>New England Journal of Medicine</italic></source><year>1983</year><volume>309</volume><issue>1</issue><fpage>13</fpage><lpage>17</lpage><pub-id pub-id-type="pmid">6602294</pub-id></element-citation></ref><ref id="B29"><label>38</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>McMichael</surname><given-names>AJ</given-names></name><name><surname>Michie</surname><given-names>CA</given-names></name><name><surname>Gotch</surname><given-names>FM</given-names></name><name><surname>Smith</surname><given-names>GL</given-names></name><name><surname>Moss</surname><given-names>B</given-names></name></person-group><article-title>Recognition of influenza A virus nucleoprotein by human cytotoxic T lymphocytes</article-title><source><italic>Journal of General Virology</italic></source><year>1986</year><volume>67</volume><issue>4</issue><fpage>719</fpage><lpage>726</lpage><pub-id pub-id-type="pmid">3485697</pub-id></element-citation></ref><ref id="B30"><label>39</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Townsend</surname><given-names>ARM</given-names></name><name><surname>Skehel</surname><given-names>JJ</given-names></name></person-group><article-title>The influenza A virus nucleoprotein gene controls the induction of both subtype specific and cross-reactive cytotoxic T cells</article-title><source><italic>Journal of Experimental Medicine</italic></source><year>1984</year><volume>160</volume><issue>2</issue><fpage>552</fpage><lpage>563</lpage><pub-id pub-id-type="pmid">6206181</pub-id></element-citation></ref><ref id="B33"><label>40</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zweerink</surname><given-names>HJ</given-names></name><name><surname>Askonas</surname><given-names>BA</given-names></name><name><surname>Millican</surname><given-names>D</given-names></name></person-group><article-title>Cytotoxic T cells to type A influenza virus; viral hemagglutinin induces A-strain specificity while infected cells confer cross-reactive cytotoxicity</article-title><source><italic>European Journal of Immunology</italic></source><year>1977</year><volume>7</volume><issue>9</issue><fpage>630</fpage><lpage>635</lpage><pub-id pub-id-type="pmid">303568</pub-id></element-citation></ref><ref id="B38"><label>41</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Smallman-Raynor</surname><given-names>M</given-names></name><name><surname>Cliff</surname><given-names>AD</given-names></name></person-group><article-title>Avian influenza A (H5N1) age distribution in humans</article-title><source><italic>Emerging Infectious Diseases</italic></source><year>2007</year><volume>13</volume><issue>3</issue><fpage>510</fpage><lpage>512</lpage><pub-id pub-id-type="pmid">17552119</pub-id></element-citation></ref><ref id="B41"><label>42</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kreijtz</surname><given-names>JH</given-names></name><name><surname>Bodewes</surname><given-names>R</given-names></name><name><surname>van den Brand</surname><given-names>JM</given-names></name><etal></etal></person-group><article-title>Infection of mice with a human influenza A/H3N2 virus induces protective immunity against lethal infection with influenza A/H5N1 virus</article-title><source><italic>Vaccine</italic></source><year>2009</year><volume>27</volume><issue>36</issue><fpage>4983</fpage><lpage>4989</lpage><pub-id pub-id-type="pmid">19538996</pub-id></element-citation></ref><ref id="B42"><label>43</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kreijtz</surname><given-names>JH</given-names></name><name><surname>Bodewes</surname><given-names>R</given-names></name><name><surname>van Amerongen</surname><given-names>G</given-names></name><etal></etal></person-group><article-title>Primary influenza A virus infection induces cross-protective immunity against a lethal infection with a heterosubtypic virus strain in mice</article-title><source><italic>Vaccine</italic></source><year>2007</year><volume>25</volume><issue>4</issue><fpage>612</fpage><lpage>620</lpage><pub-id pub-id-type="pmid">17005299</pub-id></element-citation></ref><ref id="B43"><label>44</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Benton</surname><given-names>KA</given-names></name><name><surname>Misplon</surname><given-names>JA</given-names></name><name><surname>Lo</surname><given-names>CY</given-names></name><name><surname>Brutkiewicz</surname><given-names>RR</given-names></name><name><surname>Prasad</surname><given-names>SA</given-names></name><name><surname>Epstein</surname><given-names>SL</given-names></name></person-group><article-title>Heterosubtypic immunity to influenza a virus in mice lacking IgA, all Ig, NKT cells, or <italic>γδ</italic> T cells</article-title><source><italic>Journal of Immunology</italic></source><year>2001</year><volume>166</volume><issue>12</issue><fpage>7437</fpage><lpage>7445</lpage></element-citation></ref><ref id="B44"><label>45</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Nguyen</surname><given-names>HH</given-names></name><name><surname>Moldoveanu</surname><given-names>Z</given-names></name><name><surname>Novak</surname><given-names>MJ</given-names></name><etal></etal></person-group><article-title>Heterosubtypic immunity to lethal influenza A virus infection is associated with virus-specific CD8<sup>+</sup> cytotoxic T lymphocyte responses induced in mucosa-associated tissues</article-title><source><italic>Virology</italic></source><year>1999</year><volume>254</volume><issue>1</issue><fpage>50</fpage><lpage>60</lpage><pub-id pub-id-type="pmid">9927573</pub-id></element-citation></ref><ref id="B45"><label>46</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>O’Neill</surname><given-names>E</given-names></name><name><surname>Krauss</surname><given-names>SL</given-names></name><name><surname>Riberdy</surname><given-names>JM</given-names></name><name><surname>Webster</surname><given-names>RG</given-names></name><name><surname>Woodland</surname><given-names>DL</given-names></name></person-group><article-title>Heterologous protection against lethal A/HongKong/156/97 (H5N1) influenza virus infection in C57BL/6 mice</article-title><source><italic>Journal of General Virology</italic></source><year>2000</year><volume>81</volume><issue>11</issue><fpage>2689</fpage><lpage>2696</lpage><pub-id pub-id-type="pmid">11038381</pub-id></element-citation></ref><ref id="B46"><label>47</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Schulman</surname><given-names>JL</given-names></name><name><surname>Kilbourne</surname><given-names>ED</given-names></name></person-group><article-title>Induction of partial specific heterotypic immunity in mice by a single infection with influenza a virus</article-title><source><italic>Journal of Bacteriology</italic></source><year>1965</year><volume>89</volume><issue>1</issue><fpage>170</fpage><lpage>174</lpage><pub-id pub-id-type="pmid">14255658</pub-id></element-citation></ref><ref id="B50"><label>48</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Yap</surname><given-names>KL</given-names></name><name><surname>Ada</surname><given-names>GL</given-names></name></person-group><article-title>The recovery of mice from influenza A virus infection: adoptive transfer of immunity with influenza virus specific cytotoxic T lymphocytes recognizing a common virion antigen</article-title><source><italic>Scandinavian Journal of Immunology</italic></source><year>1978</year><volume>8</volume><issue>5</issue><fpage>413</fpage><lpage>420</lpage><pub-id pub-id-type="pmid">82995</pub-id></element-citation></ref><ref id="B47"><label>49</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wells</surname><given-names>MA</given-names></name><name><surname>Ennis</surname><given-names>FA</given-names></name><name><surname>Albrecht</surname><given-names>P</given-names></name></person-group><article-title>Recovery from a viral respiratory infection. II. Passive transfer of immune spleen cells to mice with influenza pneumonia</article-title><source><italic>Journal of Immunology</italic></source><year>1981</year><volume>126</volume><issue>3</issue><fpage>1042</fpage><lpage>1046</lpage></element-citation></ref><ref id="B49"><label>50</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Taylor</surname><given-names>PM</given-names></name><name><surname>Askonas</surname><given-names>BA</given-names></name></person-group><article-title>Influenza nucleoprotein-specific cytotoxic T-cell clones are protective In Vivo</article-title><source><italic>Immunology</italic></source><year>1986</year><volume>58</volume><issue>3</issue><fpage>417</fpage><lpage>420</lpage><pub-id pub-id-type="pmid">2426185</pub-id></element-citation></ref><ref id="B156"><label>51</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wraith</surname><given-names>DC</given-names></name><name><surname>Vessey</surname><given-names>AE</given-names></name><name><surname>Askonas</surname><given-names>BA</given-names></name></person-group><article-title>Purified influenza virus nucleoprotein protects mice from lethal infection</article-title><source><italic>Journal of General Virology</italic></source><year>1987</year><volume>68</volume><issue>2</issue><fpage>433</fpage><lpage>440</lpage><pub-id pub-id-type="pmid">3493324</pub-id></element-citation></ref><ref id="B48"><label>52</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lukacher</surname><given-names>AE</given-names></name><name><surname>Braciale</surname><given-names>VL</given-names></name><name><surname>Braciale</surname><given-names>TJ</given-names></name></person-group><article-title>In Vivo effector function of influenza virus-specific cytotoxic T lymphocyte clones is highly specific</article-title><source><italic>Journal of Experimental Medicine</italic></source><year>1984</year><volume>160</volume><issue>3</issue><fpage>814</fpage><lpage>826</lpage><pub-id pub-id-type="pmid">6206190</pub-id></element-citation></ref><ref id="B157"><label>53</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Askonas</surname><given-names>BA</given-names></name><name><surname>Taylor</surname><given-names>PM</given-names></name><name><surname>Esquivel</surname><given-names>F</given-names></name></person-group><article-title>Cytotoxic T cells in influenza infection</article-title><source><italic>Annals of the New York Academy of Sciences</italic></source><year>1988</year><volume>532</volume><fpage>230</fpage><lpage>237</lpage><pub-id pub-id-type="pmid">2845845</pub-id></element-citation></ref><ref id="B53"><label>54</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Liang</surname><given-names>S</given-names></name><name><surname>Mozdzanowska</surname><given-names>K</given-names></name><name><surname>Palladino</surname><given-names>G</given-names></name><name><surname>Gerhard</surname><given-names>W</given-names></name></person-group><article-title>Heterosubtypic immunity to influenza type A virus in mice: effector mechanisms and their longevity</article-title><source><italic>Journal of Immunology</italic></source><year>1994</year><volume>152</volume><issue>4</issue><fpage>1653</fpage><lpage>1661</lpage></element-citation></ref><ref id="B52"><label>55</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Guo</surname><given-names>H</given-names></name><name><surname>Santiago</surname><given-names>F</given-names></name><name><surname>Lambert</surname><given-names>K</given-names></name><name><surname>Takimoto</surname><given-names>T</given-names></name><name><surname>Topham</surname><given-names>DJ</given-names></name></person-group><article-title>T cell-mediated protection against lethal 2009 pandemic H1N1 influenza virus infection in a mouse model</article-title><source><italic>Journal of Virology</italic></source><year>2011</year><volume>85</volume><issue>1</issue><fpage>448</fpage><lpage>455</lpage><pub-id pub-id-type="pmid">20980523</pub-id></element-citation></ref><ref