{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T06:28:11Z","timestamp":1792304891700,"version":"4.4.0"},"reference-count":203,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2018,3,26]],"date-time":"2018-03-26T00:00:00Z","timestamp":1522022400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>Next-generation vaccines that utilize T cells could potentially overcome the limitations of current influenza vaccines that rely on antibodies to provide narrow subtype-specific protection and are prone to antigenic mismatch with circulating strains. Evidence from animal models shows that T cells can provide heterosubtypic protection and are crucial for immune control of influenza virus infections. This has provided hope for the design of a universal vaccine able to prime against diverse influenza virus strains and subtypes. However, multiple hurdles exist for the realisation of a universal T cell vaccine. Overall primary concerns are: extrapolating human clinical studies, seeding durable effective T cell resident memory (Trm), population human leucocyte antigen (HLA) coverage, and the potential for T cell-mediated immune escape. Further comprehensive human clinical data is needed during natural infection to validate the protective role T cells play during infection in the absence of antibodies. Furthermore, fundamental questions still exist regarding the site, longevity and duration, quantity, and phenotype of T cells needed for optimal protection. Standardised experimental methods, and eventually simplified commercial assays, to assess peripheral influenza-specific T cell responses are needed for larger-scale clinical studies of T cells as a correlate of protection against influenza infection. The design and implementation of a T cell-inducing vaccine will require a consensus on the level of protection acceptable in the community, which may not provide sterilizing immunity but could protect the individual from severe disease, reduce the length of infection, and potentially reduce transmission in the community. Therefore, increasing the standard of care potentially offered by T cell vaccines should be considered in the context of pandemic preparedness and zoonotic infections, and in combination with improved antibody vaccine targeting methods. Current pandemic vaccine preparedness measures and ongoing clinical trials under-utilise T cell-inducing vaccines, reflecting the myriad questions that remain about how, when, where, and which T cells are needed to fight influenza virus infection. This review aims to bring together basic fundamentals of T cell biology with human clinical data, which need to be considered for the implementation of a universal vaccine against influenza that harnesses the power of T cells.<\/jats:p>","DOI":"10.3390\/vaccines6020018","type":"journal-article","created":{"date-parts":[[2018,3,26]],"date-time":"2018-03-26T12:08:25Z","timestamp":1522066105000},"page":"18","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":110,"title":["Harnessing the Power of T Cells: The Promising Hope for a Universal Influenza Vaccine"],"prefix":"10.3390","volume":"6","author":[{"given":"E.","family":"Clemens","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, The University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolien","family":"Van de Sandt","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, The University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sook","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, St. Jude Children\u2019s Research Hospital, Memphis, TN 38105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Wakim","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, The University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Valkenburg","sequence":"additional","affiliation":[{"name":"HKU Pasteur Research Pole, School of Public Health, University of Hong Kong, Hong Kong 999077, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,3,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4681","DOI":"10.1016\/j.vaccine.2017.07.053","article-title":"Survey of distribution of seasonal influenza vaccine doses in 201 countries (2004\u20132015): The 2003 World Health Assembly resolution on seasonal influenza vaccination coverage and the 2009 influenza pandemic have had very little impact on improving influenza control and pandemic preparedness","volume":"35","author":"Palache","year":"2017","journal-title":"Vaccine"},{"key":"ref_2","unstructured":"Centers for Disease Control and Prevention, Appiah, G.D., Blanton, L., D\u2019Mello, T., Kniss, K., Smith, S., Mustaquim, D., Steffens, C., Dhara, R., and Cohen, J. (2015). Influenza activity\u2014United States, 2014\u201315 season and composition of the 2015\u201316 influenza vaccine. MMWR, 64, 583\u2013590."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"15279","DOI":"10.1038\/srep15279","article-title":"H3N2 Mismatch of 2014\u201315 Northern Hemisphere Influenza Vaccines and Head-to-head Comparison between Human and Ferret Antisera derived Antigenic Maps","volume":"5","author":"Xie","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"81","DOI":"10.4161\/hv.8.1.17623","article-title":"The rationale for quadrivalent influenza vaccines","volume":"8","author":"Ambrose","year":"2012","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.1126\/science.1189132","article-title":"Reassortment of pandemic H1N1\/2009 influenza A virus in swine","volume":"328","author":"Vijaykrishna","year":"2010","journal-title":"Science"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Wu, N.C., Zost, S.J., Thompson, A.J., Oyen, D., Nycholat, C.M., McBride, R., Paulson, J.C., Hensley, S.E., and Wilson, I.A. (2017). A structural explanation for the low effectiveness of the seasonal influenza H3N2 vaccine. PLoS Pathog., 13.","DOI":"10.1371\/journal.ppat.1006682"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1136\/archdischild-2016-312165","article-title":"Live attenuated influenza vaccine (LAIV): Recent effectiveness results from the USA and implications for LAIV programmes elsewhere","volume":"103","author":"Pebody","year":"2018","journal-title":"Arch. Dis. Child."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.vaccine.2015.11.010","article-title":"Effectiveness of live attenuated influenza vaccine and inactivated influenza vaccine in children 2\u201317 years of age in 2013\u20132014 in the United States","volume":"34","author":"Caspard","year":"2016","journal-title":"Vaccine"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e25","DOI":"10.1016\/S1473-3099(17)30360-2","article-title":"Urgent challenges in implementing live attenuated influenza vaccine","volume":"18","author":"Singanayagam","year":"2018","journal-title":"Lancet Infect. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1086\/595861","article-title":"Effectiveness of inactivated influenza vaccines varied substantially with antigenic match from the 2004\u20132005 season to the 2006\u20132007 season","volume":"199","author":"Belongia","year":"2009","journal-title":"J. Infect. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1093\/infdis\/jiv099","article-title":"Impact of Adjuvants on the Immunogenicity and Efficacy of Split-Virion H7N9 Vaccine in Ferrets","volume":"212","author":"Wong","year":"2015","journal-title":"J. Infect. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2241","DOI":"10.1080\/21645515.2015.1052197","article-title":"H7N9 T-cell epitopes that mimic human sequences are less immunogenic and may induce Treg-mediated tolerance","volume":"11","author":"Liu","year":"2015","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"792","DOI":"10.4161\/hv.6.10.12915","article-title":"Pre-pandemic and pandemic influenza vaccines","volume":"6","author":"Rockman","year":"2010","journal-title":"Hum. Vaccines"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Bodewes, R., Kreijtz, J.H., Baas, C., Geelhoed-Mieras, M.M., de Mutsert, G., van Amerongen, G., van den Brand, J.M., Fouchier, R.A., Osterhaus, A.D., and Rimmelzwaan, G.F. (2009). Vaccination against human influenza A\/H3N2 virus prevents the induction of heterosubtypic immunity against lethal infection with avian influenza A\/H5N1 virus. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0005538"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.molimm.2015.06.010","article-title":"Quantifying epitope presentation using mass spectrometry","volume":"68","author":"Croft","year":"2015","journal-title":"Mol. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"12241","DOI":"10.1128\/JVI.01563-08","article-title":"Immunomic analysis of the repertoire of T-cell specificities for influenza A virus in humans","volume":"82","author":"Assarsson","year":"2008","journal-title":"J. Virol."},{"key":"ref_17","first-page":"3478","article-title":"Memory T cells established by seasonal human influenza A infection cross-react with avian influenza A (H5N1) in healthy individuals","volume":"118","author":"Lee","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1073\/pnas.1322229111","article-title":"Preexisting CD8+ T-cell immunity to the H7N9 influenza A virus varies across ethnicities","volume":"111","author":"Grant","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1684","DOI":"10.1128\/JVI.02843-13","article-title":"Human cytotoxic T lymphocytes directed to seasonal influenza A viruses cross-react with the newly emerging H7N9 virus","volume":"88","author":"Kreijtz","year":"2014","journal-title":"J. Virol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5161","DOI":"10.1128\/JVI.02694-07","article-title":"Cross-recognition of avian H5N1 influenza virus by human cytotoxic T-lymphocyte populations directed to human influenza A virus","volume":"82","author":"Kreijtz","year":"2008","journal-title":"J. Virol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1099\/vir.0.048652-0","article-title":"Human T-cells directed to seasonal influenza A virus cross-react with 2009 pandemic influenza A (H1N1) and swine-origin triple-reassortant H3N2 influenza viruses","volume":"94","author":"Hillaire","year":"2013","journal-title":"J. Gen. Virol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2339","DOI":"10.1099\/vir.0.033076-0","article-title":"Cross-protective immunity against influenza pH1N1 2009 viruses induced by seasonal influenza A (H3N2) virus is mediated by virus-specific T-cells","volume":"92","author":"Hillaire","year":"2011","journal-title":"J. Gen. Virol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1016\/j.vaccine.2006.08.036","article-title":"Primary influenza A virus infection induces cross-protective immunity against a lethal infection with a heterosubtypic virus strain in mice","volume":"25","author":"Kreijtz","year":"2007","journal-title":"Vaccine"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4983","DOI":"10.1016\/j.vaccine.2009.05.079","article-title":"Infection of mice with a human influenza A\/H3N2 virus induces protective immunity against lethal infection with influenza A\/H5N1 virus","volume":"27","author":"Kreijtz","year":"2009","journal-title":"Vaccine"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2695","DOI":"10.1128\/JVI.02371-10","article-title":"Vaccination against seasonal influenza A\/H3N2 virus reduces the induction of heterosubtypic immunity against influenza A\/H5N1 virus infection in ferrets","volume":"85","author":"Bodewes","year":"2011","journal-title":"J. Virol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"11690","DOI":"10.1128\/JVI.74.24.11690-11696.2000","article-title":"Profound protection against respiratory challenge with a lethal H7N7 influenza A virus by increasing the magnitude of CD8(+) T-cell memory","volume":"74","author":"Christensen","year":"2000","journal-title":"J. Virol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e03300","DOI":"10.7554\/eLife.03300","article-title":"The inherent mutational tolerance and antigenic evolvability of influenza hemagglutinin","volume":"3","author":"Thyagarajan","year":"2014","journal-title":"Elife"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"11275","DOI":"10.1128\/JVI.01571-15","article-title":"Positive Selection in CD8+ T-Cell Epitopes of Influenza Virus Nucleoprotein Revealed by a Comparative Analysis of Human and Swine Viral Lineages","volume":"89","author":"Machkovech","year":"2015","journal-title":"J. Virol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5676","DOI":"10.1073\/pnas.1403684111","article-title":"IL-15 adjuvanted multivalent vaccinia-based universal influenza Vaccine requires CD4+ T cells for heterosubtypic protection","volume":"111","author":"Valkenburg","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"6833","DOI":"10.1038\/ncomms7833","article-title":"Recovery from severe H7N9 disease is associated with diverse response mechanisms dominated by CD8(+) T cells","volume":"6","author":"Wang","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1186\/1743-422X-10-244","article-title":"Cross-reactive human B cell and T cell epitopes between influenza A and B viruses","volume":"10","author":"Terajima","year":"2013","journal-title":"Virol. J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"119","DOI":"10.2217\/fmb.15.120","article-title":"Knowns and unknowns of influenza B viruses","volume":"11","author":"Koutsakos","year":"2016","journal-title":"Future Microbiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1126\/science.1083317","article-title":"Defective CD8 T cell memory following acute infection without CD4 T cell help","volume":"300","author":"Sun","year":"2003","journal-title":"Science"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1038\/nri3803","article-title":"A brief history of T cell help to B cells","volume":"15","author":"Crotty","year":"2015","journal-title":"Nat. Rev. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"10857","DOI":"10.1038\/s41598-017-11313-x","article-title":"Pandemic 2009 H1N1 Influenza Venus reporter virus reveals broad diversity of MHC class II-positive antigen-bearing cells following infection in vivo","volume":"7","author":"DiPiazza","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1126\/science.286.5441.958","article-title":"A direct estimate of the human alphabeta T cell receptor diversity","volume":"286","author":"Arstila","year":"1999","journal-title":"Science"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"6123","DOI":"10.4049\/jimmunol.175.9.6123","article-title":"Selection of T cell clones expressing high-affinity public TCRs within Human cytomegalovirus-specific CD8 T cell responses","volume":"175","author":"Trautmann","year":"2005","journal-title":"J. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1885","DOI":"10.1172\/JCI41538","article-title":"Primary CTL response magnitude in mice is determined by the extent of naive T cell recruitment and subsequent clonal expansion","volume":"120","author":"Rothwell","year":"2010","journal-title":"J. Clin. Investig."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"90","DOI":"10.4049\/jimmunol.169.1.90","article-title":"Dynamics of memory T cell proliferation under conditions of heterologous immunity and bystander stimulation","volume":"169","author":"Kim","year":"2002","journal-title":"J. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"11392","DOI":"10.1128\/JVI.75.23.11392-11400.2001","article-title":"Cross-reactivity between hepatitis C virus and Influenza A virus determinant-specific cytotoxic T cells","volume":"75","author":"Wedemeyer","year":"2001","journal-title":"J. Virol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"5464","DOI":"10.1128\/JVI.77.9.5464-5474.2003","article-title":"Human papillomavirus type 16 E7 peptide-directed CD8+ T cells from patients with cervical cancer are cross-reactive with the coronavirus NS2 protein","volume":"77","author":"Nilges","year":"2003","journal-title":"J. Virol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3602","DOI":"10.1172\/JCI25078","article-title":"Cross-reactive influenza virus-specific CD8+ T cells contribute to lymphoproliferation in Epstein-Barr virus-associated infectious mononucleosis","volume":"115","author":"Clute","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"6753","DOI":"10.4049\/jimmunol.1000812","article-title":"Broad cross-reactive TCR repertoires recognizing dissimilar Epstein-Barr and influenza A virus epitopes","volume":"185","author":"Clute","year":"2010","journal-title":"J. Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1128\/JVI.73.1.398-403.1999","article-title":"Analysis of murine CD8(+) T-cell clones specific for the Dengue virus NS3 protein: Flavivirus cross-reactivity and influence of infecting serotype","volume":"73","author":"Spaulding","year":"1999","journal-title":"J. Virol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"4440","DOI":"10.1073\/pnas.1603106113","article-title":"Molecular basis for universal HLA-A*0201-restricted CD8+ T-cell immunity against influenza viruses","volume":"113","author":"Valkenburg","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"4061","DOI":"10.4049\/jimmunol.1301403","article-title":"The influenza virus-specific CTL immunodominance hierarchy in mice is determined by the relative frequency of high-avidity T cells","volume":"192","author":"Cukalac","year":"2014","journal-title":"J. Immunol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1038\/nri3905","article-title":"Sizing up the key determinants of the CD8(+) T cell response","volume":"15","author":"Tscharke","year":"2015","journal-title":"Nat. Rev. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"4212","DOI":"10.1128\/JVI.76.9.4212-4221.2002","article-title":"Induction of long-term memory CD8(+) T cells for recall of viral clearing responses against influenza virus","volume":"76","author":"Deliyannis","year":"2002","journal-title":"J. Virol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1038\/nm.2612","article-title":"Preexisting influenza-specific CD4+ T cells correlate with disease protection against influenza challenge in humans","volume":"18","author":"Wilkinson","year":"2012","journal-title":"Nat. Med."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Wagar, L.E., Rosella, L., Crowcroft, N., Lowcock, B., Drohomyrecky, P.C., Foisy, J., Gubbay, J., Rebbapragada, A., Winter, A.L., and Achonu, C. (2011). Humoral and cell-mediated immunity to pandemic H1N1 influenza in a Canadian cohort one year post-pandemic: Implications for vaccination. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0028063"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1038\/nm917","article-title":"Duration of antiviral immunity after smallpox vaccination","volume":"9","author":"Hammarlund","year":"2003","journal-title":"Nat. Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1093\/infdis\/jiv018","article-title":"Human influenza A virus-specific CD8+ T cell response is long-lived","volume":"212","author":"Hillaire","year":"2015","journal-title":"J. Infect. Dis."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.4049\/jimmunol.178.2.1030","article-title":"Priming with cold-adapted influenza A does not prevent infection but elicits long-lived protection against supralethal challenge with heterosubtypic virus","volume":"178","author":"Powell","year":"2007","journal-title":"J. Immunol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.ijid.2014.05.016","article-title":"T-cell-mediated cross-strain protective immunity elicited by prime-boost vaccination with a live attenuated influenza Vaccine","volume":"27","author":"Li","year":"2014","journal-title":"Int. J. Infect. Dis."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3854","DOI":"10.4049\/jimmunol.1202790","article-title":"Cutting edge: Rapid boosting of cross-reactive memory CD8 T cells broadens the protective capacity of the Flumist Vaccine","volume":"190","author":"Slutter","year":"2013","journal-title":"J. Immunol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1097\/01.inf.0000237829.66310.85","article-title":"Superior relative efficacy of live attenuated influenza Vaccine compared with inactivated influenza Vaccine in young children with recurrent respiratory tract infections","volume":"25","author":"Ashkenazi","year":"2006","journal-title":"Pediatr. Infect. Dis. J."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1056\/NEJMoa065368","article-title":"Live attenuated versus inactivated influenza Vaccine in infants and young children","volume":"356","author":"Belshe","year":"2007","journal-title":"N. Engl. J. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.0300-9475.2004.01382.x","article-title":"Influenza virus: Immunity and vaccination strategies. Comparison of the immune response to inactivated and live, attenuated influenza Vaccines","volume":"59","author":"Cox","year":"2004","journal-title":"Scand. J. Immunol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1093\/infdis\/jir436","article-title":"Live and inactivated influenza Vaccines induce similar humoral responses, but only live Vaccines induce diverse T-cell responses in young children","volume":"204","author":"Hoft","year":"2011","journal-title":"J. Infect. Dis."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1527","DOI":"10.1093\/infdis\/jix165","article-title":"Boosting of Cross-Reactive and Protection-Associated T Cells in Children After Live Attenuated Influenza Vaccination","volume":"215","author":"Mohn","year":"2017","journal-title":"J. Infect. Dis."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1111\/j.1365-2567.2007.02608.x","article-title":"Live-attenuated influenza viruses as delivery vectors for Chlamydia Vaccines","volume":"122","author":"He","year":"2007","journal-title":"Immunology"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2913","DOI":"10.1002\/eji.201242504","article-title":"Predominance of heterosubtypic IFN-gamma-only-secreting effector memory T cells in pandemic H1N1 naive adults","volume":"42","author":"Sridhar","year":"2012","journal-title":"Eur. J. Immunol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"11756","DOI":"10.1128\/JVI.01460-06","article-title":"Cellular immune responses in children and adults receiving inactivated or live attenuated influenza Vaccines","volume":"80","author":"He","year":"2006","journal-title":"J. Virol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1002\/(SICI)1096-9071(199610)50:2<105::AID-JMV1>3.0.CO;2-E","article-title":"Cytotoxic T lymphocyte responses of infants after natural infection or immunization with live cold-recombinant or inactivated influenza A virus Vaccine","volume":"50","author":"Mbawuike","year":"1996","journal-title":"J. Med. Virol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"623","DOI":"10.4049\/jimmunol.1203483","article-title":"Longitudinal and integrative biomodeling of effector and memory immune compartments after inactivated influenza vaccination","volume":"191","author":"Bonduelle","year":"2013","journal-title":"J. Immunol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/j.humimm.2011.03.001","article-title":"Comparison of antibody and T-cell responses elicited by licensed inactivated- and live-attenuated influenza Vaccines against H3N2 hemagglutinin","volume":"72","author":"Basha","year":"2011","journal-title":"Hum. Immunol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1541","DOI":"10.1093\/infdis\/jiu654","article-title":"Longevity of B-cell and T-cell responses after live attenuated influenza vaccination in children","volume":"211","author":"Mohn","year":"2015","journal-title":"J. Infect. Dis."