{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T11:12:03Z","timestamp":1788174723149,"version":"build-2803163510"},"reference-count":116,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2019,11,1]],"date-time":"2019-11-01T00:00:00Z","timestamp":1572566400000},"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>Vaccination is still the most efficient way to prevent an infection with influenza viruses. Nevertheless, existing commercial vaccines face serious limitations such as availability during epidemic outbreaks and their efficacy. Existing seasonal influenza vaccines mostly induce antibody responses to the surface proteins of influenza viruses, which frequently change due to antigenic shift and or drift, thus allowing influenza viruses to avoid neutralizing antibodies. Hence, influenza vaccines need a yearly formulation to protect against new seasonal viruses. A broadly protective or universal influenza vaccine must induce effective humoral as well as cellular immunity against conserved influenza antigens, offer good protection against influenza pandemics, be safe, and have a fast production platform. Nanotechnology has great potential to improve vaccine delivery, immunogenicity, and host immune responses. As new strains of human epidemic influenza virus strains could originate from poultry and swine viruses, development of a new universal influenza vaccine will require the immune responses to be directed against viruses from different hosts. This review discusses how the new vaccine platforms and nanoparticles can be beneficial in the development of a broadly protective, universal influenza vaccine.<\/jats:p>","DOI":"10.3390\/vaccines7040169","type":"journal-article","created":{"date-parts":[[2019,11,1]],"date-time":"2019-11-01T12:30:50Z","timestamp":1572611450000},"page":"169","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Development of Universal Influenza Vaccines Targeting Conserved Viral Proteins"],"prefix":"10.3390","volume":"7","author":[{"given":"Seyed Davoud","family":"Jazayeri","sequence":"first","affiliation":[{"name":"Centre for Virus and Vaccine Research, School of Science and Technology, Sunway University, Subang Jaya 47500, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8475-6291","authenticated-orcid":false,"given":"Chit Laa","family":"Poh","sequence":"additional","affiliation":[{"name":"Centre for Virus and Vaccine Research, School of Science and Technology, Sunway University, Subang Jaya 47500, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,11,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S82","DOI":"10.1038\/nm1141","article-title":"Influenza: Old and new threats","volume":"10","author":"Palese","year":"2004","journal-title":"Nat. Med."},{"key":"ref_2","unstructured":"Knipe, D.M., Howley, P.M., Griffin, D.E., Lamb, R.A., Martin, M.A., and Roizman, B. (2007). \u201cOrthomyxoviruses\u201d in Fields Virology, Lippincott Williams & Wilkins. [5th ed.]."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1016\/S0140-6736(17)30129-0","article-title":"Influenza","volume":"390","author":"Paules","year":"2017","journal-title":"Lancet"},{"key":"ref_4","unstructured":"Centers for Disease Control and Prevention (2019, April 24). Disease Burden of Influenza, Available online: https:\/\/www.cdc.gov\/flu\/about\/burden\/index.html."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1016\/S0140-6736(17)33293-2","article-title":"Estimates of global seasonal Influenza-Associated respiratory mortality: A modelling study","volume":"391","author":"Iuliano","year":"2018","journal-title":"Lancet"},{"key":"ref_6","unstructured":"WHO (2016, May 10). Influenza (Seasonal) Fact Sheet. Available online: http:\/\/www.who.int\/mediacentre\/factsheets\/fs211\/en\/."},{"key":"ref_7","unstructured":"Centers for Disease Control and Prevention (2019, March 15). Seasonal Influenza Vaccine Effectiveness, Available online: https:\/\/www.cdc.gov\/flu\/about\/season\/flu-season-2017-2018.htm."},{"key":"ref_8","unstructured":"Centers for Disease Control and Prevention (2017, July 28). Pandemic Influenza\u2014Past Pandemics, Available online: https:\/\/www.cdc.gov\/flu\/pandemic-resources\/basics\/past-pandemics.html."},{"key":"ref_9","unstructured":"WHO (2019, April 20). Influenza (Avian and Other Zoonotic). Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/influenza-(avian-and-other-zoonotic)."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1093\/infdis\/jiy103","article-title":"A Universal influenza vaccine: The strategic plan for the National Institute of Allergy and Infectious Diseases","volume":"218","author":"Erbelding","year":"2018","journal-title":"J. Infect. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.ejpb.2015.05.023","article-title":"Current and next generation influenza vaccines: Formulation and production strategies","volume":"94","author":"Soema","year":"2015","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"15279","DOI":"10.1038\/srep15279","article-title":"H3N2 Mismatch of 2014-15 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_13","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1056\/NEJMp1714916","article-title":"Chasing seasonal influenza\u2014The need for a universal influenza vaccine","volume":"378","author":"Paules","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_14","first-page":"43","article-title":"Seasonal influenza vaccines","volume":"333","author":"Fiore","year":"2009","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_15","unstructured":"Centers for Disease Control and Prevention (2019, May 20). Seasonal Influenza Vaccine Effectiveness, Available online: https:\/\/www.cdc.gov\/flu\/professionals\/vaccination\/effectiveness-studies.htm."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Sullivan, S.G., Chilver, M.B., Carville, K.S., Deng, Y.M., Grant, K.A., Higgins, G., Komadina, N., Leung, V.K., Minney-Smith, C.A., and Teng, D. (2017). Low interim influenza vaccine effectiveness, Australia, 1 May to 24 September 2017. Eurosurveillance, 22.","DOI":"10.2807\/1560-7917.ES.2017.22.43.17-00707"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"180","DOI":"10.15585\/mmwr.mm6706a2","article-title":"Interim estimates of 2017-18 seasonal influenza vaccine effectiveness-United States, February 2018","volume":"67","author":"Flannery","year":"2018","journal-title":"MMWR Morb. Mortal. Wkly. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Yamazaki, T., Chiba, J., and Akashi-Takamura, S. (2018). Neutralizing Anti-Hemagglutinin monoclonal antibodies induced by Gene-Based transfer have prophylactic and therapeutic effects on influenza virus infection. Vaccines, 6.","DOI":"10.3390\/vaccines6030035"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1002\/rmv.1713","article-title":"Contribution of antibody production against neuraminidase to the protection afforded by influenza vaccines","volume":"22","author":"Marcelin","year":"2012","journal-title":"Rev. Med. Virol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2820","DOI":"10.1128\/JVI.03246-14","article-title":"A viable recombinant rhabdovirus lacking its glycoprotein gene and expressing influenza virus hemagglutinin and neuraminidase is a potent influenza vaccine","volume":"89","author":"Ryder","year":"2015","journal-title":"J. Virol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5427","DOI":"10.1038\/s41467-018-07815-5","article-title":"Broad CD8(+) T cell cross-recognition of distinct influenza A strains in humans","volume":"9","author":"Grant","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"123","DOI":"10.3389\/fmicb.2018.00123","article-title":"Universal vaccines and vaccine platforms to protect against influenza viruses in humans and agriculture","volume":"9","author":"Rajao","year":"2018","journal-title":"Front. Microbiol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Alsharifi, M., Furuya, Y., Bowden, T.R., Lobigs, M., Koskinen, A., Regner, M., Trinidad, L., Boyle, D.B., and Mullbacher, A. (2009). Intranasal flu vaccine protective against seasonal and H5N1 avian influenza infections. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0005336"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4212","DOI":"10.1128\/JVI.02508-09","article-title":"Cytotoxic T cells are the predominant players providing Cross-Protective immunity induced by \u03b3-irradiated influenza A viruses","volume":"84","author":"Furuya","year":"2010","journal-title":"J. Virol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Kon, T.C., Onu, A., Berbecila, L., Lupulescu, E., Ghiorgisor, A., Kersten, G.F., Cui, Y.Q., Amorij, J.P., and Van der Pol, L. (2016). Influenza vaccine manufacturing: Effect of inactivation, splitting and site of manufacturing. comparison of influenza vaccine production processes. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0150700"},{"key":"ref_26","unstructured":"Centers for Disease Control and Prevention (2019, March 20). Available online: https:\/\/www.cdc.gov\/flu\/protect\/vaccine\/how-fluvaccine-made.htm#recombinant."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1111\/j.1750-2659.2008.00053.x","article-title":"FluBlok, a recombinant hemagglutinin influenza vaccine","volume":"2","author":"Cox","year":"2008","journal-title":"Influenza Other Respir. Viruses"},{"key":"ref_28","unstructured":"Centers for Disease Control and Prevention (2019, June 10). Available online: https:\/\/www.cdc.gov\/flu\/prevent\/qa_flublok-vaccine.htm."