id="B51"><label>56</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Seo</surname><given-names>SH</given-names></name><name><surname>Webster</surname><given-names>RG</given-names></name></person-group><article-title>Cross-reactive, cell-mediated immunity and protection of chickens from lethal H5N1 influenza virus infection in Hong Kong poultry markets</article-title><source><italic>Journal of Virology</italic></source><year>2001</year><volume>75</volume><issue>6</issue><fpage>2516</fpage><lpage>2525</lpage><pub-id pub-id-type="pmid">11222674</pub-id></element-citation></ref><ref id="B55"><label>57</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Seo</surname><given-names>SH</given-names></name><name><surname>Peiris</surname><given-names>M</given-names></name><name><surname>Webster</surname><given-names>RG</given-names></name></person-group><article-title>Protective cross-reactive cellular immunity to lethal A/Goose/Guangdong/1/96-like H5N1 influenza virus is correlated with the proportion of pulmonary CD8<sup>+</sup> T cells expressing <italic>γ</italic> interferon</article-title><source><italic>Journal of Virology</italic></source><year>2002</year><volume>76</volume><issue>10</issue><fpage>4886</fpage><lpage>4890</lpage><pub-id pub-id-type="pmid">11967305</pub-id></element-citation></ref><ref id="B158"><label>58</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bodewes</surname><given-names>R</given-names></name><name><surname>Kreijtz</surname><given-names>JH</given-names></name><name><surname>Geelhoed-Mieras</surname><given-names>MM</given-names></name><etal></etal></person-group><article-title>Vaccination against seasonal influenza A/H3N2 virus reduces the induction of heterosubtypic immunity against influenza A/H5N1 virus infection in ferrets</article-title><source><italic>Journal of Virology</italic></source><year>2011</year><volume>85</volume><issue>6</issue><fpage>2695</fpage><lpage>2702</lpage><pub-id pub-id-type="pmid">21228239</pub-id></element-citation></ref><ref id="B54"><label>59</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Skountzou</surname><given-names>I</given-names></name><name><surname>Koutsonanos</surname><given-names>DG</given-names></name><name><surname>Kim</surname><given-names>JH</given-names></name><etal></etal></person-group><article-title>Immunity to pre-1950 H1N1 influenza viruses confers cross-protection against the pandemic swine-origin 2009 a (H1N1) influenza virus</article-title><source><italic>Journal of Immunology</italic></source><year>2010</year><volume>185</volume><issue>3</issue><fpage>1642</fpage><lpage>1649</lpage></element-citation></ref><ref id="B56"><label>60</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Epstein</surname><given-names>SL</given-names></name></person-group><article-title>Prior H1N1 influenza infection and susceptibility of cleveland family study participants during the H2N2 pandemic of 1957: an experiment of nature</article-title><source><italic>Journal of Infectious Diseases</italic></source><year>2006</year><volume>193</volume><issue>1</issue><fpage>49</fpage><lpage>53</lpage><pub-id pub-id-type="pmid">16323131</pub-id></element-citation></ref><ref id="B57"><label>61</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Berkhoff</surname><given-names>EG</given-names></name><name><surname>Geelhoed-Mieras</surname><given-names>MM</given-names></name><name><surname>Fouchier</surname><given-names>RA</given-names></name><name><surname>Osterhaus</surname><given-names>AD</given-names></name><name><surname>Rimmelzwaan</surname><given-names>GF</given-names></name></person-group><article-title>Assessment of the extent of variation in influenza A virus cytotoxic T-lymphocyte epitopes by using virus-specific CD8<sup>+</sup> T-cell clones</article-title><source><italic>Journal of General Virology</italic></source><year>2007</year><volume>88</volume><issue>2</issue><fpage>530</fpage><lpage>535</lpage><pub-id pub-id-type="pmid">17251571</pub-id></element-citation></ref><ref id="B58"><label>62</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Voeten</surname><given-names>JT</given-names></name><name><surname>Bestebroer</surname><given-names>TM</given-names></name><name><surname>Nieuwkoop</surname><given-names>NJ</given-names></name><name><surname>Fouchier</surname><given-names>RA</given-names></name><name><surname>Osterhaus</surname><given-names>AD</given-names></name><name><surname>Rimmelzwaan</surname><given-names>GF</given-names></name></person-group><article-title>Antigenic drift in the influenza a virus (H3N2) Nucleoprotein and escape from recognition by cytotoxic T lymphocytes</article-title><source><italic>Journal of Virology</italic></source><year>2000</year><volume>74</volume><issue>15</issue><fpage>6800</fpage><lpage>6807</lpage><pub-id pub-id-type="pmid">10888619</pub-id></element-citation></ref><ref id="B59"><label>63</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Boon</surname><given-names>ACM</given-names></name><name><surname>de Mutsert</surname><given-names>G</given-names></name><name><surname>Graus</surname><given-names>YM</given-names></name><etal></etal></person-group><article-title>Sequence variation in a newly identified HLA-B35-restricted epitope in the influenza A virus nucleoprotein associated with escape from cytotoxic T lymphocytes</article-title><source><italic>Journal of Virology</italic></source><year>2002</year><volume>76</volume><issue>5</issue><fpage>2567</fpage><lpage>2572</lpage><pub-id pub-id-type="pmid">11836437</pub-id></element-citation></ref><ref id="B60"><label>64</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Rimmelzwaan</surname><given-names>GF</given-names></name><name><surname>Boon</surname><given-names>AC</given-names></name><name><surname>Voeten</surname><given-names>JT</given-names></name><name><surname>Berkhoff</surname><given-names>EG</given-names></name><name><surname>Fouchier</surname><given-names>RA</given-names></name><name><surname>Osterhaus</surname><given-names>AD</given-names></name></person-group><article-title>Sequence variation in the influenza A virus nucleoprotein associated with escape from cytotoxic T lymphocytes</article-title><source><italic>Virus Research</italic></source><year>2004</year><volume>103</volume><issue>1-2</issue><fpage>97</fpage><lpage>100</lpage><pub-id pub-id-type="pmid">15163496</pub-id></element-citation></ref><ref id="B61"><label>65</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Boon</surname><given-names>AC</given-names></name><name><surname>de Mutsert</surname><given-names>G</given-names></name><name><surname>Van Baarle</surname><given-names>D</given-names></name><etal></etal></person-group><article-title>Recognition of Homo- and Heterosubtypic Variants of Influenza A Viruses by Human CD8<sup>+</sup> T Lymphocytes</article-title><source><italic>Journal of Immunology</italic></source><year>2004</year><volume>172</volume><issue>4</issue><fpage>2453</fpage><lpage>2460</lpage></element-citation></ref><ref id="B62"><label>66</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Berkhoff</surname><given-names>EG</given-names></name><name><surname>Boon</surname><given-names>AC</given-names></name><name><surname>Nieuwkoop</surname><given-names>NJ</given-names></name><etal></etal></person-group><article-title>A mutation in the HLA-B<sup><italic>∗</italic></sup>-restricted NP<sub>383-391</sub> epitope affects the human influenza A virus-specific cytotoxic T-lymphocyte response in vitro</article-title><source><italic>Journal of Virology</italic></source><year>2004</year><volume>78</volume><issue>10</issue><fpage>5216</fpage><lpage>5222</lpage><pub-id pub-id-type="pmid">15113903</pub-id></element-citation></ref><ref id="B63"><label>67</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Berkhoff</surname><given-names>EG</given-names></name><name><surname>Geelhoed-Mieras</surname><given-names>MM</given-names></name><name><surname>Verschuren</surname><given-names>EJ</given-names></name><etal></etal></person-group><article-title>The loss of immunodominant epitopes affects interferon-<italic>γ</italic> production and lytic activity of the human influenza virus-specific cytotoxic T lymphocyte response in vitro</article-title><source><italic>Clinical and Experimental Immunology</italic></source><year>2007</year><volume>148</volume><issue>2</issue><fpage>296</fpage><lpage>306</lpage><pub-id pub-id-type="pmid">17326762</pub-id></element-citation></ref><ref id="B64"><label>68</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Rimmelzwaan</surname><given-names>GF</given-names></name><name><surname>Berkhoff</surname><given-names>EG</given-names></name><name><surname>Nieuwkoop</surname><given-names>NJ</given-names></name><name><surname>Fouchier</surname><given-names>RA</given-names></name><name><surname>Osterhaus</surname><given-names>AD</given-names></name></person-group><article-title>Functional compensation of a detrimental amino acid substitution in a cytotoxic-T-lymphocyte epitope of influenza A viruses by comutations</article-title><source><italic>Journal of Virology</italic></source><year>2004</year><volume>78</volume><issue>16</issue><fpage>8946</fpage><lpage>8949</lpage><pub-id pub-id-type="pmid">15280506</pub-id></element-citation></ref><ref id="B65"><label>69</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Rimmelzwaan</surname><given-names>GF</given-names></name><name><surname>Berkhoff</surname><given-names>EG</given-names></name><name><surname>Nieuwkoop</surname><given-names>NJ</given-names></name><name><surname>Smith</surname><given-names>DJ</given-names></name><name><surname>Fouchier</surname><given-names>RA</given-names></name><name><surname>Osterhaus</surname><given-names>AD</given-names></name></person-group><article-title>Full restoration of viral fitness by multiple compensatory co-mutations in the nucleoprotein of influenza A virus cytotoxic T-lymphocyte escape mutants</article-title><source><italic>Journal of General Virology</italic></source><year>2005</year><volume>86</volume><issue>6</issue><fpage>1801</fpage><lpage>1805</lpage><pub-id pub-id-type="pmid">15914859</pub-id></element-citation></ref><ref id="B66"><label>70</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gog</surname><given-names>JR</given-names></name><name><surname>Rimmelzwaan</surname><given-names>GF</given-names></name><name><surname>Osterhaus</surname><given-names>AD</given-names></name><name><surname>Grenfell</surname><given-names>BT</given-names></name></person-group><article-title>Population dynamics of rapid fixation in cytotoxic T lymphocyte escape mutants of influenza A</article-title><source><italic>Proceedings of the National Academy of Sciences of the United States of America</italic></source><year>2003</year><volume>100</volume><issue>19</issue><fpage>11143</fpage><lpage>11147</lpage><pub-id pub-id-type="pmid">12954978</pub-id></element-citation></ref><ref id="B67"><label>71</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Berkhoff</surname><given-names>EG</given-names></name><name><surname>de Wit</surname><given-names>E</given-names></name><name><surname>Geelhoed-Mieras</surname><given-names>MM</given-names></name><etal></etal></person-group><article-title>Functional constraints of influenza A virus epitopes limit escape from cytotoxic T lymphocytes</article-title><source><italic>Journal of Virology</italic></source><year>2005</year><volume>79</volume><issue>17</issue><fpage>11239</fpage><lpage>11246</lpage><pub-id pub-id-type="pmid">16103176</pub-id></element-citation></ref><ref id="B68"><label>72</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Berkhoff</surname><given-names>EG</given-names></name><name><surname>de Wit</surname><given-names>E</given-names></name><name><surname>Geelhoed-Mieras</surname><given-names>MM</given-names></name><etal></etal></person-group><article-title>Fitness costs limit escape from cytotoxic