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"6691","DOI":"10.1016\/j.vaccine.2017.10.018","article-title":"The M2 protein of live, attenuated influenza Vaccine encodes a mutation that reduces replication in human nasal epithelial cells","volume":"35","author":"Wohlgemuth","year":"2017","journal-title":"Vaccine"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1959","DOI":"10.1128\/JVI.80.4.1959-1964.2006","article-title":"Protection of mice and poultry from lethal H5N1 avian influenza virus through adenovirus-based immunization","volume":"80","author":"Gao","year":"2006","journal-title":"J. Virol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/cid\/ciq015","article-title":"Potent CD8+ T-cell immunogenicity in humans of a novel heterosubtypic influenza A Vaccine, MVA-NP+M1","volume":"52","author":"Berthoud","year":"2011","journal-title":"Clin. Infect. Dis."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/icb.2015.71","article-title":"Reducing the impact of influenza-associated secondary pneumococcal infections","volume":"94","author":"Mifsud","year":"2016","journal-title":"Immunol. Cell Biol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"6976","DOI":"10.1128\/JVI.00339-16","article-title":"Effects of MF59 Adjuvant on Induction of Isotype-Switched IgG Antibodies and Protection after Immunization with T-Dependent Influenza Virus Vaccine in the Absence of CD4+ T Cells","volume":"90","author":"Ko","year":"2016","journal-title":"J. Virol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"10762","DOI":"10.1128\/JVI.01443-15","article-title":"Generation of Live Attenuated Influenza Virus by Using Codon Usage Bias","volume":"89","author":"Fan","year":"2015","journal-title":"J. Virol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1742","DOI":"10.1128\/JVI.01920-08","article-title":"Live attenuated influenza viruses containing NS1 truncations as Vaccine candidates against H5N1 highly pathogenic avian influenza","volume":"83","author":"Steel","year":"2009","journal-title":"J. Virol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"e01487-15","DOI":"10.1128\/mBio.01487-15","article-title":"Nonreplicating influenza A virus Vaccines confer broad protection against lethal challenge","volume":"6","author":"Baz","year":"2015","journal-title":"MBio"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Laidlaw, B.J., Decman, V., Ali, M.A., Abt, M.C., Wolf, A.I., Monticelli, L.A., Mozdzanowska, K., Angelosanto, J.M., Artis, D., and Erikson, J. (2013). Cooperativity between CD8+ T cells, non-neutralizing antibodies, and alveolar macrophages is important for heterosubtypic influenza virus immunity. PLoS Pathog., 9.","DOI":"10.1371\/journal.ppat.1003207"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1042","DOI":"10.1128\/CVI.00397-07","article-title":"Correlation of cellular immune responses with protection against culture-confirmed influenza virus in young children","volume":"15","author":"Forrest","year":"2008","journal-title":"Clin. Vaccine Immunol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"10133","DOI":"10.1073\/pnas.1610750113","article-title":"Human mucosal-associated invariant T cells contribute to antiviral influenza immunity via IL-18-dependent activation","volume":"113","author":"Loh","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Spitaels, J., Roose, K., and Saelens, X. (2016). Influenza and Memory T Cells: How to Awake the Force. Vaccines, 4.","DOI":"10.3390\/vaccines4040033"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"10","DOI":"10.3389\/fimmu.2016.00010","article-title":"The Role of CD4 T Cell Memory in Generating Protective Immunity to Novel and Potentially Pandemic Strains of Influenza","volume":"7","author":"DiPiazza","year":"2016","journal-title":"Front. Immunol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"9762","DOI":"10.1128\/JVI.74.20.9762-9765.2000","article-title":"Diminished primary and secondary influenza virus-specific CD8(+) T-cell responses in CD4-depleted Ig(-\/-) mice","volume":"74","author":"Riberdy","year":"2000","journal-title":"J. Virol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"12388","DOI":"10.1128\/JVI.76.23.12388-12393.2002","article-title":"Compromised influenza virus-specific CD8(+)-T-cell memory in CD4(+)-T-cell-deficient mice","volume":"76","author":"Belz","year":"2002","journal-title":"J. Virol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1146\/annurev-immunol-032712-095916","article-title":"Broadly neutralizing antiviral antibodies","volume":"31","author":"Corti","year":"2013","journal-title":"Annu. Rev. Immunol."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Koutsakos, M., Wheatley, A.K., Loh, L., Clemens, E.B., Sant, S., Nussing, S., Fox, A., Chung, A.W., Laurie, K.L., and Hurt, A.C. (2018). Circulating TFH cells, serological memory, and tissue compartmentalization shape human influenza-specific B cell immunity. Sci. Transl. Med., 10.","DOI":"10.1126\/scitranslmed.aan8405"},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Alam, S., Chan, C., Qiu, X., Shannon, I., White, C.L., Sant, A.J., and Nayak, J.L. (2017). Selective pre-priming of HA-specific CD4 T cells restores immunological reactivity to HA on heterosubtypic influenza infection. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0176407"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1093\/infdis\/jiu662","article-title":"Seasonal Influenza Can Poise Hosts for CD4 T-Cell Immunity to H7N9 Avian Influenza","volume":"212","author":"Richards","year":"2015","journal-title":"J. Infect. Dis."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.1093\/infdis\/jiu616","article-title":"Effect of influenza A(H5N1) Vaccine prepandemic priming on CD4+ T-cell responses","volume":"211","author":"Nayak","year":"2015","journal-title":"J. Infect. Dis."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1126\/science.aag1322","article-title":"Potent protection against H5N1 and H7N9 influenza via childhood hemagglutinin imprinting","volume":"354","author":"Gostic","year":"2016","journal-title":"Science"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"2888","DOI":"10.4049\/jimmunol.177.5.2888","article-title":"CD4 T cell-mediated protection from lethal influenza: Perforin and antibody-mediated mechanisms give a one-two punch","volume":"177","author":"Brown","year":"2006","journal-title":"J. Immunol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"2175","DOI":"10.1056\/NEJMoa0911530","article-title":"Comparative epidemiology of pandemic and seasonal influenza A in households","volume":"362","author":"Cowling","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1086\/498980","article-title":"Prior H1N1 influenza infection and susceptibility of Cleveland Family Study participants during the H2N2 pandemic of 1957: An experiment of nature","volume":"193","author":"Epstein","year":"2006","journal-title":"J. Infect. Dis."},{"key":"ref_92","first-page":"297","article-title":"The effect of a previous attack of A1 influenza on susceptibility to A2 virus during the 1957 outbreak","volume":"20","author":"Slepushkin","year":"1959","journal-title":"Bull. World Health Organ."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1164\/rccm.201309-1616OC","article-title":"Mucosal immune responses predict clinical outcomes during influenza infection independently of age and viral load","volume":"189","author":"Oshansky","year":"2014","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1038\/nm.3350","article-title":"Cellular immune correlates of protection against symptomatic pandemic influenza","volume":"19","author":"Sridhar","year":"2013","journal-title":"Nat. Med."