{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T00:05:09Z","timestamp":1779235509192,"version":"3.51.4"},"reference-count":124,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2017,7,18]],"date-time":"2017-07-18T00:00:00Z","timestamp":1500336000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Recurrent influenza epidemics and occasional pandemics are one of the most important global public health concerns and are major causes of human morbidity and mortality. Influenza viruses can evolve through antigen drift and shift to overcome the barriers of human immunity, leading to host adaption and transmission. Mechanisms underlying this viral evolution are gradually being elucidated. Vaccination is an effective method for the prevention of influenza virus infection. However, the emergence of novel viruses, including the 2009 pandemic influenza A (H1N1), the avian influenza A virus (H7N9), and the highly pathogenic avian influenza A virus (HPAI H5N1), that have infected human populations frequently in recent years reveals the tremendous challenges to the current influenza vaccine strategy. A better vaccine that provides protection against a wide spectrum of various influenza viruses and long-lasting immunity is urgently required. Here, we review the evolutionary changes of several important influenza proteins and the influence of these changes on viral antigenicity, host adaption, and viral pathogenicity. Furthermore, we discuss the development of a potent universal influenza vaccine based on this knowledge.<\/jats:p>","DOI":"10.3390\/ijms18071554","type":"journal-article","created":{"date-parts":[[2017,7,18]],"date-time":"2017-07-18T10:33:14Z","timestamp":1500373994000},"page":"1554","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["From Variation of Influenza Viral Proteins to Vaccine Development"],"prefix":"10.3390","volume":"18","author":[{"given":"Wandi","family":"Zhu","sequence":"first","affiliation":[{"name":"Center for Inflammation, Immunity &amp; Infection, Georgia State University Institute for Biomedical Sciences, Atlanta, GA 30303, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chao","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Inflammation, Immunity &amp; Infection, Georgia State University Institute for Biomedical Sciences, Atlanta, GA 30303, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1561-4318","authenticated-orcid":false,"given":"Bao-Zhong","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Inflammation, Immunity &amp; Infection, Georgia State University Institute for Biomedical Sciences, Atlanta, GA 30303, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2017,7,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e00031-14","DOI":"10.1128\/mBio.00031-14","article-title":"Characterization of a novel influenza virus in cattle and swine: Proposal for a new genus in the orthomyxoviridae family","volume":"5","author":"Hause","year":"2014","journal-title":"mBio"},{"key":"ref_2","unstructured":"Andrew, M.Q., King, E.L., Adams, M.J., and Carstens, E.B. (2012). Virus Taxonomy: Ninth Report of the International Committee on Taxonomy of Viruses, Elsevier."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1016\/j.chom.2010.05.009","article-title":"Influenza virus evolution, host adaptation, and pandemic formation","volume":"7","author":"Taubenberger","year":"2010","journal-title":"Cell Host Microbe"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"5636","DOI":"10.1128\/JVI.03122-15","article-title":"Pathogenesis of influenza D virus in cattle","volume":"90","author":"Ferguson","year":"2016","journal-title":"J. Virol."},{"key":"ref_5","unstructured":"Lambert, T.K.K., and Leedom Larson, K.R. (2017, June 15). Influenza C and influenza D viruses. Available online: http:\/\/www.cfsph.iastate.edu\/pdf\/shic-factsheet-influenza-cd."},{"key":"ref_6","unstructured":"WHO (2017, June 15). Influenza (Seasonal). Fact Sheet. Available online: http:\/\/www.who.int\/mediacentre\/factsheets\/fs211\/en\/."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"556","DOI":"10.3201\/eid1804.110337","article-title":"Influenza-associated hospitalizations by industry, 2009\u201310 influenza season, United States","volume":"18","author":"Luckhaupt","year":"2012","journal-title":"Emerg. Infect. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1001\/jama.289.2.179","article-title":"Mortality associated with influenza and respiratory syncytial virus in the United States","volume":"289","author":"Thompson","year":"2003","journal-title":"JAMA"},{"key":"ref_9","first-page":"117","article-title":"Evaluation of clinical data and antibody response following influenza vaccination in patients with chronic obstructive pulmonary disease","volume":"33","author":"Anar","year":"2010","journal-title":"New Microbiol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Baldo, V., Baldovin, T., Pellegrini, M., Angiolelli, G., Majori, S., Floreani, A., Busana, M.C., Bertoncello, C., and Trivello, R. (2010). Immunogenicity of three different influenza vaccines against homologous and heterologous strains in nursing home elderly residents. Clin. Dev. Immunol.","DOI":"10.1155\/2010\/517198"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1001\/jama.2009.1911","article-title":"Immunogenicity of a monovalent 2009 influenza A(H1N1) vaccine in infants and children: A randomized trial","volume":"303","author":"Nolan","year":"2010","journal-title":"JAMA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"S96","DOI":"10.1016\/j.ajog.2011.03.003","article-title":"Influenza vaccination coverage among pregnant women\u2014National 2009 H1N1 Flu Survey (NHFS)","volume":"204","author":"Ding","year":"2011","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_13","unstructured":"Advisory Committee on Immunization Practices, Smith, N.M., Bresee, J.S., Shay, D.K., Uyeki, T.M., Cox, N.J., and Strikas, R.A. (2006). Prevention and control of influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. Recomm. Rep., 55, 1\u201342."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"187","DOI":"10.20506\/rst.28.1.1879","article-title":"Pandemic influenza\u2014Including a risk assessment of H5N1","volume":"28","author":"Taubenberger","year":"2009","journal-title":"Rev. Sci. Tech."},{"key":"ref_15","unstructured":"WHO\/GIP (2017, June 15). Cumulative Number of Confirmed Human Cases for Avian influenza A(H5N1) Reported to WHO. Available online: http:\/\/www.who.int\/influenza\/human_animal_interface\/H5N1_cumulative_table_archives\/en\/."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5637","DOI":"10.1016\/j.vaccine.2006.10.051","article-title":"An overview of the epidemiology of avian influenza","volume":"25","author":"Alexander","year":"2007","journal-title":"Vaccine"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1356","DOI":"10.1073\/pnas.0308352100","article-title":"Avian influenza A virus (H7N7) associated with human conjunctivitis and a fatal case of acute respiratory distress syndrome","volume":"101","author":"Fouchier","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2196","DOI":"10.3201\/eid1012.040961","article-title":"Human illness from avian influenza H7N3, British Columbia","volume":"10","author":"Tweed","year":"2004","journal-title":"Emerg. Infect. Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"120","DOI":"10.5582\/bst.2017.01040","article-title":"Global concern regarding the fifth epidemic of human infection with avian influenza A (H7N9) virus in China","volume":"11","author":"Shen","year":"2017","journal-title":"Biosci. Trends"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Marshall, N., Priyamvada, L., Ende, Z., Steel, J., and Lowen, A.C. (2013). Influenza virus reassortment occurs with high frequency in the absence of segment mismatch. PLoS Pathog., 9.","DOI":"10.1371\/journal.ppat.1003421"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1111\/nyas.12462","article-title":"Continuing challenges in influenza","volume":"1323","author":"Webster","year":"2014","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"8701","DOI":"10.1073\/pnas.0903427106","article-title":"Differential neutralization efficiency of hemagglutinin epitopes, antibody interference, and the design of influenza vaccines","volume":"106","author":"Ndifon","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"10905","DOI":"10.1128\/JVI.00700-11","article-title":"A broadly neutralizing human monoclonal antibody that recognizes a conserved, novel epitope on the globular head of the influenza H1N1 virus hemagglutinin","volume":"85","author":"Krause","year":"2011","journal-title":"J. Virol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"14216","DOI":"10.1073\/pnas.1111497108","article-title":"Broadly neutralizing human antibody that recognizes the receptor-binding pocket of influenza virus hemagglutinin","volume":"108","author":"Whittle","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/j.coviro.2013.07.007","article-title":"Influenza virus hemagglutinin stalk-based antibodies and vaccines","volume":"3","author":"Krammer","year":"2013","journal-title":"Curr. Opin. Virol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1126\/science.1171491","article-title":"Antibody recognition of a highly conserved influenza virus epitope","volume":"324","author":"Ekiert","year":"2009","journal-title":"Science"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2552","DOI":"10.1128\/jvi.67.5.2552-2558.1993","article-title":"A common neutralizing epitope conserved between the hemagglutinins of influenza\u2014A virus