T lymphocytes by influenza A viruses</article-title><source><italic>Vaccine</italic></source><year>2006</year><volume>24</volume><issue>44–46</issue><fpage>6594</fpage><lpage>6596</lpage><pub-id pub-id-type="pmid">16837112</pub-id></element-citation></ref><ref id="B69"><label>73</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Yewdell</surname><given-names>JW</given-names></name><name><surname>Bennink</surname><given-names>JR</given-names></name></person-group><article-title>Immunodominance in major histocompatibility complex class I-restricted T lymphocyte responses</article-title><source><italic>Annual Review of Immunology</italic></source><year>1999</year><volume>17</volume><fpage>51</fpage><lpage>88</lpage></element-citation></ref><ref id="B70"><label>74</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Yewdell</surname><given-names>JW</given-names></name><name><surname>Del Val</surname><given-names>M</given-names></name></person-group><article-title>Immunodominance in TCD8<sup>+</sup> responses to viruses: cell biology, cellular immunology, and mathematical models</article-title><source><italic>Immunity</italic></source><year>2004</year><volume>21</volume><issue>2</issue><fpage>149</fpage><lpage>153</lpage><pub-id pub-id-type="pmid">15308096</pub-id></element-citation></ref><ref id="B71"><label>75</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Yewdell</surname><given-names>JW</given-names></name></person-group><article-title>Confronting complexity: real-world immunodominance in antiviral CD8<sup>+</sup> T cell responses</article-title><source><italic>Immunity</italic></source><year>2006</year><volume>25</volume><issue>4</issue><fpage>533</fpage><lpage>543</lpage><pub-id pub-id-type="pmid">17046682</pub-id></element-citation></ref><ref id="B72"><label>76</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Chen</surname><given-names>W</given-names></name><name><surname>Pang</surname><given-names>K</given-names></name><name><surname>Masterman</surname><given-names>KA</given-names></name><etal></etal></person-group><article-title>Reversal in the immunodominance hierarchy in secondary CD8<sup>+</sup> T cell responses to influenza A virus: roles for cross-presentation and lysis-independent immunodomination</article-title><source><italic>Journal of Immunology</italic></source><year>2004</year><volume>173</volume><issue>8</issue><fpage>5021</fpage><lpage>5027</lpage></element-citation></ref><ref id="B73"><label>77</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Boon</surname><given-names>AC</given-names></name><name><surname>de Mutsert</surname><given-names>G</given-names></name><name><surname>Graus</surname><given-names>YM</given-names></name><etal></etal></person-group><article-title>The magnitude and specificity of influenza A virus-specific cytotoxic T-lymphocyte responses in humans is related to HLA-A and -B phenotype</article-title><source><italic>Journal of Virology</italic></source><year>2002</year><volume>76</volume><issue>2</issue><fpage>582</fpage><lpage>590</lpage><pub-id pub-id-type="pmid">11752149</pub-id></element-citation></ref><ref id="B74"><label>78</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Belz</surname><given-names>GT</given-names></name><name><surname>Xie</surname><given-names>W</given-names></name><name><surname>Altman</surname><given-names>JD</given-names></name><name><surname>Doherty</surname><given-names>PC</given-names></name></person-group><article-title>A previously unrecognized H-2Db-restricted peptide prominent in the primary influenza a virus-specific CD8<sup>+</sup> T-cell response is much less apparent following secondary challenge</article-title><source><italic>Journal of Virology</italic></source><year>2000</year><volume>74</volume><issue>8</issue><fpage>3486</fpage><lpage>3493</lpage><pub-id pub-id-type="pmid">10729122</pub-id></element-citation></ref><ref id="B75"><label>79</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Belz</surname><given-names>GT</given-names></name><name><surname>Stevenson</surname><given-names>PG</given-names></name><name><surname>Doherty</surname><given-names>PC</given-names></name></person-group><article-title>Contemporary analysis of MHC-related immunodominance hierarchies in the CD8<sup>+</sup> T cell response to influenza A viruses</article-title><source><italic>Journal of Immunology</italic></source><year>2000</year><volume>165</volume><issue>5</issue><fpage>2404</fpage><lpage>2409</lpage></element-citation></ref><ref id="B76"><label>80</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Boon</surname><given-names>AC</given-names></name><name><surname>de Mutsert</surname><given-names>G</given-names></name><name><surname>Fouchier</surname><given-names>RA</given-names></name><name><surname>Sintnicolaas</surname><given-names>K</given-names></name><name><surname>Osterhaus</surname><given-names>AD</given-names></name><name><surname>Rimmelzwaan</surname><given-names>GF</given-names></name></person-group><article-title>Preferential HLA usage in the influenza virus-specific CTL response</article-title><source><italic>Journal of Immunology</italic></source><year>2004</year><volume>172</volume><issue>7</issue><fpage>4435</fpage><lpage>4443</lpage></element-citation></ref><ref id="B77"><label>81</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Tussey</surname><given-names>LG</given-names></name><name><surname>Rowland-Jones</surname><given-names>S</given-names></name><name><surname>Zheng</surname><given-names>TS</given-names></name><etal></etal></person-group><article-title>Different MHC class I alleles compete for presentation of overlapping viral epitopes</article-title><source><italic>Immunity</italic></source><year>1995</year><volume>3</volume><issue>1</issue><fpage>65</fpage><lpage>77</lpage><pub-id pub-id-type="pmid">7542549</pub-id></element-citation></ref><ref id="B78"><label>82</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Cho</surname><given-names>Y</given-names></name><name><surname>Basta</surname><given-names>S</given-names></name><name><surname>Chen</surname><given-names>W</given-names></name><name><surname>Bennink</surname><given-names>JR</given-names></name><name><surname>Yewdell</surname><given-names>JW</given-names></name></person-group><article-title>Heat-aggregated noninfectious influenza virus induces a more balanced CD8<sup>+</sup>-T-lymphocyte immunodominance hierarchy than infectious virus</article-title><source><italic>Journal of Virology</italic></source><year>2003</year><volume>77</volume><issue>8</issue><fpage>4679</fpage><lpage>4684</lpage><pub-id pub-id-type="pmid">12663774</pub-id></element-citation></ref><ref id="B79"><label>83</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Cui</surname><given-names>W</given-names></name><name><surname>Kaech</surname><given-names>SM</given-names></name></person-group><article-title>Generation of effector CD8<sup>+</sup> T cells and their conversion to memory T cells</article-title><source><italic>Immunological Reviews</italic></source><year>2010</year><volume>236</volume><issue>1</issue><fpage>151</fpage><lpage>166</lpage><pub-id pub-id-type="pmid">20636815</pub-id></element-citation></ref><ref id="B80"><label>84</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Schanen</surname><given-names>BC</given-names></name><name><surname>de Groot</surname><given-names>AS</given-names></name><name><surname>Moise</surname><given-names>L</given-names></name><etal></etal></person-group><article-title>Coupling sensitive in vitro and in silico techniques to assess cross-reactive CD4<sup>+</sup> T cells against the swine-origin H1N1 influenza virus</article-title><source><italic>Vaccine</italic></source><year>2011</year><volume>29</volume><issue>17</issue><fpage>3299</fpage><lpage>3309</lpage><pub-id pub-id-type="pmid">21349362</pub-id></element-citation></ref><ref id="B81"><label>85</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Roti</surname><given-names>M</given-names></name><name><surname>Yang</surname><given-names>J</given-names></name><name><surname>Berger</surname><given-names>D</given-names></name><name><surname>Huston</surname><given-names>L</given-names></name><name><surname>James</surname><given-names>EA</given-names></name><name><surname>Kwok</surname><given-names>WW</given-names></name></person-group><article-title>Healthy human subjects have CD4<sup>+</sup> T cells directed against H5N1 influenza virus</article-title><source><italic>Journal of Immunology</italic></source><year>2008</year><volume>180</volume><issue>3</issue><fpage>1758</fpage><lpage>1768</lpage></element-citation></ref><ref id="B82"><label>86</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Carragher</surname><given-names>DM</given-names></name><name><surname>Kaminski</surname><given-names>DA</given-names></name><name><surname>Moquin</surname><given-names>A</given-names></name><name><surname>Hartson</surname><given-names>L</given-names></name><name><surname>Randall</surname><given-names>TD</given-names></name></person-group><article-title>A novel role for non-neutralizing antibodies against nucleoprotein in facilitating resistance to influenza virus</article-title><source><italic>Journal of Immunology</italic></source><year>2008</year><volume>181</volume><issue>6</issue><fpage>4168</fpage><lpage>4176</lpage></element-citation></ref><ref id="B83"><label>87</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Nguyen</surname><given-names>HH</given-names></name><name><surname>van Ginkel</surname><given-names>FW</given-names></name><name><surname>Vu</surname><given-names>HL</given-names></name><name><surname>McGhee</surname><given-names>JR</given-names></name><name><surname>Mestecky</surname><given-names>J</given-names></name></person-group><article-title>Heterosubtypic immunity to influenza A virus infection requires B cells but not CD8<sup>+</sup> cytotoxic T lymphocytes</article-title><source><italic>Journal of Infectious Diseases</italic></source><year>2001</year><volume>183</volume><issue>3</issue><fpage>368</fpage><lpage>376</lpage><pub-id pub-id-type="pmid">11133367</pub-id></element-citation></ref><ref id="B84"><label>88</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Epstein</surname><given-names>SL</given-names></name><name><surname>Lo</surname><given-names>CY</given-names></name><name><surname>Misplon</surname><given-names>JA</given-names></name><etal></etal></person-group><article-title>Mechanisms of heterosubtypic immunity to lethal influenza A virus infection in fully immunocompetent, T cell-depleted, <italic>β</italic>2-microglobulin-deficient, and J chain-deficient mice</article-title><source><italic>Journal of Immunology</italic></source><year>1997</year><volume>158</volume><issue>3</issue><fpage>1222</fpage><lpage>1230</lpage></element-citation></ref><ref id="B85"><label>89</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Throsby</surname><given-names>M</given-names></name><name><surname>van den Brink</surname><given-names>E</given-names></name><name><surname>Jongeneelen</surname><given-names>M</given-names></name><etal></etal></person-group><article-title>Heterosubtypic neutralizing monoclonal antibodies cross-protective against H5N1 and H1N1 recovered from human IgM<sup>+</sup> memory B cells</article-title><source><italic>PLoS ONE</italic></source><year>2008</year><volume>3</volume><issue>12</issue><comment>Article ID e3942.