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1422","DOI":"10.1164\/rccm.201411-1988OC","article-title":"Natural T Cell-mediated Protection against Seasonal and Pandemic Influenza. Results of the Flu Watch Cohort Study","volume":"191","author":"Hayward","year":"2015","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Fox, A., Le, N.M., Horby, P., van Doorn, H.R., Nguyen, V.T., Nguyen, H.H., Nguyen, T.C., Vu, D.P., Nguyen, M.H., and Diep, N.T. (2012). Severe pandemic H1N1 2009 infection is associated with transient NK and T deficiency and aberrant CD8 responses. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0031535"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1093\/infdis\/jix571","article-title":"Severe influenza is characterized by prolonged immune activation: Results from the SHIVERS cohort study","volume":"217","author":"Wong","year":"2017","journal-title":"J. Infect. Dis."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1292","DOI":"10.1164\/rccm.201207-1245OC","article-title":"High levels of virus-specific CD4+ T cells predict severe pandemic influenza A virus infection","volume":"186","author":"Zhao","year":"2012","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1056\/NEJM198307073090103","article-title":"Cytotoxic T-cell immunity to influenza","volume":"309","author":"McMichael","year":"1983","journal-title":"N. Engl. J. Med."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Diao, H., Cui, G., Wei, Y., Chen, J., Zuo, J., Cao, H., Chen, Y., Yao, H., Tian, Z., and Li, L. (2014). Severe H7N9 infection is associated with decreased antigen-presenting capacity of CD14+ cells. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0092823"},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Davey, R.T., Lynfield, R., Dwyer, D.E., Losso, M.H., Cozzi-Lepri, A., Wentworth, D., Lane, H.C., Dewar, R., Rupert, A., and Metcalf, J.A. (2013). The association between serum biomarkers and disease outcome in influenza A(H1N1)pdm09 virus infection: Results of two international observational cohort studies. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0057121"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.3389\/fimmu.2017.01423","article-title":"Cytokine Profiles of Severe Influenza Virus-Related Complications in Children","volume":"8","author":"Agan","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1016\/j.immuni.2013.09.013","article-title":"Lung airway-surveilling CXCR3(hi) memory CD8(+) T cells are critical for protection against influenza A virus","volume":"39","author":"Slutter","year":"2013","journal-title":"Immunity"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"25","DOI":"10.3389\/fimmu.2016.00025","article-title":"Balancing Immune Protection and Immune Pathology by CD8(+) T-Cell Responses to Influenza Infection","volume":"7","author":"Duan","year":"2016","journal-title":"Front. Immunol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1165\/rcmb.2016-0377OC","article-title":"Human CD8+ T Cells Damage Noninfected Epithelial Cells during Influenza Virus Infection In Vitro","volume":"57","author":"Barcena","year":"2017","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Mohn, K.G., Cox, R.J., Tunheim, G., Berdal, J.E., Hauge, A.G., Jul-Larsen, A., Norwegian Pandemic, G., Peters, B., Oftung, F., and Jonassen, C.M. (2015). Immune Responses in Acute and Convalescent Patients with Mild, Moderate and Severe Disease during the 2009 Influenza Pandemic in Norway. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0143281"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"237","DOI":"10.3851\/IMP1722","article-title":"Viral clearance and inflammatory response patterns in adults hospitalized for pandemic 2009 influenza A(H1N1) virus pneumonia","volume":"16","author":"Lee","year":"2011","journal-title":"Antivir. Ther."},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Yang, Z.F., Mok, C.K., Liu, X.Q., Li, X.B., He, J.F., Guan, W.D., Xu, Y.H., Pan, W.Q., Chen, L.Y., and Lin, Y.P. (2015). Clinical, virological and immunological features from patients infected with re-emergent avian-origin human H7N9 influenza disease of varying severity in Guangdong province. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0117846"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1073\/pnas.1321748111","article-title":"Early hypercytokinemia is associated with interferon-induced transmembrane protein-3 dysfunction and predictive of fatal H7N9 infection","volume":"111","author":"Wang","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1718","DOI":"10.1086\/517612","article-title":"Characterization of CD4+ memory T cell responses directed against common respiratory pathogens in peripheral blood and lung","volume":"195","author":"Daniels","year":"2007","journal-title":"J. Infect. Dis."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"44727","DOI":"10.1038\/srep44727","article-title":"The immune correlates of protection for an avian influenza H5N1 Vaccine in the ferret model using oil-in-water adjuvants","volume":"7","author":"Wong","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1016\/j.immuni.2014.12.007","article-title":"Tissue-resident memory T cells","volume":"41","author":"Schenkel","year":"2014","journal-title":"Immunity"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.1084\/jem.20051365","article-title":"Selective accumulation of differentiated CD8+ T cells specific for respiratory viruses in the human lung","volume":"202","author":"Out","year":"2005","journal-title":"J. Exp. Med."},{"key":"ref_114","doi-asserted-by":"crossref","unstructured":"Purwar, R., Campbell, J., Murphy, G., Richards, W.G., Clark, R.A., and Kupper, T.S. (2011). Resident memory T cells (T(RM)) are abundant in human lung: Diversity, function, and antigen specificity. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0016245"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1016\/j.cell.2015.03.031","article-title":"Quantifying Memory CD8 T Cells Reveals Regionalization of Immunosurveillance","volume":"161","author":"Steinert","year":"2015","journal-title":"Cell"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1038\/nri.2015.3","article-title":"Tissue-resident memory T cells: Local specialists in immune defence","volume":"16","author":"Mueller","year":"2016","journal-title":"Nat. Rev. Immunol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1038\/ni.1718","article-title":"Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus","volume":"10","author":"Gebhardt","year":"2009","journal-title":"Nat. Immunol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"7037","DOI":"10.1073\/pnas.1202288109","article-title":"Long-lived epithelial immunity by tissue-resident memory T (TRM) cells in the absence of persisting local antigen presentation","volume":"109","author":"Mackay","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1126\/science.1254803","article-title":"T cell memory. Skin-resident memory CD8(+) T cells trigger a state of tissue-wide pathogen alert","volume":"346","author":"Ariotti","year":"2014","journal-title":"Science"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1038\/ni.2568","article-title":"Sensing and alarm function of resident memory CD8(+) T cells","volume":"14","author":"Schenkel","year":"2013","journal-title":"Nat. Immunol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"5510","DOI":"10.4049\/jimmunol.1102243","article-title":"Cutting edge: Tissue-retentive lung memory CD4 T cells mediate optimal protection to respiratory virus infection","volume":"187","author":"Teijaro","year":"2011","journal-title":"J. Immunol."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1038\/mi.2013.67","article-title":"Lung niches for the generation and maintenance of tissue-resident memory T cells","volume":"7","author":"Turner","year":"2013","journal-title":"Mucosal Immunol."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.1038\/ni.3589","article-title":"Programs for the persistence, vigilance and control of human CD8(+) lung-resident memory T cells","volume":"17","author":"Hombrink","year":"2016","journal-title":"Nat. Immunol."