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3589","DOI":"10.3390\/v4123589","article-title":"Development of live-attenuated influenza vaccines against outbreaks of H5N1 influenza","volume":"4","author":"Zheng","year":"2012","journal-title":"Viruses"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"643","DOI":"10.15585\/mmwr.mm6722a5","article-title":"Update: ACIP Recommendations for the Use of Quadrivalent Live Attenuated Influenza Vaccine (LAIV4)-United States, 2018\u20132019 Influenza Season","volume":"67","author":"Grohskopf","year":"2018","journal-title":"MMWR Morb. Mortal. Wkly. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"100031","DOI":"10.1016\/j.jvacx.2019.100031","article-title":"Evaluation of A(H1N1)pdm09 LAIV vaccine candidates stability and replication efficiency in primary human nasal epithelial cells","volume":"2","author":"Shcherbik","year":"2019","journal-title":"Vaccine X"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Skowronski, D.M., Janjua, N.Z., De Serres, G., Sabaiduc, S., Eshaghi, A., Dickinson, J.A., Fonseca, K., Winter, A.L., Gubbay, J.B., and Krajden, M. (2014). Low 2012-13 influenza vaccine effectiveness associated with mutation in the Egg-Adapted H3N2 vaccine strain not antigenic drift in circulating viruses. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0092153"},{"key":"ref_33","unstructured":"Centers for Disease Control and Prevention (2018, February 02). Transcript for CDC Update on Flu Activity, Available online: https:\/\/www.cdc.gov\/media\/releases\/2018\/t0202-flu-update-activity.html."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1128\/CMR.00097-12","article-title":"Traditional and new influenza vaccines","volume":"26","author":"Wong","year":"2013","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1177\/2051013615595595","article-title":"Safety, efficacy, and immunogenicity of Flublok in the prevention of seasonal influenza in adults","volume":"3","author":"Cox","year":"2015","journal-title":"Ther. Adv. Vaccines"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"11014","DOI":"10.1128\/JVI.79.17.11014-11021.2005","article-title":"Multiple gene segments control the temperature sensitivity and attenuation phenotypes of ca B\/Ann Arbor\/1\/66","volume":"79","author":"Hoffmann","year":"2005","journal-title":"J. Virol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1038\/nrmicro.2017.118","article-title":"The evolution of seasonal influenza viruses","volume":"16","author":"Petrova","year":"2018","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"a028845","DOI":"10.1101\/cshperspect.a028845","article-title":"Is it possible to develop a \u201cuniversal\u201d influenza virus vaccine? Potential target antigens and critical aspects for a universal influenza vaccine","volume":"10","author":"Krammer","year":"2018","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.coi.2018.04.009","article-title":"Shaping a universally broad antibody response to influenza amidst a variable immunoglobulin landscape","volume":"53","author":"Andrews","year":"2018","journal-title":"Curr. Opin. Immunol."},{"key":"ref_40","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_41","doi-asserted-by":"crossref","first-page":"1891","DOI":"10.1016\/j.bbapap.2014.05.010","article-title":"Immunogen design for HIV-1 and influenza","volume":"1844","author":"Rathore","year":"2014","journal-title":"Biochim. Biophys. Acta."},{"key":"ref_42","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_43","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_44","doi-asserted-by":"crossref","unstructured":"Stepanova, L.A., Kotlyarov, R.Y., Kovaleva, A.A., Potapchuk, M.V., Korotkov, A.V., Sergeeva, M.V., Kasianenko, M.A., Kuprianov, V.V., Ravin, N.V., and Tsybalova, L.M. (2015). Protection against multiple influenza A virus strains induced by candidate recombinant vaccine based on heterologous M2e peptides linked to flagellin. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0119520"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"6019","DOI":"10.1128\/JVI.03101-13","article-title":"Mucosal immunization with a candidate universal influenza vaccine reduces virus transmission in a mouse model","volume":"88","author":"Price","year":"2014","journal-title":"J. Virol."},{"key":"ref_46","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_47","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_48","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_49","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_50","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.coviro.2016.01.016","article-title":"Human influenza viruses and CD8(+) T cell responses","volume":"16","author":"Grant","year":"2016","journal-title":"Curr. Opin. Virol."