</comment></element-citation></ref><ref id="B86"><label>90</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Rangel-Moreno</surname><given-names>J</given-names></name><name><surname>Carragher</surname><given-names>DM</given-names></name><name><surname>Misra</surname><given-names>RS</given-names></name><etal></etal></person-group><article-title>B cells promote resistance to heterosubtypic strains of influenza via multiple mechanisms</article-title><source><italic>Journal of Immunology</italic></source><year>2008</year><volume>180</volume><issue>1</issue><fpage>454</fpage><lpage>463</lpage></element-citation></ref><ref id="B87"><label>91</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gorse</surname><given-names>GJ</given-names></name><name><surname>Belshe</surname><given-names>RB</given-names></name></person-group><article-title>Enhancement of anti-influenza A virus cytotoxicity following influenza A virus vaccination in older, chronically ill adults</article-title><source><italic>Journal of Clinical Microbiology</italic></source><year>1990</year><volume>28</volume><issue>11</issue><fpage>2539</fpage><lpage>2550</lpage><pub-id pub-id-type="pmid">2123886</pub-id></element-citation></ref><ref id="B88"><label>92</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gorse</surname><given-names>GJ</given-names></name><name><surname>Belshe</surname><given-names>RB</given-names></name></person-group><article-title>Enhanced lymphoproliferation to influenza A virus following vaccination of older, chronically ill adults with live-attenuated viruses</article-title><source><italic>Scandinavian Journal of Infectious Diseases</italic></source><year>1991</year><volume>23</volume><issue>1</issue><fpage>7</fpage><lpage>17</lpage><pub-id pub-id-type="pmid">2028230</pub-id></element-citation></ref><ref id="B89"><label>93</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gorse</surname><given-names>GJ</given-names></name><name><surname>Campbell</surname><given-names>MJ</given-names></name><name><surname>Otto</surname><given-names>EE</given-names></name><name><surname>Powers</surname><given-names>DC</given-names></name><name><surname>Chambers</surname><given-names>GW</given-names></name><name><surname>Newman</surname><given-names>FK</given-names></name></person-group><article-title>Increased anti-influenza A virus cytotoxic T cell activity following vaccination of the chronically ill elderly with live attenuated or inactivated influenza virus vaccine</article-title><source><italic>Journal of Infectious Diseases</italic></source><year>1995</year><volume>172</volume><issue>1</issue><fpage>1</fpage><lpage>10</lpage><pub-id pub-id-type="pmid">7797897</pub-id></element-citation></ref><ref id="B90"><label>94</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Basha</surname><given-names>S</given-names></name><name><surname>Hazenfeld</surname><given-names>S</given-names></name><name><surname>Brady</surname><given-names>RC</given-names></name><name><surname>Subbramanian</surname><given-names>RA</given-names></name></person-group><article-title>Comparison of antibody and T-cell responses elicited by licensed inactivated- and live-attenuated influenza vaccines against H3N2 hemagglutinin</article-title><source><italic>Human Immunology</italic></source><year>2011</year><volume>72</volume><issue>6</issue><fpage>463</fpage><lpage>469</lpage><pub-id pub-id-type="pmid">21414368</pub-id></element-citation></ref><ref id="B91"><label>95</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>He</surname><given-names>XS</given-names></name><name><surname>Holmes</surname><given-names>TH</given-names></name><name><surname>Zhang</surname><given-names>C</given-names></name><etal></etal></person-group><article-title>Cellular immune responses in children and adults receiving inactivated or live attenuated influenza vaccines</article-title><source><italic>Journal of Virology</italic></source><year>2006</year><volume>80</volume><issue>23</issue><fpage>11756</fpage><lpage>11766</lpage><pub-id pub-id-type="pmid">16971435</pub-id></element-citation></ref><ref id="B92"><label>96</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Powell</surname><given-names>TJ</given-names></name><name><surname>Strutt</surname><given-names>T</given-names></name><name><surname>Reome</surname><given-names>J</given-names></name><etal></etal></person-group><article-title>Priming with cold-adapted influenza A does not prevent infection but elicits long-lived protection against supralethal challenge with heterosubtypic virus</article-title><source><italic>Journal of Immunology</italic></source><year>2007</year><volume>178</volume><issue>2</issue><fpage>1030</fpage><lpage>1038</lpage></element-citation></ref><ref id="B93"><label>97</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Chen</surname><given-names>GL</given-names></name><name><surname>Lau</surname><given-names>YF</given-names></name><name><surname>Lamirande</surname><given-names>EW</given-names></name><name><surname>McCall</surname><given-names>AW</given-names></name><name><surname>Subbarao</surname><given-names>K</given-names></name></person-group><article-title>Seasonal influenza infection and live vaccine prime for a response to the 2009 pandemic H1N1 vaccine</article-title><source><italic>Proceedings of the National Academy of Sciences of the United States of America</italic></source><year>2011</year><volume>108</volume><issue>3</issue><fpage>1140</fpage><lpage>1145</lpage><pub-id pub-id-type="pmid">21199945</pub-id></element-citation></ref><ref id="B94"><label>98</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sun</surname><given-names>K</given-names></name><name><surname>Ye</surname><given-names>J</given-names></name><name><surname>Perez</surname><given-names>DR</given-names></name><name><surname>Metzger</surname><given-names>DW</given-names></name></person-group><article-title>Seasonal FluMist vaccination induces cross-reactive T cell immunity against H1N1 (2009) influenza and secondary bacterial infections</article-title><source><italic>Journal of Immunology</italic></source><year>2011</year><volume>186</volume><issue>2</issue><fpage>987</fpage><lpage>993</lpage></element-citation></ref><ref id="B95"><label>99</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lu</surname><given-names>X</given-names></name><name><surname>Edwards</surname><given-names>LE</given-names></name><name><surname>Desheva</surname><given-names>JA</given-names></name><etal></etal></person-group><article-title>Cross-protective immunity in mice induced by live-attenuated or inactivated vaccines against highly pathogenic influenza A (H5N1) viruses</article-title><source><italic>Vaccine</italic></source><year>2006</year><volume>24</volume><issue>44–46</issue><fpage>6588</fpage><lpage>6593</lpage><pub-id pub-id-type="pmid">17030078</pub-id></element-citation></ref><ref id="B96"><label>100</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>García-Sastre</surname><given-names>A</given-names></name><name><surname>Egorov</surname><given-names>A</given-names></name><name><surname>Matassov</surname><given-names>D</given-names></name><etal></etal></person-group><article-title>Influenza A virus lacking the NS1 gene replicates in interferon-deficient systems</article-title><source><italic>Virology</italic></source><year>1998</year><volume>252</volume><issue>2</issue><fpage>324</fpage><lpage>330</lpage><pub-id pub-id-type="pmid">9878611</pub-id></element-citation></ref><ref id="B97"><label>101</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wang</surname><given-names>X</given-names></name><name><surname>Li</surname><given-names>M</given-names></name><name><surname>Zheng</surname><given-names>H</given-names></name><etal></etal></person-group><article-title>Influenza A virus NS1 protein prevents activation of NF-<italic>κ</italic>B and induction of <italic>α</italic>/<italic>β</italic> interferon</article-title><source><italic>Journal of Virology</italic></source><year>2000</year><volume>74</volume><issue>24</issue><fpage>11566</fpage><lpage>11573</lpage><pub-id pub-id-type="pmid">11090154</pub-id></element-citation></ref><ref id="B98"><label>102</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Donelan</surname><given-names>NR</given-names></name><name><surname>Basler</surname><given-names>CF</given-names></name><name><surname>García-Sastre</surname><given-names>A</given-names></name></person-group><article-title>A recombinant influenza A virus expressing an RNA-binding-defective NS1 protein induces high levels of <italic>β</italic> interferon and is attenuated in mice</article-title><source><italic>Journal of Virology</italic></source><year>2003</year><volume>77</volume><issue>24</issue><fpage>13257</fpage><lpage>13266</lpage><pub-id pub-id-type="pmid">14645582</pub-id></element-citation></ref><ref id="B99"><label>103</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Mueller</surname><given-names>SN</given-names></name><name><surname>Langley</surname><given-names>WA</given-names></name><name><surname>Carnero</surname><given-names>E</given-names></name><name><surname>García-Sastre</surname><given-names>A</given-names></name><name><surname>Ahmed</surname><given-names>R</given-names></name></person-group><article-title>Immunization with live attenuated influenza viruses that express altered NS1 proteins results in potent and protective memory CD8<sup>+</sup> T-cell responses</article-title><source><italic>Journal of Virology</italic></source><year>2010</year><volume>84</volume><issue>4</issue><fpage>1847</fpage><lpage>1855</lpage><pub-id pub-id-type="pmid">19939929</pub-id></element-citation></ref><ref id="B100"><label>104</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Xie</surname><given-names>H</given-names></name><name><surname>Liu</surname><given-names>TM</given-names></name><name><surname>Lu</surname><given-names>X</given-names></name><etal></etal></person-group><article-title>A live attenuated H1N1 M1 mutant provides broad cross-protection against influenza A viruses, including highly pathogenic A/Vietnam/1203/2004, in Mice</article-title><source><italic>Journal of Infectious Diseases</italic></source><year>2009</year><volume>200</volume><issue>12</issue><fpage>1874</fpage><lpage>1883</lpage><pub-id pub-id-type="pmid">19909080</pub-id></element-citation></ref><ref id="B101"><label>105</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ulmer</surname><given-names>JB</given-names></name></person-group><article-title>Influenza DNA vaccines</article-title><source><italic>Vaccine</italic></source><year>2002</year><volume>20</volume><issue>supplement 2</issue><fpage>S74</fpage><lpage>S76</lpage><pub-id pub-id-type="pmid">12110264</pub-id></element-citation></ref><ref id="B102"><label>106</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Moss</surname><given-names>RB</given-names></name></person-group><article-title>Prospects for control of emerging infectious diseases with plasmid DNA vaccines</article-title><source><italic>Journal of Immune Based Therapies and Vaccines</italic></source><year>2009</year><volume>7</volume><fpage>p. 3</fpage></element-citation></ref><ref id="B103"><label>107</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Laddy</surname><given-names>DJ</given-names></name><name><surname>Weiner</surname><given-names>DB</given-names></name></person-group><article-title>From plasmids to protection: a review of DNA vaccines against infectious diseases</article-title><source><italic>International Reviews of Immunology</italic></source><year>2006</year><volume>25</volume><issue>3-4</issue><fpage>99</fpage><lpage>123</lpage><pub-id pub-id-type="pmid">16818367</pub-id></element-citation></ref><ref id="B104"><label>108</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ulmer</surname><given-names>JB</given-names></name><name><surname>Donnelly</surname><given-names>JJ</given-names></name><name><surname>Parker</surname><given-names>SE</given-names></name><etal></etal></person-group><article-title>Heterologous protection against influenza by injection of DNA encoding a viral protein</article-title><source><italic>Science</italic></source><year>1993</year><volume>259</volume><issue>5102</issue><fpage>1745</fpage><lpage>1749</lpage><pub-id pub-id-type="pmid">8456302</pub-id></element-citation></ref><ref