H1 and H2 strains","volume":"67","author":"Okuno","year":"1993","journal-title":"J. Virol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1073\/pnas.1319058110","article-title":"A common solution to group 2 influenza virus neutralization","volume":"111","author":"Friesen","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1126\/science.1205669","article-title":"A neutralizing antibody selected from plasma cells that binds to group 1 and group 2 influenza A hemagglutinins","volume":"333","author":"Corti","year":"2011","journal-title":"Science"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1126\/science.1222908","article-title":"Highly conserved protective epitopes on influenza B viruses","volume":"337","author":"Dreyfus","year":"2012","journal-title":"Science"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"13580","DOI":"10.1128\/JVI.02289-14","article-title":"Characterization of a broadly neutralizing monoclonal antibody that targets the fusion domain of group 2 influenza A virus hemagglutinin","volume":"88","author":"Tan","year":"2014","journal-title":"J. Virol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Brandenburg, B., Koudstaal, W., Goudsmit, J., Klaren, V., Tang, C., Bujny, M.V., Korse, H.J., Kwaks, T., Otterstrom, J.J., and Juraszek, J. (2013). Mechanisms of hemagglutinin targeted influenza virus neutralization. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0080034"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1038\/nm.3443","article-title":"Broadly neutralizing hemagglutinin stalk-specific antibodies require Fc\u03b3R interactions for protection against influenza virus in vivo","volume":"20","author":"DiLillo","year":"2014","journal-title":"Nat. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"469","DOI":"10.4049\/jimmunol.1400432","article-title":"Influenza-specific antibody-dependent cellular cytotoxicity: Toward a universal influenza vaccine","volume":"193","author":"Jegaskanda","year":"2014","journal-title":"J. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"10435","DOI":"10.1128\/JVI.01715-13","article-title":"Hemagglutinin stalk-based universal vaccine constructs protect against group 2 influenza A viruses","volume":"87","author":"Margine","year":"2013","journal-title":"J. Virol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"6542","DOI":"10.1128\/JVI.00641-13","article-title":"Chimeric hemagglutinin influenza virus vaccine constructs elicit broadly protective stalk-specific antibodies","volume":"87","author":"Krammer","year":"2013","journal-title":"J. Virol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"22666","DOI":"10.1038\/srep22666","article-title":"Stalking influenza by vaccination with pre-fusion headless HA mini-stem","volume":"6","author":"Valkenburg","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"329","DOI":"10.3389\/fimmu.2015.00329","article-title":"Hemagglutinin sequence conservation guided stem immunogen design from influenza A H3 subtype","volume":"6","author":"Mallajosyula","year":"2015","journal-title":"Front. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Klausberger, M., Tscheliessnig, R., Neff, S., Nachbagauer, R., Wohlbold, T.J., Wilde, M., Palmberger, D., Krammer, F., Jungbauer, A., and Grabherr, R. (2016). Globular head-displayed conserved influenza H1 hemagglutinin stalk epitopes confer protection against heterologous H1N1 virus. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0153579"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1038\/nature12202","article-title":"Self-assembling influenza nanoparticle vaccines elicit broadly neutralizing H1N1 antibodies","volume":"499","author":"Kanekiyo","year":"2013","journal-title":"Nature"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1294","DOI":"10.3390\/v6031294","article-title":"Playing hide and seek: How glycosylation of the influenza virus hemagglutinin can modulate the immune response to infection","volume":"6","author":"Tate","year":"2014","journal-title":"Viruses"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Gao, Y., Zhang, Y., Shinya, K., Deng, G., Jiang, Y., Li, Z., Guan, Y., Tian, G., Li, Y., and Shi, J. (2009). Identification of amino acids in HA and PB2 critical for the transmission of H5N1 avian influenza viruses in a mammalian host. PLoS Pathog., 5.","DOI":"10.1371\/journal.ppat.1000709"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1016\/j.vetmic.2014.12.011","article-title":"Hemagglutinin glycosylation modulates the pathogenicity and antigenicity of the H5N1 avian influenza virus","volume":"175","author":"Zhang","year":"2015","journal-title":"Vet. Microbiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"187ra170","DOI":"10.1126\/scitranslmed.3005996","article-title":"Glycosylations in the globular head of the hemagglutinin protein modulate the virulence and antigenic properties of the H1N1 influenza viruses","volume":"5","author":"Medina","year":"2013","journal-title":"Sci. Transl. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"8756","DOI":"10.1128\/JVI.00593-13","article-title":"N-linked glycosylation of the hemagglutinin protein influences virulence and antigenicity of the 1918 pandemic and seasonal H1N1 influenza A viruses","volume":"87","author":"Sun","year":"2013","journal-title":"J. Virol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.virol.2011.01.036","article-title":"Gl ycosylation of the hemagglutinin modulates the sensitivity of H3N2 influenza viruses to innate proteins in airway secretions and virulence in mice","volume":"413","author":"Tate","year":"2011","journal-title":"Virology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"36216","DOI":"10.1038\/srep36216","article-title":"Glycosylation changes in the globular head of H3N2 influenza hemagglutinin modulate receptor binding without affecting virus virulence","volume":"6","author":"Alymova","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1128\/JVI.02608-13","article-title":"Guiding the immune response against influenza virus hemagglutinin toward the conserved stalk domain by hyperglycosylation of the globular head domain","volume":"88","author":"Eggink","year":"2014","journal-title":"J. Virol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3048","DOI":"10.1128\/jvi.67.6.3048-3060.1993","article-title":"Role of conserved glycosylation sites in maturation and transport of influenza A virus hemagglutinin","volume":"67","author":"Roberts","year":"1993","journal-title":"J. Virol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/S1097-2765(02)00821-3","article-title":"N-linked glycans direct the cotranslational folding pathway of influenza hemagglutinin","volume":"11","author":"Daniels","year":"2003","journal-title":"Mol. Cell"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3719","DOI":"10.1128\/jvi.71.5.3719-3725.1997","article-title":"Oligosaccharides in the stem region maintain the influenza virus hemagglutinin in the metastable form required for fusion activity","volume":"71","author":"Ohuchi","year":"1997","journal-title":"J. Virol."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Nao, N., Yamagishi, J., Miyamoto, H., Igarashi, M., Manzoor, R., Ohnuma, A., Tsuda, Y., Furuyama, W., Shigeno, A., and Kajihara, M. (2017). Genetic predisposition to acquire a polybasic cleavage site for highly pathogenic avian influenza virus hemagglutinin. mBio, 8.","DOI":"10.1128\/mBio.02298-16"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"6924","DOI":"10.1128\/JVI.07142-11","article-title":"A single amino acid at the hemagglutinin cleavage site contributes to the pathogenicity and neurovirulence of H5N1 influenza virus in mice","volume":"86","author":"Zhang","year":"2012","journal-title":"J. Virol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1038\/nm1256","article-title":"A new approach to an influenza live vaccine: Modification of the cleavage site of hemagglutinin","volume":"11","author":"Stech","year":"2005","journal-title":"Nat. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"7380","DOI":"10.1128\/JVI.79.12.7380-7388.2005","article-title":"Universal influenza B vaccine based on the maturational cleavage site of the hemagglutinin precursor","volume":"79","author":"Bianchi","year":"2005","journal-title":"J. Virol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"10986","DOI":"10.1128\/JVI.01077-14","article-title":"Recent H3N2 influenza virus clinical isolates rapidly acquire hemagglutinin or neuraminidase mutations when propagated for antigenic analyses","volume":"88","author":"Chambers","year":"2014","journal-title":"J. Virol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"12387","DOI":"10.1128\/JVI.05570-11","article-title":"Analysis of influenza virus hemagglutinin receptor binding mutants with limited receptor recognition properties and conditional replication characteristics","volume":"85","author":"Bradley","year":"2011","journal-title":"J. Virol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"11168","DOI":"10.1128\/JVI.01414-13","article-title":"Compensatory hemagglutinin mutations alter antigenic properties of influenza viruses","volume":"87","author":"Myers","year":"2013","journal-title":"J. Virol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1111\/j.1750-2659.2011.00304.x","article-title":"Influenza neuraminidase","volume":"6","author":"Air","year":"2012","journal-title":"Influ. Other Respir. Viruses"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Yang, X.Y., Steukers, L., Forier, K., Xiong, R.H., Braeckmans, K., van Reeth, K., and Nauwynck, H. (2014). A beneficiary role for neuraminidase in influenza virus penetration through the respiratory mucus. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0110026"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1186\/1743-422X-10-321","article-title":"Influenza A penetrates host mucus by cleaving sialic acids with neuraminidase","volume":"10","author":"Cohen","year":"2013","journal-title":"Virol. J."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.chom.2016.01.001","article-title":"The Interaction between respiratory pathogens and mucus","volume":"19","author":"Zanin","year":"2016","journal-title":"Cell Host Microbe"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"3053","DOI":"10.1128\/JVI.02434-12","article-title":"Neuraminidase-inhibiting antibody is a correlate of cross-protection against lethal H5N1 influenza virus in ferrets immunized with seasonal influenza vaccine","volume":"87","author":"Rockman","year":"2013","journal-title":"J. Virol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"e02556-14","DOI":"10.1128\/mBio.02556-14","article-title":"Vaccination with Adjuvanted recombinant neuraminidase induces broad heterologous, but not heterosubtypic, cross-protection against influenza virus infection in mice","volume":"6","author":"Wohlbold","year":"2015","journal-title":"mBio"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.virol.2012.06.003","article-title":"Protection against a lethal H5N1 influenza challenge by intranasal immunization with virus-like particles containing 2009 pandemic H1N1 neuraminidase in mice","volume":"432","author":"Easterbrook","year":"2012","journal-title":"Virology"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.clim.2012.01.015","article-title":"Immunodominance: A pivotal principle in host response to viral infections","volume":"143","author":"Akram","year":"2012","journal-title":"Clin. Immunol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1128\/jvi.63.3.1239-1246.1989","article-title":"Purified influenza virus hemagglutinin and neuraminidase are equivalent in stimulation of antibody response but induce contrasting types of immunity to infection","volume":"63","author":"Johansson","year":"1989","journal-title":"J. Virol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"199","DOI":"10.4161\/hv.7.0.14595","article-title":"An influenza N1 neuraminidase-specific monoclonal antibody with broad neuraminidase inhibition activity against H5N1 HPAI viruses","volume":"7","author":"Shoji","year":"2011","journal-title":"Hum. Vaccines"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Wu, C.Y., Yeh, Y.C., Chan, J.T., Yang, Y.C., Yang, J.R., Liu, M.T., Wu, H.S., and Hsiao, P.W. (2012). A VLP vaccine induces broad-spectrum cross-protective antibody immunity against H5N1 and H1N1 subtypes of influenza A virus. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0042363"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1093\/cid\/cir693","article-title":"Revisiting the 1976 \u201cSwine Flu\u201d vaccine clinical trials: Cross-reactive hemagglutinin and neuraminidase antibodies and their role in protection against the 2009 H1N1 pandemic virus in mice","volume":"53","author":"Xie","year":"2011","journal-title":"Clin. Infect. Dis."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"10539","DOI":"10.1128\/JVI.00967-13","article-title":"The short stalk length of highly pathogenic avian influenza H5N1 virus neuraminidase limits transmission of pandemic H1N1 virus in ferrets","volume":"87","author":"Blumenkrantz","year":"2013","journal-title":"J. Virol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"13493","DOI":"10.1038\/srep13493","article-title":"The neuraminidase stalk deletion serves as major virulence determinant of H5N1 highly pathogenic avian influenza viruses in chicken","volume":"5","author":"Stech","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Li, Y.F., Chen, S.J., Zhang, X.J., Fu, Q., Zhang, Z.Y., Shi, S.H., Zhu, Y.B., Gu, M., Peng, D.X., and Liu, X.F. (2014). A 20-amino-acid deletion in the neuraminidase stalk and a five-amino-acid deletion in the NS1 protein both contribute to the pathogenicity of H5N1 avian influenza viruses in mallard ducks. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0095539"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1073\/pnas.1617174114","article-title":"Influenza A surface glycosylation and vaccine design","volume":"114","author":"Wu","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"e00868","DOI":"10.1128\/JVI.00868-16","article-title":"An amino acid in the stalk domain of N1 neuraminidase is critical for enzymatic activity","volume":"91","author":"Zanin","year":"2017","journal-title":"J. Virol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1016\/j.antiviral.2013.09.018","article-title":"Universal anti-neuraminidase antibody inhibiting all influenza A subtypes","volume":"100","author":"Doyle","year":"2013","journal-title":"Antivir. Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.bbrc.2013.10.041","article-title":"A monoclonal antibody targeting a highly conserved epitope in influenza B neuraminidase provides protection against drug resistant strains","volume":"441","author":"Doyle","year":"2013","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1016\/0092-8674(85)90211-9","article-title":"Influenza virus M2 protein is an integral membrane protein expressed on the infected-cell surface","volume":"40","author":"Lamb","year":"1985","journal-title":"Cell"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"9973","DOI":"10.1128\/JVI.01363-13","article-title":"The amphipathic helix of influenza A virus M2 protein is required for filamentous bud formation and scission of filamentous and spherical particles","volume":"87","author":"Roberts","year":"2013","journal-title":"J. Virol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"12","DOI":"10.7774\/cevr.2014.3.1.12","article-title":"New vaccines against influenza virus","volume":"3","author":"Lee","year":"2014","journal-title":"Clin. Exp. Vaccine Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1038\/nature08722","article-title":"Structure of the amantadine binding site of influenza M2 proton channels in lipid bilayers","volume":"463","author":"Cady","year":"2010","journal-title":"Nature"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"4457","DOI":"10.1128\/AAC.00650-09","article-title":"Large-scale sequence analysis of M gene of influenza A viruses from different species: Mechanisms for emergence and spread of amantadine resistance","volume":"53","author":"Furuse","year":"2009","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1099\/vir.2008.007260-0","article-title":"High prevalence of amantadine resistance among circulating European porcine influenza A viruses","volume":"90","author":"Krumbholz","year":"2009","journal-title":"J. Gen. Virol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1073\/pnas.1216526110","article-title":"Structure and inhibition of the drug-resistant S31N mutant of the M2 ion channel of influenza A virus","volume":"110","author":"Wang","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Balgi, A.D., Wang, J., Cheng, D.Y.H., Ma, C.L., Pfeifer, T.A., Shimizu, Y., Anderson, H.J., Pinto, L.H., Lamb, R.A., and DeGrado, W.F. (2013). Inhibitors of the influenza A virus M2 proton channel discovered using a high-throughput yeast growth restoration assay. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0055271"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1021\/acs.jmedchem.5b01910","article-title":"Discovery of highly potent inhibitors targeting the predominant drug-resistant S31N mutant of the influenza A virus M2 proton channel","volume":"59","author":"Li","year":"2016","journal-title":"J. Med. Chem."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1124\/mol.116.105346","article-title":"Pharmacological characterization of the spectrum of antiviral activity and genetic barrier to drug resistance of M2-S31N channel blockers","volume":"90","author":"Ma","year":"2016","journal-title":"Mol. Pharmacol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"4603","DOI":"10.1128\/jvi.63.11.4603-4608.1989","article-title":"Avian-to-human transmission of the PB1 gene of influenza A viruses in the 1957 and 1968 pandemics","volume":"63","author":"Kawaoka","year":"1989","journal-title":"J. Virol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"13436","DOI":"10.1128\/JVI.01093-14","article-title":"Mutations to PB2 and NP proteins of an avian influenza virus combine to confer efficient growth in primary human respiratory cells","volume":"88","author":"Danzy","year":"2014","journal-title":"J. Virol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1761","DOI":"10.1128\/jvi.67.4.1761-1764.1993","article-title":"A single amino-acid in the PB2 gene of influenza A virus is a determinant of host range","volume":"67","author":"Subbarao","year":"1993","journal-title":"J. Virol."