},{"key":"ref_51","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_52","doi-asserted-by":"crossref","first-page":"4198","DOI":"10.1016\/j.vaccine.2018.06.007","article-title":"Protection by universal influenza vaccine is mediated by memory CD4 T cells","volume":"36","author":"Valkenburg","year":"2018","journal-title":"Vaccine"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"3063","DOI":"10.4049\/jimmunol.0803467","article-title":"Vaccinia Virus-Based multivalent H5N1 avian influenza vaccines adjuvanted with IL-15 confer sterile cross-clade protection in mice","volume":"182","author":"Poon","year":"2009","journal-title":"J. Immunol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"3233","DOI":"10.1093\/bioinformatics\/btw399","article-title":"Towards the knowledge-based design of universal influenza epitope ensemble vaccines","volume":"32","author":"Sheikh","year":"2016","journal-title":"Bioinformatics"},{"key":"ref_55","first-page":"2336","article-title":"Enhancing immunogenicity of a CTL epitope from carcinoembryonic antigen by selective amino acid replacements","volume":"8","author":"Huarte","year":"2002","journal-title":"Clin. Cancer Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1093\/intimm\/12.3.375","article-title":"Minimal peptide length requirements for CD4(+) T cell clones\u2014Implications for molecular mimicry and T cell survival","volume":"12","author":"Hemmer","year":"2000","journal-title":"Int. Immunol."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Singh, H., Ansari, H.R., and Raghava, G.P. (2013). Improved method for linear B-cell epitope prediction using antigen\u2019s primary sequence. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0062216"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.virol.2017.11.018","article-title":"A novel Peptide-Based vaccine candidate with protective efficacy against influenza A in a mouse model","volume":"515","author":"Meijerhof","year":"2018","journal-title":"Virology"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1038\/cmi.2016.20","article-title":"Identification of a CD4 T-cell epitope in the hemagglutinin stalk domain of pandemic H1N1 influenza virus and its antigen-driven TCR usage signature in BALB\/c mice","volume":"14","author":"Lu","year":"2017","journal-title":"Cell. Mol. Immunol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1093\/intimm\/11.7.1043","article-title":"Intranasal administration of peptide vaccine protects human\/mouse radiation chimera from influenza infection","volume":"11","author":"Marcus","year":"1999","journal-title":"Int. Immunol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1007\/s10875-011-9632-5","article-title":"Safety and immunogenicity of multimeric-001--a novel universal influenza vaccine","volume":"32","author":"Atsmon","year":"2012","journal-title":"J. Clin. Immunol."},{"key":"ref_62","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_63","unstructured":"Clinical Trials.Gov (2019, March 01). Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/study\/NCT03058692."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Tsybalova, L.M., Stepanova, L.A., Shuklina, M.A., Mardanova, E.S., Kotlyarov, R.Y., Potapchuk, M.V., Petrov, S.A., Blokhina, E.A., and Ravin, N.V. (2018). Combination of M2e peptide with stalk HA epitopes of influenza A virus enhances protective properties of recombinant vaccine. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0201429"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"S68","DOI":"10.1093\/infdis\/jiz003","article-title":"The Role of Matrix Protein 2 Ectodomain in the Development of Universal Influenza Vaccines","volume":"219","author":"Saelens","year":"2019","journal-title":"J. Infect. Dis."},{"key":"ref_66","unstructured":"(2008, October 10). Safety Study of Recombinant M2e Influenza\u2014A Vaccine in Healthy Adults (FLU-A), Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT00819013?term=Acam-flu-A&rank=1."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"105","DOI":"10.3390\/vaccines3010105","article-title":"M2e-Based Universal Influenza A Vaccines","volume":"3","author":"Deng","year":"2015","journal-title":"Vaccines"},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Rosendahl Huber, S.K., Camps, M.G., Jacobi, R.H., Mouthaan, J., van Dijken, H., van Beek, J., Ossendorp, F., and de Jonge, J. (2015). Synthetic long peptide influenza vaccine containing conserved T and B cell epitopes reduces viral load in lungs of mice and ferrets. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0127969"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Tutykhina, I., Esmagambetov, I., Bagaev, A., Pichugin, A., Lysenko, A., Shcherbinin, D., Sedova, E., Logunov, D., Shmarov, M., and Ataullakhanov, R. (2018). Vaccination potential of B and T epitope-enriched NP and M2 against Influenza A viruses from different clades and hosts. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0191574"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1021\/acs.accounts.7b00129","article-title":"Protein Epitope Mimetics: From New Antibiotics to Supramolecular Synthetic Vaccines","volume":"50","author":"Zerbe","year":"2017","journal-title":"Acc. Chem. Res."},{"key":"ref_71","first-page":"2001","article-title":"H1N1 influenza virus epitopes classified by monoclonal antibodies","volume":"16","author":"Guo","year":"2018","journal-title":"Exp. Ther. Med."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Andersen, T.K., Zhou, F., Cox, R., Bogen, B., and Grodeland, G. (2017). A DNA vaccine that targets hemagglutinin to antigen-presenting cells protects mice against H7 influenza. J. Virol., 91.","DOI":"10.1128\/JVI.01340-17"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1568","DOI":"10.3389\/fimmu.2018.01568","article-title":"A Review of DNA Vaccines against Influenza","volume":"9","author":"Lee","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1016\/j.vaccine.2009.10.103","article-title":"Universal influenza DNA vaccine encoding conserved CD4+ T cell epitopes protects against lethal viral challenge in HLA-DR transgenic mice","volume":"28","author":"Alexander","year":"2010","journal-title":"Vaccine"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Wang, S., Hackett, A., Jia, N., Zhang, C., Zhang, L., Parker, C., Zhou, A., Li, J., Cao, W.C., and Huang, Z. (2011). Polyvalent DNA vaccines expressing HA antigens of H5N1 influenza viruses with an optimized leader sequence elicit Cross-Protective antibody responses. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0028757"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Koday, M.T., Leonard, J.A., Munson, P., Forero, A., Koday, M., Bratt, D.L., Fuller, J.T., Murnane, R., Qin, S., and Reinhart, T.A. (2017). Multigenic DNA vaccine induces protective Cross-Reactive T cell responses against heterologous influenza virus in nonhuman primates. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0189780"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.vetimm.2017.11.007","article-title":"Protective effect of a polyvalent influenza DNA vaccine in pigs","volume":"195","author":"Karlsson","year":"2018","journal-title":"Vet. Immunol. Immunopathol."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Houser, K.V., Yamshchikov, G.V., Bellamy, A.R., May, J., Enama, M.E., Sarwar, U., Larkin, B., Bailer, R.T., Koup, R., and Paskel, M. (2018). DNA vaccine priming for seasonal influenza vaccine in children and adolescents 6 to 17 years of age: A phase 1 randomized clinical trial. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0206837"},{"key":"ref_79","unstructured":"(2019, March 22). AgriLabs: First DNA Vaccine Licensed for Chickens: Cision. Available online: https:\/\/www.prnewswire.com\/news-releases\/first-dna-vaccine-licensed-for-chickens-300554855.html."},{"key":"ref_80","first-page":"1833","article-title":"Development of nucleic acid vaccines: Use of self-amplifying RNA in lipid nanoparticles","volume":"9","author":"Solinis","year":"2014","journal-title":"Int. J. Nanomed."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1517\/17425247.2014.901308","article-title":"Nucleic acid vaccines: Prospects for non-viral delivery of mRNA vaccines","volume":"11","author":"Deering","year":"2014","journal-title":"Expert Opin. Drug Deliv."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"594","DOI":"10.3389\/fimmu.2019.00594","article-title":"Advances in mRNA Vaccines for Infectious Diseases","volume":"10","author":"Zhang","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Magini, D., Giovani, C., Mangiavacchi, S., Maccari, S., Cecchi, R., Ulmer, J.B., De Gregorio, E., Geall, A.J., Brazzoli, M., and Bertholet, S. (2016). Self-Amplifying mRNA Vaccines Expressing Multiple Conserved Influenza Antigens Confer Protection against Homologous and Heterosubtypic Viral Challenge. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0161193"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1038\/nrd4529","article-title":"Advances in the development of influenza virus vaccines","volume":"14","author":"Krammer","year":"2015","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"e52","DOI":"10.1038\/emi.2013.54","article-title":"Rapidly produced SAM((R)) vaccine against H7N9 influenza is immunogenic in mice","volume":"2","author":"Hekele","year":"2013","journal-title":"Emerg. Microbes Infect."