id="B105"><label>109</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Tao</surname><given-names>P</given-names></name><name><surname>Luo</surname><given-names>M</given-names></name><name><surname>Pan</surname><given-names>R</given-names></name><etal></etal></person-group><article-title>Enhanced protective immunity against H5N1 influenza virus challenge by vaccination with DNA expressing a chimeric hemagglutinin in combination with an MHC class I-restricted epitope of nucleoprotein in mice</article-title><source><italic>Antiviral Research</italic></source><year>2009</year><volume>81</volume><issue>3</issue><fpage>253</fpage><lpage>260</lpage><pub-id pub-id-type="pmid">19135483</pub-id></element-citation></ref><ref id="B106"><label>110</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Donnelly</surname><given-names>JJ</given-names></name><name><surname>Friedman</surname><given-names>A</given-names></name><name><surname>Ulmer</surname><given-names>JB</given-names></name><name><surname>Liu</surname><given-names>MA</given-names></name></person-group><article-title>Further protection against antigenic drift of influenza virus in a ferret model by DNA vaccination</article-title><source><italic>Vaccine</italic></source><year>1997</year><volume>15</volume><issue>8</issue><fpage>865</fpage><lpage>868</lpage><pub-id pub-id-type="pmid">9234535</pub-id></element-citation></ref><ref id="B107"><label>111</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ulmer</surname><given-names>JB</given-names></name><name><surname>Fu</surname><given-names>TM</given-names></name><name><surname>Deck</surname><given-names>RR</given-names></name><etal></etal></person-group><article-title>Protective CD4<sup>+</sup> and CD8<sup>+</sup> T cells against influenza virus induced by vaccination with nucleoprotein DNA</article-title><source><italic>Journal of Virology</italic></source><year>1998</year><volume>72</volume><issue>7</issue><fpage>5648</fpage><lpage>5653</lpage><pub-id pub-id-type="pmid">9621023</pub-id></element-citation></ref><ref id="B108"><label>112</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Fu</surname><given-names>TM</given-names></name><name><surname>Guan</surname><given-names>L</given-names></name><name><surname>Friedman</surname><given-names>A</given-names></name><etal></etal></person-group><article-title>Dose dependence of CTL precursor frequency induced by a DNA vaccine and correlation with protective immunity against influenza virus challenge</article-title><source><italic>Journal of Immunology</italic></source><year>1999</year><volume>162</volume><issue>7</issue><fpage>4163</fpage><lpage>4170</lpage></element-citation></ref><ref id="B109"><label>113</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ulmer</surname><given-names>JB</given-names></name><name><surname>Deck</surname><given-names>RR</given-names></name><name><surname>Dewitt</surname><given-names>CM</given-names></name><name><surname>Donnelly</surname><given-names>JJ</given-names></name><name><surname>Liu</surname><given-names>MA</given-names></name></person-group><article-title>Generation of MHC class I-restricted cytotoxic T lymphocytes by expression of a viral protein in muscle cells: antigen presentation by non-muscle cells</article-title><source><italic>Immunology</italic></source><year>1996</year><volume>89</volume><issue>1</issue><fpage>59</fpage><lpage>67</lpage><pub-id pub-id-type="pmid">8911141</pub-id></element-citation></ref><ref id="B110"><label>114</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Saha</surname><given-names>S</given-names></name><name><surname>Yoshida</surname><given-names>S</given-names></name><name><surname>Ohba</surname><given-names>K</given-names></name><etal></etal></person-group><article-title>A fused gene of nucleoprotein (NP) and herpes simplex virus genes (VP22) induces highly protective immunity against different subtypes of influenza virus</article-title><source><italic>Virology</italic></source><year>2006</year><volume>354</volume><issue>1</issue><fpage>48</fpage><lpage>57</lpage><pub-id pub-id-type="pmid">16945400</pub-id></element-citation></ref><ref id="B111"><label>115</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Laddy</surname><given-names>DJ</given-names></name><name><surname>Yan</surname><given-names>J</given-names></name><name><surname>Kutzler</surname><given-names>M</given-names></name><etal></etal></person-group><article-title>Heterosubtypic protection against pathogenic human and avian influenza viruses via In Vivo electroporation of synthetic consensus DNA antigens</article-title><source><italic>PLoS ONE</italic></source><year>2008</year><volume>3</volume><issue>6</issue><comment>Article ID e2517.</comment></element-citation></ref><ref id="B112"><label>116</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Smith</surname><given-names>LR</given-names></name><name><surname>Wloch</surname><given-names>MK</given-names></name><name><surname>Ye</surname><given-names>M</given-names></name><etal></etal></person-group><article-title>Phase 1 clinical trials of the safety and immunogenicity of adjuvanted plasmid DNA vaccines encoding influenza A virus H5 hemagglutinin</article-title><source><italic>Vaccine</italic></source><year>2010</year><volume>28</volume><issue>13</issue><fpage>2565</fpage><lpage>2572</lpage><pub-id pub-id-type="pmid">20117262</pub-id></element-citation></ref><ref id="B113"><label>117</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Klinman</surname><given-names>DM</given-names></name><name><surname>Takeno</surname><given-names>M</given-names></name><name><surname>Ichino</surname><given-names>M</given-names></name><etal></etal></person-group><article-title>DNA vaccines: safety and efficacy issues</article-title><source><italic>Springer Seminars in Immunopathology</italic></source><year>1997</year><volume>19</volume><issue>2</issue><fpage>245</fpage><lpage>256</lpage><pub-id pub-id-type="pmid">9406350</pub-id></element-citation></ref><ref id="B114"><label>118</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Chen</surname><given-names>CY</given-names></name><name><surname>Liu</surname><given-names>HJ</given-names></name><name><surname>Tsai</surname><given-names>CP</given-names></name><etal></etal></person-group><article-title>Baculovirus as an avian influenza vaccine vector: differential immune responses elicited by different vector forms</article-title><source><italic>Vaccine</italic></source><year>2010</year><volume>28</volume><issue>48</issue><fpage>7644</fpage><lpage>7651</lpage><pub-id pub-id-type="pmid">20883735</pub-id></element-citation></ref><ref id="B115"><label>119</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Barefoot</surname><given-names>BE</given-names></name><name><surname>Sample</surname><given-names>CJ</given-names></name><name><surname>Ramsburg</surname><given-names>EA</given-names></name></person-group><article-title>Recombinant vesicular stomatitis virus expressing influenza nucleoprotein induces CD8 T-cell responses that enhance antibody-mediated protection after lethal challenge with influenza virus</article-title><source><italic>Clinical and Vaccine Immunology</italic></source><year>2009</year><volume>16</volume><issue>4</issue><fpage>488</fpage><lpage>498</lpage><pub-id pub-id-type="pmid">19244472</pub-id></element-citation></ref><ref id="B116"><label>120</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Barefoot</surname><given-names>BE</given-names></name><name><surname>Athearn</surname><given-names>K</given-names></name><name><surname>Sample</surname><given-names>CJ</given-names></name><name><surname>Ramsburg</surname><given-names>EA</given-names></name></person-group><article-title>Intramuscular immunization with a vesicular stomatitis virus recombinant expressing the influenza hemagglutinin provides post-exposure protection against lethal influenza challenge</article-title><source><italic>Vaccine</italic></source><year>2009</year><volume>28</volume><issue>1</issue><fpage>79</fpage><lpage>89</lpage><pub-id pub-id-type="pmid">19819211</pub-id></element-citation></ref><ref id="B117"><label>121</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Berglund</surname><given-names>P</given-names></name><name><surname>Fleeton</surname><given-names>MN</given-names></name><name><surname>Smerdou</surname><given-names>C</given-names></name><name><surname>Liljeström</surname><given-names>P</given-names></name></person-group><article-title>Immunization with recombinant semliki forest virus induces protection against influenza challenge in mice</article-title><source><italic>Vaccine</italic></source><year>1999</year><volume>17</volume><issue>5</issue><fpage>497</fpage><lpage>507</lpage><pub-id pub-id-type="pmid">10073729</pub-id></element-citation></ref><ref id="B118"><label>122</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Vemula</surname><given-names>SV</given-names></name><name><surname>Mittal</surname><given-names>SK</given-names></name></person-group><article-title>Production of adenovirus vectors and their use as a delivery system for influenza vaccines</article-title><source><italic>Expert Opinion on Biological Therapy</italic></source><year>2010</year><volume>10</volume><issue>10</issue><fpage>1469</fpage><lpage>1487</lpage><pub-id pub-id-type="pmid">20822477</pub-id></element-citation></ref><ref id="B119"><label>123</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>He</surname><given-names>F</given-names></name><name><surname>Madhan</surname><given-names>S</given-names></name><name><surname>Kwang</surname><given-names>J</given-names></name></person-group><article-title>Baculovirus vector as a delivery vehicle for influenza vaccines</article-title><source><italic>Expert Review of Vaccines</italic></source><year>2009</year><volume>8</volume><issue>4</issue><fpage>455</fpage><lpage>467</lpage><pub-id pub-id-type="pmid">19348561</pub-id></element-citation></ref><ref id="B120"><label>124</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Rimmelzwaan</surname><given-names>GF</given-names></name><name><surname>Sutter</surname><given-names>G</given-names></name></person-group><article-title>Candidate influenza vaccines based on recombinant modified vaccinia virus Ankara</article-title><source><italic>Expert Review of Vaccines</italic></source><year>2009</year><volume>8</volume><issue>4</issue><fpage>447</fpage><lpage>454</lpage><pub-id pub-id-type="pmid">19348560</pub-id></element-citation></ref><ref id="B121"><label>125</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hoelscher</surname><given-names>MA</given-names></name><name><surname>Singh</surname><given-names>N</given-names></name><name><surname>Garg</surname><given-names>S</given-names></name><etal></etal></person-group><article-title>A broadly protective vaccine against globally dispersed clade 1 and clade 2 H5N1 influenza viruses</article-title><source><italic>Journal of Infectious Diseases</italic></source><year>2008</year><volume>197</volume><issue>8</issue><fpage>1185</fpage><lpage>1188</lpage><pub-id pub-id-type="pmid">18462165</pub-id></element-citation></ref><ref id="B122"><label>126</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Holman</surname><given-names>DH</given-names></name><name><surname>Wang</surname><given-names>D</given-names></name><name><surname>Raja</surname><given-names>NU</given-names></name><etal></etal></person-group><article-title>Multi-antigen vaccines based on complex adenovirus vectors induce protective immune responses against H5N1 avian influenza viruses</article-title><source><italic>Vaccine</italic></source><year>2008</year><volume>26</volume><issue>21</issue><fpage>2627</fpage><lpage>2639</lpage><pub-id pub-id-type="pmid">18395306</pub-id></element-citation></ref><ref id="B123"><label>127</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Prasad</surname><given-names>SA</given-names></name><name><surname>Norbury</surname><given-names>CC</given-names></name><name><surname>Chen</surname><given-names>W</given-names></name><name><surname>Bennink</surname><given-names>JR</given-names></name><name><surname>Yewdell</surname><given-names>JW</given-names></name></person-group><article-title>Cutting edge: recombinant adenoviruses induce CD8 T cell responses to an inserted protein whose expression is limited to nonimmune cells</article-title><source><italic>Journal of Immunology</italic></source><year>2001</year><volume>166</volume><issue>8</issue><fpage>4809</fpage><lpage>4812</lpage></element-citation></ref><ref id="B124"><label>128</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Roy</surname><given-names>S</given-names></name><name><surname>Kobinger</surname><given-names>GP</given-names></name><name><surname>Lin</surname><given-names>J</given-names></name><etal></etal></person-group><article-title>Partial protection against H5N1 influenza in mice with a single dose of a chimpanzee adenovirus vector expressing nucleoprotein</article-title><source><italic>Vaccine</italic></source><year>2007</year><volume>25</volume><issue>39-40</issue><fpage>6845</fpage><lpage>6851</lpage><pub-id pub-id-type="pmid">17728024</pub-id></element-citation></ref><ref id="B125"><label>129</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Steitz</surname><given-names>J</given-names></name><name><surname>Barlow</surname><given-names>PG</given-names></name><name><surname>Hossain</surname><given-names>J</given-names></name><etal></etal></person-group><article-title>A candidate H1N1 pandemic influenza vaccine elicits protective immunity in Mice</article-title><source><italic>PLoS ONE</italic></source><year>2010</year><volume>5</volume><issue>5</issue><comment>Article ID e10492.