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Steel, J., Lowen, A.C., Mubareka, S., and Palese, P. (2009). Transmission of influenza virus in a mammalian host is increased by PB2 amino acids 627K or 627E\/701N. PLoS Pathog., 5.","DOI":"10.1371\/journal.ppat.1000252"},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Arai, Y., Kawashita, N., Daidoji, T., Ibrahim, M.S., El-Gendy, E.M., Takagi, T., Takahashi, K., Suzuki, Y., Ikuta, K., and Nakaya, T. (2016). Novel polymerase gene mutations for human adaptation in clinical isolates of avian H5N1 influenza viruses. PLoS Pathog., 12.","DOI":"10.1371\/journal.ppat.1005583"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"8735","DOI":"10.1128\/JVI.00422-14","article-title":"PB2 mutations D701N and S714R promote adaptation of an influenza H5N1 virus to a mammalian host","volume":"88","author":"Otte","year":"2014","journal-title":"J. Virol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"14170","DOI":"10.1038\/srep14170","article-title":"Dual E627K and D701N mutations in the PB2 protein of A(H7N9) influenza virus increased its virulence in mammalian models","volume":"5","author":"Zhu","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"7491","DOI":"10.1038\/ncomms8491","article-title":"Identification of mammalian-adapting mutations in the polymerase complex of an avian H5N1 influenza virus","volume":"6","author":"Taft","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1750","DOI":"10.1128\/JVI.06203-11","article-title":"Reassortment and mutation of the avian influenza virus polymerase PA subunit overcome species barriers","volume":"86","author":"Mehle","year":"2012","journal-title":"J. Virol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"2180","DOI":"10.1128\/JVI.01975-10","article-title":"The PA protein directly contributes to the virulence of H5N1 avian influenza viruses in domestic ducks","volume":"85","author":"Song","year":"2011","journal-title":"J. Virol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"13737","DOI":"10.1128\/JVI.01081-14","article-title":"Amino acid changes in the influenza A virus PA protein that attenuate avian H5N1 viruses in mammals","volume":"88","author":"Fan","year":"2014","journal-title":"J. Virol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"3684","DOI":"10.1128\/JVI.03101-15","article-title":"Codon deletions in the influenza A virus PA Gene generate temperature-sensitive viruses","volume":"90","author":"Meyer","year":"2016","journal-title":"J. Virol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"e42","DOI":"10.1038\/emi.2012.38","article-title":"Adaptive mutation in influenza A virus non-structural gene is linked to host switching and induces a novel protein by alternative splicing","volume":"1","author":"Selman","year":"2012","journal-title":"Emerg. Microbes Infect."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"9693","DOI":"10.1128\/JVI.01039-16","article-title":"NS1 protein mutation I64T affects interferon responses and virulence of circulating H3N2 human influenza A viruses","volume":"90","author":"DeDiego","year":"2016","journal-title":"J. Virol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.1128\/JVI.01698-07","article-title":"A single-amino-acid substitution in the NS1 protein changes the pathogenicity of H5N1 avian influenza viruses in mice","volume":"82","author":"Jiao","year":"2008","journal-title":"J. Virol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"11115","DOI":"10.1128\/JVI.00993-06","article-title":"The NS1 gene contributes to the virulence of H5N1 avian influenza viruses","volume":"80","author":"Li","year":"2006","journal-title":"J. Virol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"4381","DOI":"10.1073\/pnas.0800482105","article-title":"A new influenza virus virulence determinant: The NS1 protein four C-terminal residues modulate pathogenicity","volume":"105","author":"Jackson","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/1743-422X-8-13","article-title":"Influenza A virus NS1 gene mutations F103L and M106I increase replication and virulence","volume":"8","author":"Dankar","year":"2011","journal-title":"Virol. J."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"e01930","DOI":"10.1128\/JVI.01930-16","article-title":"NS1 protein amino acid changes D189N and V194I affect interferon responses, thermosensitivity, and virulence of circulating H3N2 human influenza A viruses","volume":"91","author":"Nogales","year":"2017","journal-title":"J. Virol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"10293","DOI":"10.1128\/JVI.01131-12","article-title":"NS1-truncated live attenuated virus vaccine provides robust protection to aged mice from viral challenge","volume":"86","author":"Pica","year":"2012","journal-title":"J. Virol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"10580","DOI":"10.1128\/JVI.01213-08","article-title":"Influenza B virus NS1-truncated mutants: Live-attenuated vaccine approach","volume":"82","author":"Hai","year":"2008","journal-title":"J. Virol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1016\/j.vaccine.2015.11.045","article-title":"Cross-clade protective immune responses of NS1-truncated live attenuated H5N1 avian influenza vaccines","volume":"34","author":"Shi","year":"2016","journal-title":"Vaccine"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"257","DOI":"10.4065\/mcp.2009.0615","article-title":"Influenza vaccines: From surveillance through production to protection","volume":"85","author":"Tosh","year":"2010","journal-title":"Mayo Clin. Proc."