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1189\/jlb.0313180","article-title":"Lung-resident memory CD8 T cells (TRM) are indispensable for optimal cross-protection against pulmonary virus infection","volume":"95","author":"Wu","year":"2014","journal-title":"J. Leukoc. Biol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"4085","DOI":"10.1128\/JVI.02493-10","article-title":"Environmental and antigen receptor-derived signals support sustained surveillance of the lungs by pathogen-specific cytotoxic T lymphocytes","volume":"85","author":"Lee","year":"2011","journal-title":"J. Virol."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"2254","DOI":"10.1172\/JCI44675","article-title":"CD8(+) T cells with an intraepithelial phenotype upregulate cytotoxic function upon influenza infection in human lung","volume":"121","author":"Piet","year":"2011","journal-title":"J. Clin. Investig."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.immuni.2012.09.020","article-title":"Distribution and compartmentalization of human circulating and tissue-resident memory T cell subsets","volume":"38","author":"Sathaliyawala","year":"2013","journal-title":"Immunity"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1172\/JCI96957","article-title":"Influenza-specific lung-resident memory T cells are proliferative and polyfunctional and maintain diverse TCR profiles","volume":"128","author":"Pizzolla","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_129","doi-asserted-by":"crossref","unstructured":"Oja, A.E., Piet, B., Helbig, C., Stark, R., van der Zwan, D., Blaauwgeers, H., Remmerswaal, E.B.M., Amsen, D., Jonkers, R.E., and Moerland, P.D. (2017). Trigger-happy resident memory CD4(+) T cells inhabit the human lungs. Mucosal Immunol.","DOI":"10.1038\/mi.2017.94"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1016\/j.immuni.2015.11.008","article-title":"T-box Transcription Factors Combine with the Cytokines TGF-beta and IL-15 to Control Tissue-Resident Memory T Cell Fate","volume":"43","author":"Mackay","year":"2015","journal-title":"Immunity"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1038\/mi.2014.133","article-title":"Antibody-targeted vaccination to lung dendritic cells generates tissue-resident memory CD8 T cells that are highly protective against influenza virus infection","volume":"8","author":"Wakim","year":"2015","journal-title":"Mucosal Immunol."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1016\/j.immuni.2013.08.019","article-title":"Transforming Growth Factor-beta Signaling Controls the Formation and Maintenance of Gut-Resident Memory T Cells by Regulating Migration and Retention","volume":"39","author":"Zhang","year":"2013","journal-title":"Immunity"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1038\/ni.2745","article-title":"Transcriptional downregulation of S1pr1 is required for the establishment of resident memory CD8+ T cells","volume":"14","author":"Skon","year":"2013","journal-title":"Nat. Immunol."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1126\/science.aad2035","article-title":"Hobit and Blimp1 instruct a universal transcriptional program of tissue residency in lymphocytes","volume":"352","author":"Mackay","year":"2016","journal-title":"Science"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"3057","DOI":"10.1084\/jem.20160938","article-title":"Specific niches for lung-resident memory CD8+ T cells at the site of tissue regeneration enable CD69-independent maintenance","volume":"213","author":"Takamura","year":"2016","journal-title":"J. Exp. Med."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1038\/ni.2525","article-title":"Enhanced survival of lung tissue-resident memory CD8(+) T cells during infection with influenza virus due to selective expression of IFITM3","volume":"14","author":"Wakim","year":"2013","journal-title":"Nat. Immunol."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"17872","DOI":"10.1073\/pnas.1010201107","article-title":"Memory T cells persisting within the brain after local infection show functional adaptations to their tissue of residence","volume":"107","author":"Wakim","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1038\/nature11522","article-title":"A Vaccine strategy that protects against genital herpes by establishing local memory T cells","volume":"491","author":"Shin","year":"2012","journal-title":"Nature"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"1800","DOI":"10.1016\/j.celrep.2016.07.037","article-title":"A Distinct Lung-Interstitium-Resident Memory CD8(+) T Cell Subset Confers Enhanced Protection to Lower Respiratory Tract Infection","volume":"16","author":"Gilchuk","year":"2016","journal-title":"Cell Rep."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1002\/eji.200535217","article-title":"Intranasal lipopeptide primes lung-resident memory CD8+ T cells for long-term pulmonary protection against influenza","volume":"36","author":"Deliyannis","year":"2006","journal-title":"Eur. J. Immunol."},{"key":"ref_141","doi-asserted-by":"crossref","unstructured":"Gasper, D.J., Neldner, B., Plisch, E.H., Rustom, H., Carrow, E., Imai, H., Kawaoka, Y., and Suresh, M. (2016). Effective Respiratory CD8 T-Cell Immunity to Influenza Virus Induced by Intranasal Carbomer-Lecithin-Adjuvanted Non-replicating Vaccines. PLoS Pathog., 12.","DOI":"10.1371\/journal.ppat.1006064"},{"key":"ref_142","doi-asserted-by":"crossref","unstructured":"Pizzolla, A., Nguyen, T.H.O., Smith, J.M., Brooks, A.G., Kedzieska, K., Heath, W.R., Reading, P.C., and Wakim, L.M. (2017). Resident memory CD8+ T cells in the upper respiratory tract prevent pulmonary influenza virus infection. Sci. Immunol., 2.","DOI":"10.1126\/sciimmunol.aam6970"},{"key":"ref_143","doi-asserted-by":"crossref","unstructured":"Zens, K.D., Chen, J.K., and Farber, D.L. (2016). Vaccine-generated lung tissue-resident memory T cells provide heterosubtypic protection to influenza infection. JCI Insight, 1.","DOI":"10.1172\/jci.insight.85832"},{"key":"ref_144","doi-asserted-by":"crossref","unstructured":"Slutter, B., Van Braeckel-Budimir, N., Abboud, G., Varga, S.M., Salek-Ardakani, S., and Harty, J.T. (2017). Dynamics of influenza-induced lung-resident memory T cells underlie waning heterosubtypic immunity. Sci. Immunol., 2.","DOI":"10.1126\/sciimmunol.aag2031"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1038\/nature24633","article-title":"Origin and differentiation of human memory CD8 T cells after vaccination","volume":"552","author":"Akondy","year":"2017","journal-title":"Nature"},{"key":"ref_146","unstructured":"IPD-IMGT\/HLA (2017, December 22). IMGT\/HLA Statistics. Available online: https:\/\/www.ebi.ac.uk\/ipd\/imgt\/hla\/stats.html."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"6319","DOI":"10.4049\/jimmunol.1000883","article-title":"Effect of MHC class I diversification on influenza epitope-specific CD8+ T cell precursor frequency and subsequent effector function","volume":"186","author":"Day","year":"2011","journal-title":"J. Immunol."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"2151","DOI":"10.1073\/pnas.1423482112","article-title":"Physical detection of influenza A epitopes identifies a stealth subset on human lung epithelium evading natural CD8 immunity","volume":"112","author":"Keskin","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1073\/pnas.0811271106","article-title":"HLA class I molecules consistently present internal influenza epitopes","volume":"106","author":"Wahl","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_150","unstructured":"NCBI (2017, December 22). dbMHC Anthropology, Available online: https:\/\/www.ncbi.nlm.nih.gov\/gv\/mhc\/ihwg.cgi?cmd=page&page=AnthroMain."