</comment></element-citation></ref><ref id="B126"><label>130</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hoelscher</surname><given-names>MA</given-names></name><name><surname>Jayashankar</surname><given-names>L</given-names></name><name><surname>Garg</surname><given-names>S</given-names></name><etal></etal></person-group><article-title>New pre-pandemic influenza vaccines: an egg- and adjuvant-independent human adenoviral vector strategy induces long-lasting protective immune responses in mice</article-title><source><italic>Clinical Pharmacology and Therapeutics</italic></source><year>2007</year><volume>82</volume><issue>6</issue><fpage>665</fpage><lpage>671</lpage><pub-id pub-id-type="pmid">17957181</pub-id></element-citation></ref><ref id="B127"><label>131</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hoelscher</surname><given-names>MA</given-names></name><name><surname>Garg</surname><given-names>S</given-names></name><name><surname>Bangari</surname><given-names>DS</given-names></name><etal></etal></person-group><article-title>Development of adenoviral-vector-based pandemic influenza vaccine against antigenically distinct human H5N1 strains in mice</article-title><source><italic>The Lancet</italic></source><year>2006</year><volume>367</volume><issue>9509</issue><fpage>475</fpage><lpage>481</lpage></element-citation></ref><ref id="B128"><label>132</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gao</surname><given-names>W</given-names></name><name><surname>Soloff</surname><given-names>AC</given-names></name><name><surname>Lu</surname><given-names>X</given-names></name><etal></etal></person-group><article-title>Protection of mice and poultry from lethal H5N1 avian influenza virus through adenovirus-based immunization</article-title><source><italic>Journal of Virology</italic></source><year>2006</year><volume>80</volume><issue>4</issue><fpage>1959</fpage><lpage>1964</lpage><pub-id pub-id-type="pmid">16439551</pub-id></element-citation></ref><ref id="B129"><label>133</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Singh</surname><given-names>S</given-names></name><name><surname>Toro</surname><given-names>H</given-names></name><name><surname>Tang</surname><given-names>DC</given-names></name><etal></etal></person-group><article-title>Non-replicating adenovirus vectors expressing avian influenza virus hemagglutinin and nucleocapsid proteins induce chicken specific effector, memory and effector memory CD8<sup>+</sup> T lymphocytes</article-title><source><italic>Virology</italic></source><year>2010</year><volume>405</volume><issue>1</issue><fpage>62</fpage><lpage>69</lpage><pub-id pub-id-type="pmid">20557918</pub-id></element-citation></ref><ref id="B130"><label>134</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sipo</surname><given-names>I</given-names></name><name><surname>Knauf</surname><given-names>M</given-names></name><name><surname>Fechner</surname><given-names>H</given-names></name><etal></etal></person-group><article-title>Vaccine protection against lethal homologous and heterologous challenge using recombinant AAV vectors expressing codon-optimized genes from pandemic swine origin influenza virus (SOIV)</article-title><source><italic>Vaccine</italic></source><year>2011</year><volume>29</volume><issue>8</issue><fpage>1690</fpage><lpage>1699</lpage><pub-id pub-id-type="pmid">21195079</pub-id></element-citation></ref><ref id="B131"><label>135</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kreijtz</surname><given-names>JH</given-names></name><name><surname>Suezer</surname><given-names>Y</given-names></name><name><surname>de Mutsert</surname><given-names>G</given-names></name><etal></etal></person-group><article-title>Preclinical evaluation of a modified vaccinia virus Ankara (MVA)-based vaccine against influenza A/H5N1 viruses</article-title><source><italic>Vaccine</italic></source><year>2009</year><volume>27</volume><issue>45</issue><fpage>6296</fpage><lpage>6299</lpage><pub-id pub-id-type="pmid">19840663</pub-id></element-citation></ref><ref id="B132"><label>136</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kreijtz</surname><given-names>JH</given-names></name><name><surname>Suezer</surname><given-names>Y</given-names></name><name><surname>de Mutsert</surname><given-names>G</given-names></name><etal></etal></person-group><article-title>MVA-based H5N1 vaccine affords cross-clade protection in mice against influenz a A/H5N1 viruses at low doses and after single immunization</article-title><source><italic>PLoS ONE</italic></source><year>2009</year><volume>4</volume><issue>11</issue><comment>Article ID e7790.</comment></element-citation></ref><ref id="B133"><label>137</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kreijtz</surname><given-names>JH</given-names></name><name><surname>Suzer</surname><given-names>Y</given-names></name><name><surname>Bodewes</surname><given-names>R</given-names></name><etal></etal></person-group><article-title>Evaluation of a modified vaccinia virus Ankara (MVA)-based candidate pandemic influenza A/H1N1 vaccine in the ferret model</article-title><source><italic>Journal of General Virology</italic></source><year>2010</year><volume>91</volume><issue>11</issue><fpage>2745</fpage><lpage>2752</lpage><pub-id pub-id-type="pmid">20719991</pub-id></element-citation></ref><ref id="B134"><label>138</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sutter</surname><given-names>G</given-names></name><name><surname>Wyatt</surname><given-names>LS</given-names></name><name><surname>Foley</surname><given-names>PL</given-names></name><name><surname>Bennink</surname><given-names>JR</given-names></name><name><surname>Moss</surname><given-names>B</given-names></name></person-group><article-title>A recombinant vector derived from the host range-restricted and highly attenuated MVA strain of vaccinia virus stimulates protective immunity in mice to influenza virus</article-title><source><italic>Vaccine</italic></source><year>1994</year><volume>12</volume><issue>11</issue><fpage>1032</fpage><lpage>1040</lpage><pub-id pub-id-type="pmid">7975844</pub-id></element-citation></ref><ref id="B135"><label>139</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hessel</surname><given-names>A</given-names></name><name><surname>Schwendinger</surname><given-names>M</given-names></name><name><surname>Holzer</surname><given-names>GW</given-names></name><etal></etal></person-group><article-title>Vectors based on modified vaccinia Ankara expressing influenza H5N1 hemagglutinin induce substantial cross-clade protective immunity</article-title><source><italic>PLoS ONE</italic></source><year>2011</year><volume>6</volume><issue>1</issue><comment>Article ID e16247.</comment></element-citation></ref><ref id="B136"><label>140</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Breathnach</surname><given-names>CC</given-names></name><name><surname>Clark</surname><given-names>HJ</given-names></name><name><surname>Clark</surname><given-names>RC</given-names></name><name><surname>Olsen</surname><given-names>CW</given-names></name><name><surname>Townsend</surname><given-names>HG</given-names></name><name><surname>Lunn</surname><given-names>DP</given-names></name></person-group><article-title>Immunization with recombinant modified vaccinia Ankara (rMVA) constructs encoding the HA or NP gene protects ponies from equine influenza virus challenge</article-title><source><italic>Vaccine</italic></source><year>2006</year><volume>24</volume><issue>8</issue><fpage>1180</fpage><lpage>1190</lpage><pub-id pub-id-type="pmid">16194586</pub-id></element-citation></ref><ref id="B137"><label>141</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Berthoud</surname><given-names>TK</given-names></name><name><surname>Hamill</surname><given-names>M</given-names></name><name><surname>Lillie</surname><given-names>PJ</given-names></name><etal></etal></person-group><article-title>Potent CD8<sup>+</sup> T-cell immunogenicity in humans of a novel heterosubtypic influenza a vaccine, MVA-NP+M1</article-title><source><italic>Clinical Infectious Diseases</italic></source><year>2011</year><volume>52</volume><issue>1</issue><fpage>1</fpage><lpage>7</lpage><pub-id pub-id-type="pmid">21148512</pub-id></element-citation></ref><ref id="B138"><label>142</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Galarza</surname><given-names>JM</given-names></name><name><surname>Latham</surname><given-names>T</given-names></name><name><surname>Cupo</surname><given-names>A</given-names></name></person-group><article-title>Virus-like particle (VLP) vaccine conferred complete protection against a lethal influenza virus challenge</article-title><source><italic>Viral Immunology</italic></source><year>2005</year><volume>18</volume><issue>1</issue><fpage>244</fpage><lpage>251</lpage><pub-id pub-id-type="pmid">15802970</pub-id></element-citation></ref><ref id="B139"><label>143</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Layton</surname><given-names>GT</given-names></name><name><surname>Harris</surname><given-names>SJ</given-names></name><name><surname>Myhan</surname><given-names>J</given-names></name><etal></etal></person-group><article-title>Induction of single and dual cytotoxic T-lymphocyte responses to viral proteins in mice using recombinant hybrid Ty-virus-like particles</article-title><source><italic>Immunology</italic></source><year>1996</year><volume>87</volume><issue>2</issue><fpage>171</fpage><lpage>178</lpage><pub-id pub-id-type="pmid">8698376</pub-id></element-citation></ref><ref id="B140"><label>144</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ross</surname><given-names>TM</given-names></name><name><surname>Mahmood</surname><given-names>K</given-names></name><name><surname>Crevar</surname><given-names>CJ</given-names></name><name><surname>Schneider-Ohrum</surname><given-names>K</given-names></name><name><surname>Heaton</surname><given-names>PM</given-names></name><name><surname>Bright</surname><given-names>RA</given-names></name></person-group><article-title>A trivalent virus-like particle vaccine elicits protective immune responses against seasonal influenza strains in mice and ferrets</article-title><source><italic>PLoS ONE</italic></source><year>2009</year><volume>4</volume><issue>6</issue><comment>Article ID e6032.