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"3123","DOI":"10.1016\/S0264-410X(02)00261-X","article-title":"Intranasal administration of a synthetic peptide vaccine encapsulated in liposome together with an anti-CD40 antibody induces protective immunity against influenza A virus in mice","volume":"20","author":"Ninomiya","year":"2002","journal-title":"Vaccine"},{"key":"ref_112","doi-asserted-by":"crossref","unstructured":"Taneichi, M., Tanaka, Y., Kakiuchi, T., and Uchida, T. (2010). Liposome-coupled peptides induce long-lived memory CD8 T cells without CD4 T cells. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0015091"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"2187","DOI":"10.4049\/jimmunol.179.4.2187","article-title":"The context of epitope presentation can influence functional quality of recalled influenza A virus-specific memory CD8+ T cells","volume":"179","author":"Day","year":"2007","journal-title":"J. Immunol."},{"key":"ref_114","doi-asserted-by":"crossref","unstructured":"Ichihashi, T., Satoh, T., Sugimoto, C., and Kajino, K. (2013). Emulsified phosphatidylserine, simple and effective peptide carrier for induction of potent epitope-specific T cell responses. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0060068"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.1007\/s11095-014-1556-3","article-title":"Influenza T-cell epitope-loaded virosomes adjuvanted with CpG as a potential influenza vaccine","volume":"32","author":"Soema","year":"2015","journal-title":"Pharm. Res."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"5816","DOI":"10.1016\/j.vaccine.2014.08.031","article-title":"Priming by a novel universal influenza vaccine (Multimeric-001)-A gateway for improving immune response in the elderly population","volume":"32","author":"Atsmon","year":"2014","journal-title":"Vaccine"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1016\/j.vaccine.2014.06.006","article-title":"A novel peptide-based pan-influenza A vaccine: A double blind, randomised clinical trial of immunogenicity and safety","volume":"33","author":"Francis","year":"2015","journal-title":"Vaccine"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1186\/1743-422X-10-227","article-title":"An M2e-based synthetic peptide vaccine for influenza A virus confers heterosubtypic protection from lethal virus challenge","volume":"10","author":"Ma","year":"2013","journal-title":"Virol. J."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"534","DOI":"10.3389\/fimmu.2015.00534","article-title":"Functional specialization of skin dendritic cell subsets in regulating T cell responses","volume":"6","author":"Clausen","year":"2015","journal-title":"Front. Immunol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1038\/ni.2680","article-title":"The skin-resident and migratory immune system in steady state and memory: Innate lymphocytes, dendritic cells and T cells","volume":"14","author":"Heath","year":"2013","journal-title":"Nat. Immunol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1038\/nm.2182","article-title":"Dissolving polymer microneedle patches for influenza vaccination","volume":"16","author":"Sullivan","year":"2010","journal-title":"Nat. Med."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jconrel.2014.01.002","article-title":"Microneedle delivery of an M2e\u2013TLR5 ligand fusion protein to skin confers broadly cross-protective influenza immunity","volume":"178","author":"Wang","year":"2014","journal-title":"J. Controll. Release"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.jconrel.2016.06.026","article-title":"Tetanus vaccination with a dissolving microneedle patch confers protective immune responses in pregnancy","volume":"236","author":"Esser","year":"2016","journal-title":"J. Controll. Release"},{"key":"ref_124","doi-asserted-by":"crossref","unstructured":"Zhu, W., Pewin, W., Wang, C., Luo, Y., Gonzalez, G.X., Mohan, T., Prausnitz, M.R., and Wang, B.Z. (2017). A boosting skin vaccination with dissolving microneedle patch encapsulating M2e vaccine broadens the protective efficacy of conventional influenza vaccines. J. Controll. Release.","DOI":"10.1016\/j.jconrel.2017.06.017"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/7\/1554\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:43:03Z","timestamp":1760208183000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/7\/1554"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,7,18]]},"references-count":124,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2017,7]]}},"alternative-id":["ijms18071554"],"URL":"https:\/\/doi.org\/10.3390\/ijms18071554","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,7,18]]}}}