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"13492","DOI":"10.1073\/pnas.1221555110","article-title":"HLA targeting efficiency correlates with human T-cell response magnitude and with mortality from influenza A infection","volume":"110","author":"Hertz","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"D784","DOI":"10.1093\/nar\/gku1166","article-title":"Allele frequency net 2015 update: New features for HLA epitopes, KIR and disease and HLA adverse drug reaction associations","volume":"43","author":"Takeshita","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1038\/icb.2015.93","article-title":"Towards identification of immune and genetic correlates of severe influenza disease in Indigenous Australians","volume":"94","author":"Clemens","year":"2016","journal-title":"Immunol. Cell Biol."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/S0198-8859(98)00009-3","article-title":"HLA-A*24-B*07-DRB1*01 haplotype implicated with genetic disposition of peak bone mass in healthy young Japanese women","volume":"59","author":"Tsuji","year":"1998","journal-title":"Hum. Immunol."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1136\/jmg.2009.066647","article-title":"The effect of the MHC locus on autoantibodies in type 1 diabetes","volume":"46","author":"Qu","year":"2009","journal-title":"J. Med. Genet."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1038\/nrendo.2011.183","article-title":"The worldwide epidemiology of type 2 diabetes mellitus\u2014Present and future perspectives","volume":"8","author":"Chen","year":"2011","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1146\/annurev.med.54.101601.152346","article-title":"The influence of HLA genotype on AIDS","volume":"54","author":"Carrington","year":"2003","journal-title":"Annu. Rev. Med."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1038\/nature03113","article-title":"Dominant influence of HLA-B in mediating the potential co-evolution of HIV and HLA","volume":"432","author":"Kiepiela","year":"2004","journal-title":"Nature"},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1002\/hep.21049","article-title":"Dominant influence of an HLA-B27 restricted CD8+ T cell response in mediating HCV clearance and evolution","volume":"43","author":"McKiernan","year":"2006","journal-title":"Hepatology"},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1016\/j.immuni.2012.09.005","article-title":"HIV and HLA class I: An evolving relationship","volume":"37","author":"Goulder","year":"2012","journal-title":"Immunity"},{"key":"ref_161","unstructured":"Centers for Disease Control and Prevention (2009). Deaths related to 2009 pandemic influenza A (H1N1) among American Indian\/Alaska Natives\u201412 States, 2009. MMWR, 58, 1341\u20131344."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"617","DOI":"10.5694\/j.1326-5377.2010.tb03654.x","article-title":"Disproportionate impact of pandemic (H1N1) 2009 influenza on Indigenous people in the Top End of Australia\u2019s Northern Territory","volume":"192","author":"Flint","year":"2010","journal-title":"Med. J. Aust."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"1925","DOI":"10.1056\/NEJMoa0908481","article-title":"Critical care services and 2009 H1N1 influenza in Australia and New Zealand","volume":"361","author":"Investigators","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"1872","DOI":"10.1001\/jama.2009.1496","article-title":"Critically ill patients with 2009 influenza A(H1N1) infection in Canada","volume":"302","author":"Kumar","year":"2009","journal-title":"JAMA"},{"key":"ref_165","first-page":"19366","article-title":"The 2009 pandemic H1N1 influenza and indigenous populations of the Americas and the Pacific","volume":"14","author":"Tarantola","year":"2009","journal-title":"EuroSurveillance"},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1038\/nm1592","article-title":"Multifunctional TH1 cells define a correlate of Vaccine-mediated protection against Leishmania major","volume":"13","author":"Darrah","year":"2007","journal-title":"Nat. Med."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"4102","DOI":"10.1128\/JVI.02212-07","article-title":"Virological outcome after structured interruption of antiretroviral therapy for human immunodeficiency virus infection is associated with the functional profile of virus-specific CD8+ T cells","volume":"82","author":"Daucher","year":"2008","journal-title":"J. Virol."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"16233","DOI":"10.1073\/pnas.0707570104","article-title":"Skewed association of polyfunctional antigen-specific CD8 T cell populations with HLA-B genotype","volume":"104","author":"Harari","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1128\/JVI.76.2.582-590.2002","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","volume":"76","author":"Boon","year":"2002","journal-title":"J. Virol."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1084\/jem.182.6.1703","article-title":"T cell receptor repertoire for a viral epitope in humans is diversified by tolerance to a background major histocompatibility complex antigen","volume":"182","author":"Burrows","year":"1995","journal-title":"J. Exp. Med."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"1675","DOI":"10.1084\/jem.178.5.1675","article-title":"Determinant capture as a possible mechanism of protection afforded by major histocompatibility complex class II molecules in autoimmune disease","volume":"178","author":"Deng","year":"1993","journal-title":"J. Exp. Med."},{"key":"ref_172","first-page":"225","article-title":"Quantitative variation in H-2-antigen expression. I. Estimation of H-2K and H-2D expression in different strains of mice","volume":"11","author":"McKenzie","year":"1980","journal-title":"Immunogenetics"},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"1999","DOI":"10.1002\/eji.1830230841","article-title":"An antigen processing polymorphism revealed by HLA-B8-restricted cytotoxic T lymphocytes which does not correlate with TAP gene polymorphism","volume":"23","author":"Powis","year":"1993","journal-title":"Eur. J. Immunol."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"5615","DOI":"10.4049\/jimmunol.169.10.5615","article-title":"Competition between MHC class I alleles for cell surface expression alters CTL responses to influenza A virus","volume":"169","author":"Tourdot","year":"2002","journal-title":"J. Immunol."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/1074-7613(95)90159-0","article-title":"Different MHC class I alleles compete for presentation of overlapping viral epitopes","volume":"3","author":"Tussey","year":"1995","journal-title":"Immunity"},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"5570","DOI":"10.1073\/pnas.1302935110","article-title":"Preemptive priming readily overcomes structure-based mechanisms of virus escape","volume":"110","author":"Valkenburg","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_177","first-page":"1009","article-title":"Differential Recognition of Influenza A Viruses by M158-66 Epitope-Specific CD8+ T Cells Is Determined by Extraepitopic Amino Acid Residues","volume":"90","author":"Kreijtz","year":"2015","journal-title":"J. Virol."},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"1438","DOI":"10.3390\/v4091438","article-title":"Evasion of influenza A viruses from innate and adaptive immune responses","volume":"4","author":"Kreijtz","year":"2012","journal-title":"Viruses"},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"6800","DOI":"10.1128\/JVI.74.15.6800-6807.2000","article-title":"Antigenic drift in the influenza A virus (H3N2) nucleoprotein and escape from recognition by cytotoxic T lymphocytes","volume":"74","author":"Voeten","year":"2000","journal-title":"J. Virol."