</comment></element-citation></ref><ref id="B141"><label>145</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lee</surname><given-names>DH</given-names></name><name><surname>Park</surname><given-names>JK</given-names></name><name><surname>Lee</surname><given-names>YN</given-names></name><etal></etal></person-group><article-title>H9N2 avian influenza virus-like particle vaccine provides protective immunity and a strategy for the differentiation of infected from vaccinated animals</article-title><source><italic>Vaccine</italic></source><year>2011</year><volume>29</volume><issue>23</issue><fpage>4003</fpage><lpage>4007</lpage><pub-id pub-id-type="pmid">21463681</pub-id></element-citation></ref><ref id="B142"><label>146</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Furuya</surname><given-names>Y</given-names></name><name><surname>Chan</surname><given-names>J</given-names></name><name><surname>Regner</surname><given-names>M</given-names></name><etal></etal></person-group><article-title>Cytotoxic T cells are the predominant players providing cross-protective immunity induced by <italic>γ</italic>-irradiated influenza A viruses</article-title><source><italic>Journal of Virology</italic></source><year>2010</year><volume>84</volume><issue>9</issue><fpage>4212</fpage><lpage>4221</lpage><pub-id pub-id-type="pmid">20164231</pub-id></element-citation></ref><ref id="B143"><label>147</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Morein</surname><given-names>B</given-names></name><name><surname>Sundquist</surname><given-names>B</given-names></name><name><surname>Hoglund</surname><given-names>S</given-names></name><name><surname>Dalsgaard</surname><given-names>K</given-names></name><name><surname>Osterhaus</surname><given-names>A</given-names></name></person-group><article-title>Iscom, a novel structure for antigenic presentation of membrane proteins from enveloped viruses</article-title><source><italic>Nature</italic></source><year>1984</year><volume>308</volume><issue>5958</issue><fpage>457</fpage><lpage>460</lpage><pub-id pub-id-type="pmid">6709052</pub-id></element-citation></ref><ref id="B144"><label>148</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Voeten</surname><given-names>JT</given-names></name><name><surname>Rimmelzwaan</surname><given-names>GF</given-names></name><name><surname>Nieuwkoop</surname><given-names>NJ</given-names></name><name><surname>Lövgren-Bengtsson</surname><given-names>K</given-names></name><name><surname>Osterhaus</surname><given-names>AD</given-names></name></person-group><article-title>Introduction of the haemagglutinin transmembrane region in the influenza virus matrix protein facilitates its incorporation into ISCOM and activation of specific CD8<sup>+</sup> cytotoxic T lymphocytes</article-title><source><italic>Vaccine</italic></source><year>2000</year><volume>19</volume><issue>4-5</issue><fpage>514</fpage><lpage>522</lpage><pub-id pub-id-type="pmid">11027816</pub-id></element-citation></ref><ref id="B145"><label>149</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sambhara</surname><given-names>S</given-names></name><name><surname>Kurichh</surname><given-names>A</given-names></name><name><surname>Miranda</surname><given-names>R</given-names></name><etal></etal></person-group><article-title>Heterosubtypic immunity against human influenza A viruses, including recently emerged avian H5 and H9 viruses, induced by FLU-ISCOM vaccine in mice requires both cytotoxic T-lymphocyte and macrophage function</article-title><source><italic>Cellular Immunology</italic></source><year>2001</year><volume>211</volume><issue>2</issue><fpage>143</fpage><lpage>153</lpage><pub-id pub-id-type="pmid">11591118</pub-id></element-citation></ref><ref id="B146"><label>150</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Glück</surname><given-names>R</given-names></name><name><surname>Mischler</surname><given-names>R</given-names></name><name><surname>Finkel</surname><given-names>B</given-names></name><name><surname>Que</surname><given-names>JU</given-names></name><name><surname>Scarpa</surname><given-names>B</given-names></name><name><surname>Cryz</surname><given-names>SJ</given-names><suffix>Jr.</suffix></name></person-group><article-title>Immunogenicity of new virosome influenza vaccine in elderly people</article-title><source><italic>The Lancet</italic></source><year>1994</year><volume>344</volume><issue>8916</issue><fpage>160</fpage><lpage>163</lpage></element-citation></ref><ref id="B147"><label>151</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Rimmelzwaan</surname><given-names>GF</given-names></name><name><surname>Nieuwkoop</surname><given-names>N</given-names></name><name><surname>Brandenburg</surname><given-names>A</given-names></name><etal></etal></person-group><article-title>A randomized, double blind study in young healthy adults comparing cell mediated and humoral immune responses induced by influenza ISCOM vaccines and conventional vaccines</article-title><source><italic>Vaccine</italic></source><year>2000</year><volume>19</volume><issue>9-10</issue><fpage>1180</fpage><lpage>1187</lpage><pub-id pub-id-type="pmid">11137255</pub-id></element-citation></ref><ref id="B148"><label>152</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ennis</surname><given-names>FA</given-names></name><name><surname>Cruz</surname><given-names>J</given-names></name><name><surname>Jameson</surname><given-names>J</given-names></name><name><surname>Klein</surname><given-names>M</given-names></name><name><surname>Burt</surname><given-names>D</given-names></name><name><surname>Thipphawong</surname><given-names>J</given-names></name></person-group><article-title>Augmentation of human influenza A virus-specific cytotoxic T lymphocyte memory by influenza vaccine and adjuvanted carriers (ISCOMS)</article-title><source><italic>Virology</italic></source><year>1999</year><volume>259</volume><issue>2</issue><fpage>256</fpage><lpage>261</lpage><pub-id pub-id-type="pmid">10388649</pub-id></element-citation></ref><ref id="B149"><label>153</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wilschut</surname><given-names>J</given-names></name></person-group><article-title>Influenza vaccines: the virosome concept</article-title><source><italic>Immunology Letters</italic></source><year>2009</year><volume>122</volume><issue>2</issue><fpage>118</fpage><lpage>121</lpage><pub-id pub-id-type="pmid">19100779</pub-id></element-citation></ref><ref id="B150"><label>154</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bungener</surname><given-names>L</given-names></name><name><surname>Huckriede</surname><given-names>A</given-names></name><name><surname>de Mare</surname><given-names>A</given-names></name><name><surname>de Vries-Idema</surname><given-names>J</given-names></name><name><surname>Wilschut</surname><given-names>J</given-names></name><name><surname>Daemen</surname><given-names>T</given-names></name></person-group><article-title>Virosome-mediated delivery of protein antigens In Vivo: efficient induction of class I MHC-restricted cytotoxic T lymphocyte activity</article-title><source><italic>Vaccine</italic></source><year>2005</year><volume>23</volume><issue>10</issue><fpage>1232</fpage><lpage>1241</lpage><pub-id pub-id-type="pmid">15652665</pub-id></element-citation></ref><ref id="B151"><label>155</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bungener</surname><given-names>L</given-names></name><name><surname>Serre</surname><given-names>K</given-names></name><name><surname>Bijl</surname><given-names>L</given-names></name><etal></etal></person-group><article-title>Virosome-mediated delivery of protein antigens to dendritic cells</article-title><source><italic>Vaccine</italic></source><year>2002</year><volume>20</volume><issue>17-18</issue><fpage>2287</fpage><lpage>2295</lpage><pub-id pub-id-type="pmid">12009284</pub-id></element-citation></ref><ref id="B152"><label>156</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Conne</surname><given-names>P</given-names></name><name><surname>Gauthey</surname><given-names>L</given-names></name><name><surname>Vernet</surname><given-names>P</given-names></name><etal></etal></person-group><article-title>Immunogenicity of trivalent subunit versus virosome-formulated influenza vaccines in geriatric patients</article-title><source><italic>Vaccine</italic></source><year>1997</year><volume>15</volume><issue>15</issue><fpage>1675</fpage><lpage>1679</lpage><pub-id pub-id-type="pmid">9364699</pub-id></element-citation></ref><ref id="B153"><label>157</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Pregliasco</surname><given-names>F</given-names></name><name><surname>Mensi</surname><given-names>C</given-names></name><name><surname>Serpilli</surname><given-names>W</given-names></name><name><surname>Speccher</surname><given-names>L</given-names></name><name><surname>Masella</surname><given-names>P</given-names></name><name><surname>Belloni</surname><given-names>A</given-names></name></person-group><article-title>Immunogenicity and safety of three commercial influenza vaccines in institutionalized elderly</article-title><source><italic>Aging</italic></source><year>2001</year><volume>13</volume><issue>1</issue><fpage>38</fpage><lpage>43</lpage><pub-id pub-id-type="pmid">11292151</pub-id></element-citation></ref><ref id="B154"><label>158</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>de Bruijn</surname><given-names>IA</given-names></name><name><surname>Nauta</surname><given-names>J</given-names></name><name><surname>Gerez</surname><given-names>L</given-names></name><name><surname>Palache</surname><given-names>AM</given-names></name></person-group><article-title>The virosomal influenza vaccine Invivac: immunogenicity and tolerability compared to an adjuvanted influenza vaccine (Fluad) in elderly subjects</article-title><source><italic>Vaccine</italic></source><year>2006</year><volume>24</volume><issue>44–46</issue><fpage>6629</fpage><lpage>6631</lpage><pub-id pub-id-type="pmid">16901593</pub-id></element-citation></ref></ref-list></back><floats-group><table-wrap id="tab1" position="float"><label>Table 1</label><caption><p>Evidence for cross-reactivity of influenza virus-specific CTL.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="center" colspan="2" rowspan="1">Subtype</th><th align="left" rowspan="1" colspan="1"></th><th align="left" rowspan="2" colspan="1">Comments</th><th align="center" rowspan="2" colspan="1">Ref.