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1038\/s41541-017-0032-6","article-title":"Unmodified mRNA in LNPs constitutes a competitive technology for prophylactic vaccines","volume":"2","author":"Lutz","year":"2017","journal-title":"npj Vaccines"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"3361","DOI":"10.1038\/s41467-018-05482-0","article-title":"Nucleoside-Modified mRNA immunization elicits influenza virus hemagglutinin stalk-specific antibodies","volume":"9","author":"Pardi","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1128\/JVI.01786-15","article-title":"Induction of Broad-Based immunity and protective efficacy by Self-Amplifying mRNA vaccines encoding influenza virus hemagglutinin","volume":"90","author":"Brazzoli","year":"2016","journal-title":"J. Virol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1038\/nbt.2436","article-title":"Protective efficacy of in vitro synthesized, specific mRNA vaccines against influenza A virus infection","volume":"30","author":"Petsch","year":"2012","journal-title":"Nat. Biotechnol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"600","DOI":"10.3389\/fimmu.2018.00600","article-title":"Novel Platforms for the Development of a Universal Influenza Vaccine","volume":"9","author":"Kumar","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1002\/wnan.119","article-title":"Viral nanoparticles and Virus-Like particles: Platforms for contemporary vaccine design","volume":"3","author":"Plummer","year":"2011","journal-title":"Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1089\/vim.2005.18.244","article-title":"Virus-Like particle (VLP) vaccine conferred complete protection against a lethal influenza virus challenge","volume":"18","author":"Galarza","year":"2005","journal-title":"Viral Immunol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.antiviral.2013.01.010","article-title":"Enhanced Influenza VLP vaccines comprising matrix-2 ectodomain and nucleoprotein epitopes protects mice from lethal challenge","volume":"98","author":"Gao","year":"2013","journal-title":"Antivir. Res."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"e01044","DOI":"10.1128\/mBio.01044-15","article-title":"An intranasal Virus-Like particle vaccine broadly protects mice from multiple subtypes of influenza A virus","volume":"6","author":"Schwartzman","year":"2015","journal-title":"mBio"},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Valero-Pacheco, N., Perez-Toledo, M., Villasis-Keever, M.A., Nunez-Valencia, A., Bosco-Garate, I., Lozano-Dubernard, B., Lara-Puente, H., Espitia, C., Alpuche-Aranda, C., and Bonifaz, L.C. (2016). Antibody persistence in adults two years after vaccination with an H1N1 2009 pandemic influenza Virus-Like particle vaccine. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0150146"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"4577","DOI":"10.1038\/s41598-018-22874-w","article-title":"Sequential Immunizations with heterosubtypic Virus-Like particles elicit cross protection against divergent influenza A viruses in mice","volume":"8","author":"Luo","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1038\/mt.2012.246","article-title":"Virus-Like particles containing multiple M2 extracellular domains confer improved cross-protection against various subtypes of influenza virus","volume":"21","author":"Kim","year":"2013","journal-title":"Mol. Ther."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"5824","DOI":"10.1016\/j.vaccine.2014.08.030","article-title":"Influenza M2 Virus-Like particles confer a broader range of cross protection to the Strain-Specific pre-existing immunity","volume":"32","author":"Kim","year":"2014","journal-title":"Vaccine"},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Hu, C.J., Chien, C.Y., Liu, M.T., Fang, Z.S., Chang, S.Y., Juang, R.H., Chang, S.C., and Chen, H.W. (2017). Multi-Antigen avian influenza a (H7N9) Virus-Like particles: Particulate characterizations and immunogenicity evaluation in murine and avian models. BMC Biotechnol., 17.","DOI":"10.1186\/s12896-016-0321-6"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.virol.2016.12.001","article-title":"Virus-Like particles displaying H5, H7, H9 hemagglutinins and N1 neuraminidase elicit protective immunity to heterologous avian influenza viruses in chickens","volume":"501","author":"Pushko","year":"2017","journal-title":"Virology"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1016\/j.vaccine.2011.12.083","article-title":"Pandemic