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"2663","DOI":"10.1038\/ncomms3663","article-title":"Acute emergence and reversion of influenza A virus quasispecies within CD8+ T cell antigenic peptides","volume":"4","author":"Valkenburg","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"5216","DOI":"10.1128\/JVI.78.10.5216-5222.2004","article-title":"A mutation in the HLA-B*2705-restricted NP383-391 epitope affects the human influenza A virus-specific cytotoxic T-lymphocyte response in vitro","volume":"78","author":"Berkhoff","year":"2004","journal-title":"J. Virol."},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1099\/vir.0.82120-0","article-title":"Assessment of the extent of variation in influenza A virus cytotoxic T-lymphocyte epitopes by using virus-specific CD8+ T-cell clones","volume":"88","author":"Berkhoff","year":"2007","journal-title":"J. Gen. Virol."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"1853","DOI":"10.1084\/jem.191.11.1853","article-title":"Viral escape by selection of cytotoxic T cell-resistant variants in influenza A virus pneumonia","volume":"191","author":"Price","year":"2000","journal-title":"J. Exp. Med."},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.virusres.2004.02.020","article-title":"Sequence variation in the influenza A virus nucleoprotein associated with escape from cytotoxic T lymphocytes","volume":"103","author":"Rimmelzwaan","year":"2004","journal-title":"Virus Res."},{"key":"ref_185","doi-asserted-by":"crossref","unstructured":"Valkenburg, S.A., Gras, S., Guillonneau, C., La Gruta, N.L., Thomas, P.G., Purcell, A.W., Rossjohn, J., Doherty, P.C., Turner, S.J., and Kedzierska, K. (2010). Protective efficacy of cross-reactive CD8+ T cells recognising mutant viral epitopes depends on peptide-MHC-I structural interactions and T cell activation threshold. PLoS Pathog., 6.","DOI":"10.1371\/journal.ppat.1001039"},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"12599","DOI":"10.1073\/pnas.1007270107","article-title":"Cross-reactive CD8+ T-cell immunity between the pandemic H1N1-2009 and H1N1-1918 influenza A viruses","volume":"107","author":"Gras","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1111\/j.1365-2249.2007.03340.x","article-title":"The loss of immunodominant epitopes affects interferon-gamma production and lytic activity of the human influenza virus-specific cytotoxic T lymphocyte response in vitro","volume":"148","author":"Berkhoff","year":"2007","journal-title":"Clin. Exp. Immunol."},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"11239","DOI":"10.1128\/JVI.79.17.11239-11246.2005","article-title":"Functional constraints of influenza A virus epitopes limit escape from cytotoxic T lymphocytes","volume":"79","author":"Berkhoff","year":"2005","journal-title":"J. Virol."},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"9206","DOI":"10.1128\/JVI.00932-09","article-title":"T-cell tolerance for variability in an HLA class I-presented influenza A virus epitope","volume":"83","author":"Wahl","year":"2009","journal-title":"J. Virol."},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"316","DOI":"10.2174\/1874285801711010316","article-title":"Live Attenuated Reassortant Vaccines Based on A\/Leningrad\/134\/17\/57 Master Donor Virus Against H5 Avian Influenza","volume":"11","author":"Kiseleva","year":"2017","journal-title":"Open Microbiol. J."},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"3239","DOI":"10.1084\/jem.20162123","article-title":"Role of HIV-specific CD8+ T cells in pediatric HIV cure strategies after widespread early viral escape","volume":"214","author":"Leitman","year":"2017","journal-title":"J. Exp. Med."},{"key":"ref_192","doi-asserted-by":"crossref","first-page":"1188","DOI":"10.1038\/ni1530","article-title":"Protective immunity and susceptibility to infectious diseases: Lessons from the 1918 influenza pandemic","volume":"8","author":"Ahmed","year":"2007","journal-title":"Nat. Immunol."},{"key":"ref_193","unstructured":"WHO (2017, November 20). WHO Recommendations on the Composition of Influenza Virus Vaccines. Available online: http:\/\/www.who.int\/influenza\/Vaccines\/virus\/recommendations\/en\/."},{"key":"ref_194","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1093\/cid\/cis327","article-title":"Preliminary assessment of the efficacy of a T-cell-based influenza Vaccine, MVA-NP+M1, in humans","volume":"55","author":"Lillie","year":"2012","journal-title":"Clin. Infect. Dis."},{"key":"ref_195","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.antiviral.2017.05.009","article-title":"Distinct patterns of cellular immune response elicited by influenza non-adjuvanted and AS03-adjuvanted monovalent H1N1(pdm09) Vaccine","volume":"144","author":"Mourao","year":"2017","journal-title":"Antivir. Res."},{"key":"ref_196","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1586\/erv.11.23","article-title":"MF59 adjuvant: The best insurance against influenza strain diversity","volume":"10","author":"Rappuoli","year":"2011","journal-title":"Expert Rev Vaccines"},{"key":"ref_197","doi-asserted-by":"crossref","unstructured":"Couch, R.B., Bayas, J.M., Caso, C., Mbawuike, I.N., Lopez, C.N., Claeys, C., El Idrissi, M., Herve, C., Laupeze, B., and Oostvogels, L. (2014). Superior antigen-specific CD4+ T-cell response with AS03-adjuvantation of a trivalent influenza Vaccine in a randomised trial of adults aged 65 and older. BMC Infect. Dis., 14.","DOI":"10.1186\/1471-2334-14-425"},{"key":"ref_198","doi-asserted-by":"crossref","first-page":"2048","DOI":"10.1080\/21645515.2017.1337615","article-title":"Cellular immune responses of older adults to four influenza Vaccines: Results of a randomized, controlled comparison","volume":"13","author":"Kumar","year":"2017","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_199","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1080\/14760584.2017.1299576","article-title":"Strategies to induce broadly protective antibody responses to viral glycoproteins","volume":"16","author":"Krammer","year":"2017","journal-title":"Expert Rev. Vaccines"},{"key":"ref_200","doi-asserted-by":"crossref","first-page":"1663","DOI":"10.1172\/JCI41902","article-title":"Heterosubtypic neutralizing antibodies are produced by individuals immunized with a seasonal influenza Vaccine","volume":"120","author":"Corti","year":"2010","journal-title":"J. Clin. Investig."},{"key":"ref_201","doi-asserted-by":"crossref","unstructured":"Bolton, K.J., McCaw, J.M., Brown, L., Jackson, D., Kedzierska, K., and McVernon, J. (2015). Prior population immunity reduces the expected impact of CTL-inducing Vaccines for pandemic influenza control. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0120138"},{"key":"ref_202","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1128\/CVI.00613-15","article-title":"Standardization of Hemagglutination Inhibition Assay for Influenza Serology Allows for High Reproducibility between Laboratories","volume":"23","author":"Zacour","year":"2016","journal-title":"Clin. Vaccines Immunol."},{"key":"ref_203","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1111\/irv.12445","article-title":"Workshop report: Immunoassay standardisation for \u201cuniversal\u201d influenza Vaccines","volume":"11","author":"Pavlova","year":"2017","journal-title":"Influenza Other Respir. Viruses"}],"container-title":["Vaccines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-393X\/6\/2\/18\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T14:58:31Z","timestamp":1760194711000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-393X\/6\/2\/18"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,3,26]]},"references-count":203,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2018,6]]}},"alternative-id":["vaccines6020018"],"URL":"https:\/\/doi.org\/10.3390\/vaccines6020018","relation":{},"ISSN":["2076-393X"],"issn-type":[{"value":"2076-393X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,3,26]]}}}