</th></tr><tr><th align="left" rowspan="1" colspan="1">Priming subtype</th><th align="center" rowspan="1" colspan="1">Cross-reaction with</th><th align="left" rowspan="1" colspan="1">Species</th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">H2N1</td><td align="center" rowspan="1" colspan="1">H3N2</td><td align="left" rowspan="1" colspan="1">Mouse</td><td align="left" rowspan="1" colspan="1">Cross-reactivity confirmed in Cr-release assays using cultured splenocytes of primed mice</td><td align="center" rowspan="1" colspan="1">[<xref ref-type="bibr" rid="B34">28</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">H1N1</td><td align="center" rowspan="1" colspan="1">H2N2<break></break>H3N2</td><td align="left" rowspan="1" colspan="1">Mouse</td><td align="left" rowspan="1" colspan="1">Cross-reactivity confirmed in Cr-release assays using splenocytes of primed mice</td><td align="center" rowspan="1" colspan="1">[<xref ref-type="bibr" rid="B24">24</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">H3N2</td><td align="center" rowspan="1" colspan="1">H1N1</td><td align="left" rowspan="1" colspan="1">Mouse</td><td align="left" rowspan="1" colspan="1">Target cells expressing NP from H1N1 recognized by cultured splenocytes from primed mice</td><td align="center" rowspan="1" colspan="1">[<xref ref-type="bibr" rid="B32">29</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">H3N2</td><td align="center" rowspan="1" colspan="1">H1N1</td><td align="left" rowspan="1" colspan="1">Mouse</td><td align="left" rowspan="1" colspan="1">Cross-reactive cultured splenocytes recognize inner proteins of influenza A virus</td><td align="center" rowspan="1" colspan="1">[<xref ref-type="bibr" rid="B155">30</xref>] </td></tr><tr><td align="center" colspan="5" rowspan="1"><hr></hr></td></tr><tr><td align="left" rowspan="1" colspan="1">H3N2</td><td align="center" rowspan="1" colspan="1">H1N1</td><td align="left" rowspan="1" colspan="1">Human</td><td align="left" rowspan="1" colspan="1">Cross-reactive CTLs recognize NP, M1, or PB2</td><td align="center" rowspan="1" colspan="1">[<xref ref-type="bibr" rid="B31">31</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Seasonal influenza</td><td align="center" rowspan="1" colspan="1">H5N1</td><td align="left" rowspan="1" colspan="1">Human</td><td align="left" rowspan="1" colspan="1">Cross-reactive CTLs were detected in the blood of healthy human subjects not exposed to H5N1 virus</td><td align="center" rowspan="1" colspan="1">[<xref ref-type="bibr" rid="B35">32</xref>–<xref ref-type="bibr" rid="B37">34</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">pH1N1</td><td align="center" rowspan="1" colspan="1">H1N1</td><td align="left" rowspan="1" colspan="1">Human</td><td align="left" rowspan="1" colspan="1">T cells specific for the NP418 epitope induced by the 2009 pH1N1 cross-react with the 1918-H1N1 variant but not with contemporary variants</td><td align="center" rowspan="1" colspan="1">[<xref ref-type="bibr" rid="B40">35</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Seasonal influenza</td><td align="center" rowspan="1" colspan="1">2009 pH1N1</td><td align="left" rowspan="1" colspan="1">Human</td><td align="left" rowspan="1" colspan="1">Cross-reactive CTLs were detected in the blood of healthy human subjects not exposed to 2009 pH1N1 virus</td><td align="center" rowspan="1" colspan="1">[<xref ref-type="bibr" rid="B39">36</xref>]</td></tr></tbody></table></table-wrap><table-wrap id="tab2" position="float"><label>Table 2</label><caption><p>Evidence for a role of CTLs in cross-protective immunity against influenza virus infections.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="center" colspan="2" rowspan="1">Subtype used</th><th align="center" rowspan="1" colspan="1"></th><th align="left" rowspan="1" colspan="1"></th><th align="left" rowspan="1" colspan="1"></th><th align="center" rowspan="1" colspan="1"></th></tr><tr><th align="left" rowspan="1" colspan="1">Priming</th><th align="center" rowspan="1" colspan="1">Challenge</th><th align="center" rowspan="1" colspan="1">Species</th><th align="left" rowspan="1" colspan="1">Experiment</th><th align="left" rowspan="1" colspan="1">Comments</th><th align="center" rowspan="1" colspan="1">Ref</th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">H1N1</td><td align="center" rowspan="1" colspan="1">H1N1</td><td align="center" rowspan="1" colspan="1">Mouse</td><td align="left" rowspan="1" colspan="1">Adoptive transfer</td><td align="left" rowspan="1" colspan="1">Splenocytes depleted from CD8<sup>+</sup> T cells failed to protect against infection.</td><td align="center" rowspan="1" colspan="1">[<xref ref-type="bibr" rid="B25">25</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">H1N1 or H3N2</td><td align="center" rowspan="1" colspan="1">H1N1 or H3N2</td><td align="center" rowspan="1" colspan="1">Mouse</td><td align="left" rowspan="1" colspan="1">Adoptive transfer</td><td align="left" rowspan="1" colspan="1">T cells afford protection against infection with heterosubtypic strain.</td><td align="center" rowspan="1" colspan="1">[<xref ref-type="bibr" rid="B50">48</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">H3N2</td><td align="center" rowspan="1" colspan="1">H3N2</td><td align="center" rowspan="1" colspan="1">Nude mouse</td><td align="left" rowspan="1" colspan="1">Adoptive transfer</td><td align="left" rowspan="1" colspan="1">Immune spleen cells from Balb-c mice mediated more rapid clearance of virus infection and correlated with cytolytic activity.</td><td align="center" rowspan="1" colspan="1">[<xref ref-type="bibr" rid="B47">49</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">H3N2</td><td align="center" rowspan="1" colspan="1">H1N1 <break></break>H3N2<break></break>H2N2</td><td align="center" rowspan="1" colspan="1">Mouse</td><td align="left" rowspan="1" colspan="1">Adoptive transfer</td><td align="left" rowspan="1" colspan="1">Mouse NP-specific CTL clone afforded protection.</td><td align="center" rowspan="1" colspan="1">[<xref ref-type="bibr" rid="B49">50</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">NP from H3N2</td><td align="center" rowspan="1" colspan="1">H1N1</td><td align="center" rowspan="1" colspan="1">Mouse</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">NP priming promoted recovery and was attributed to cross-reactive CTLs.</td><td align="center" rowspan="1" colspan="1">[<xref ref-type="bibr" rid="B156">51</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">H2N2</td><td align="center" rowspan="1" colspan="1">H1N1</td><td align="center" rowspan="1" colspan="1">Mouse</td><td align="left" rowspan="1" colspan="1">Adoptive transfer</td><td align="left" rowspan="1" colspan="1">Cross-reactive CTL clones conferred protection.</td><td align="center" rowspan="1" colspan="1">[<xref ref-type="bibr" rid="B48">52</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">H3N2</td><td align="center" rowspan="1" colspan="1">H3N2</td><td align="center" rowspan="1" colspan="1">Mouse</td><td align="left" rowspan="1" colspan="1">Adoptive transfer</td><td align="left" rowspan="1" colspan="1">NP-specific CTL clone reduced lung virus titers and mortality rates.</td><td align="center" rowspan="1" colspan="1">[<xref ref-type="bibr" rid="B157">53</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">H1N1</td><td align="center" rowspan="1" colspan="1">H3N2</td><td align="center" rowspan="1" colspan="1">Mouse</td><td align="left" rowspan="1" colspan="1">Depletion of T cells</td><td align="left" rowspan="1" colspan="1">CTLs conferred heterosubtypic immunity and reduced virus titers in the respiratory tract.</td><td align="center" rowspan="1" colspan="1">[<xref ref-type="bibr" rid="B53">54</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">H3N2</td><td align="center" rowspan="1" colspan="1">H1N1</td><td align="center" rowspan="1" colspan="1">Mouse</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Protection correlated with CTL response.</td><td align="center" rowspan="1" colspan="1">[<xref ref-type="bibr" rid="B44">45</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">H9N2</td><td align="center" rowspan="1" colspan="1">H5N1</td><td align="center" rowspan="1" colspan="1">Mouse</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Protection correlated with CTL response to NP or PB2.</td><td align="center" rowspan="1" colspan="1">[<xref ref-type="bibr" rid="B45">46</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">H1N1</td><td align="center" rowspan="1" colspan="1">H2N2</td><td align="center" rowspan="1" colspan="1">Mice KO for Ig or <italic>γ</italic>/<italic>δ</italic> T cells</td><td align="left" rowspan="1" colspan="1">Acute depletion of CD8<sup>+</sup> T cells</td><td align="left" rowspan="1" colspan="1">In absence of Ig or <italic>γ</italic>/<italic>δ</italic> T cells, CTLs conferred protection.</td><td align="center" rowspan="1" colspan="1">[<xref ref-type="bibr" rid="B43">44</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">H1N1</td><td align="center" rowspan="1" colspan="1">H3N2</td><td align="center" rowspan="1" colspan="1">Mouse</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Protection correlated with CTL response to NP.</td><td align="center" rowspan="1" colspan="1">[<xref ref-type="bibr" rid="B42">43</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">H3N2</td><td align="center" rowspan="1" colspan="1">H5N1</td><td align="center" rowspan="1" colspan="1">Mouse</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Protection correlated with CTL response to NP and PA.</td><td align="center" rowspan="1" colspan="1">[<xref ref-type="bibr" rid="B41">42</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Gamma-irradiated viruses</td><td align="center" rowspan="1" colspan="1">H1N1</td><td align="center" rowspan="1" colspan="1">Mouse</td><td align="left" rowspan="1" colspan="1">Adoptive transfer of CD8<sup>+</sup> T cells</td><td align="left" rowspan="1" colspan="1">CTL but not B cells afforded protection.</td><td align="center" rowspan="1" colspan="1">[<xref ref-type="bibr" rid="B39">36</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">H3N2</td><td align="center" rowspan="1" colspan="1">2009 pH1N1</td><td align="center" rowspan="1" colspan="1">Mouse</td><td align="left" rowspan="1" colspan="1">Depletion of CD8<sup>+</sup> T cells</td><td align="left" rowspan="1" colspan="1">CTL conferred heterosubtypic immunity to 2009 pH1N1 virus.</td><td align="center" rowspan="1" colspan="1">[<xref ref-type="bibr" rid="B52">55</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">H3N2</td><td align="center" rowspan="1" colspan="1">2009 pH1N1</td><td align="center" rowspan="1" colspan="1">Mouse</td><td align="left" rowspan="1" colspan="1">Adoptive transfer of CD8<sup>+</sup> and CD4<sup>+</sup> T cells</td><td align="left" rowspan="1" colspan="1">CTL conferred heterosubtypic immunity to 2009 pH1N1 virus.</td><td align="center" rowspan="1" colspan="1">[<xref ref-type="bibr" rid="B22">22</xref>] </td></tr><tr><td align="center" colspan="6" rowspan="1"><hr></hr></td></tr><tr><td align="left" rowspan="1" colspan="1">H9N2</td><td align="center" rowspan="1" colspan="1">H5N1</td><td align="center" rowspan="1" colspan="1">Chicken</td><td align="left" rowspan="1" colspan="1">Adoptive transfer of CD8<sup>+</sup> T cells</td><td align="left" rowspan="1" colspan="1">CTLs reduced mortality rates.</td><td align="center" rowspan="1" colspan="1">[<xref ref-type="bibr" rid="B51">56</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">H9N2</td><td align="center" rowspan="1" colspan="1">H5N1</td><td align="center" rowspan="1" colspan="1">Chicken</td><td align="left" rowspan="1" colspan="1">Depletion</td><td align="left" rowspan="1" colspan="1">CTLs reduced mortality rates.</td><td align="center" rowspan="1" colspan="1">[<xref ref-type="bibr" rid="B55">57</xref>] </td></tr><tr><td align="center" colspan="6" rowspan="1"><hr></hr></td></tr><tr><td align="left" rowspan="1" colspan="1">H3N2</td><td align="center" rowspan="1" colspan="1">H5N1</td><td align="center" rowspan="1" colspan="1">Ferret</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Protection correlated with CTL response.</td><td align="center" rowspan="1" colspan="1">[<xref ref-type="bibr" rid="B158">58</xref>] </td></tr><tr><td align="center" colspan="6" rowspan="1"><hr></hr></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1">H1N1</td><td align="center" rowspan="1" colspan="1">Human</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">CTL activity correlated with protection in absence of antibodies.</td><td align="center" rowspan="1" colspan="1">[<xref ref-type="bibr" rid="B28">37</xref>]</td></tr></tbody></table></table-wrap></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Sante/explor/H2N2V1/Data/Pmc/Corpus
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000D88 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd -nk 000D88 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Sante
|area= H2N2V1
|flux= Pmc
|étape= Corpus
|type= RBID
|clé=
|texte=
}}
| This area was generated with Dilib version V0.6.33. |  |