H1N1 influenza Virus-Like particles are immunogenic and provide protective immunity to pigs","volume":"30","author":"Pyo","year":"2012","journal-title":"Vaccine"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.clim.2016.03.008","article-title":"A Plant-Derived quadrivalent virus like particle influenza vaccine induces cross-reactive antibody and T cell response in healthy adults","volume":"168","author":"Pillet","year":"2016","journal-title":"Clin. Immunol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1586\/erv.12.147","article-title":"Virus-Like particles produced in plants as potential vaccines","volume":"12","author":"Scotti","year":"2013","journal-title":"Expert Rev. Vaccines"},{"key":"ref_104","unstructured":"Clinical Trials.Gov (2018, November 15). Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/study\/NCT03739112."},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Hodgins, B., Pillet, S., Landry, N., and Ward, B.J. (2019). A Plant-Derived VLP influenza vaccine elicits a balanced immune response even in very old mice with Co-Morbidities. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0210009"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1656","DOI":"10.1021\/acsinfecdis.8b00206","article-title":"A Perspective on Nanoparticle Universal Influenza Vaccines","volume":"4","author":"Deng","year":"2018","journal-title":"ACS Infect. Dis."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"2563","DOI":"10.1007\/s11095-014-1419-y","article-title":"Biomaterials for nanoparticle vaccine delivery systems","volume":"31","author":"Sahdev","year":"2014","journal-title":"Pharm. Res."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1080\/21645515.2017.1415684","article-title":"Adjuvanted influenza vaccines","volume":"14","author":"Tregoning","year":"2018","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.it.2008.09.006","article-title":"New horizons in adjuvants for vaccine development","volume":"30","author":"Reed","year":"2009","journal-title":"Trends Immunol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1080\/14760584.2018.1541408","article-title":"Universal influenza vaccines: From viruses to nanoparticles","volume":"17","author":"Wang","year":"2018","journal-title":"Expert Rev. Vaccines"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1038\/s41467-017-02725-4","article-title":"Double-layered protein nanoparticles induce broad protection against divergent influenza A viruses","volume":"9","author":"Deng","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_112","doi-asserted-by":"crossref","unstructured":"Hiremath, J., Kang, K.I., Xia, M., Elaish, M., Binjawadagi, B., Ouyang, K., Dhakal, S., Arcos, J., Torrelles, J.B., and Jiang, X. (2016). Entrapment of H1N1 Influenza Virus Derived Conserved Peptides in PLGA Nanoparticles Enhances T Cell Response and Vaccine Efficacy in Pigs. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0151922"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"6699","DOI":"10.2147\/IJN.S178809","article-title":"Liposomal Nanoparticle-Based conserved peptide influenza vaccine and monosodium urate crystal adjuvant elicit protective immune response in pigs","volume":"13","author":"Dhakal","year":"2018","journal-title":"Int. J. Nanomed."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1016\/j.ymthe.2017.03.035","article-title":"Preclinical and clinical demonstration of immunogenicity by mRNA vaccines against H10N8 and H7N9 influenza viruses","volume":"25","author":"Bahl","year":"2017","journal-title":"Mol. Ther."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.antiviral.2017.01.021","article-title":"Consensus M2e peptide conjugated to gold nanoparticles confers protection against H1N1, H3N2 and H5N1 influenza A viruses","volume":"141","author":"Tao","year":"2017","journal-title":"Antivir. Res."},{"key":"ref_116","unstructured":"ClinicalTrials.Gov (2019, August 19). Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/study\/NCT03814720."}],"container-title":["Vaccines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-393X\/7\/4\/169\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:31:13Z","timestamp":1760189473000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-393X\/7\/4\/169"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,1]]},"references-count":116,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["vaccines7040169"],"URL":"https:\/\/doi.org\/10.3390\/vaccines7040169","relation":{},"ISSN":["2076-393X"],"issn-type":[{"value":"2076-393X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,11,1]]}}}