{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T16:19:21Z","timestamp":1793031561395,"version":"4.5.0"},"reference-count":88,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2018,3,30]],"date-time":"2018-03-30T00:00:00Z","timestamp":1522368000000},"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>Influenza viruses infect approximately 20% of the global population annually, resulting in hundreds of thousands of deaths. While there are Food and Drug Administration (FDA) approved antiviral drugs for combating the disease, vaccination remains the best strategy for preventing infection. Due to the rapid mutation rate of influenza viruses, vaccine formulations need to be updated every year to provide adequate protection. In recent years, a great amount of effort has been focused on the development of a universal vaccine capable of eliciting broadly protective immunity. While universal influenza vaccines clearly have the best potential to provide long-lasting protection against influenza viruses, the timeline for their development, as well as the true universality of protection they afford, remains uncertain. In an attempt to reduce influenza disease burden while universal vaccines are developed and tested, many groups are working on a variety of strategies to improve the efficacy of the standard seasonal vaccine. This review will highlight the different techniques and technologies that have been, or are being, developed to improve the seasonal vaccination efforts against influenza viruses.<\/jats:p>","DOI":"10.3390\/vaccines6020019","type":"journal-article","created":{"date-parts":[[2018,3,30]],"date-time":"2018-03-30T12:43:48Z","timestamp":1522413828000},"page":"19","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":113,"title":["Efforts to Improve the Seasonal Influenza Vaccine"],"prefix":"10.3390","volume":"6","author":[{"given":"Alfred","family":"Harding","sequence":"first","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Duke University, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5307-3428","authenticated-orcid":false,"given":"Nicholas","family":"Heaton","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Duke University, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,3,30]]},"reference":[{"key":"ref_1","unstructured":"Knipe, D.M., and Howley, P.M. (2013). Orthomyxoviruses. Fields Virology, Lippincott Williams and Wilkins."},{"key":"ref_2","unstructured":"World Health Organization (WHO) (2018, February 12). Influenza (Seasonal). Available online: http:\/\/www.who.int\/mediacentre\/factsheets\/fs211\/en\/."},{"key":"ref_3","unstructured":"CDC (2018, February 12). Key Facts about Seasonal Flu Vaccine, Available online: https:\/\/www.cdc.gov\/flu\/protect\/keyfacts.htm."},{"key":"ref_4","unstructured":"CDC (2018, February 12). Quadrivalent Influenza Vaccine, Available online: https:\/\/www.cdc.gov\/flu\/protect\/vaccine\/quadrivalent.htm."},{"key":"ref_5","unstructured":"CDC (2018, February 12). Selecting Viruses for the Seasonal Influenza Vaccine, Available online: https:\/\/www.cdc.gov\/flu\/about\/season\/vaccine-selection.htm."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1053\/jinf.2000.0652","article-title":"Influenza virus: A master of metamorphosis","volume":"40","author":"Rimmelzwaan","year":"2000","journal-title":"J. Infect."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1146\/annurev.mi.41.100187.002205","article-title":"Rapid evolution of rna viruses","volume":"41","author":"Steinhauer","year":"1987","journal-title":"Annu. Rev. Microbiol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Kim, H., Webster, R.G., and Webby, R.J. (2018). Influenza virus: Dealing with a drifting and shifting pathogen. Viral Immunol.","DOI":"10.1089\/vim.2017.0141"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1007\/BF03256397","article-title":"The influenza pandemic of 2009: Lessons and implications","volume":"15","author":"Shapshak","year":"2011","journal-title":"Mol. Diagn. Ther."},{"key":"ref_10","unstructured":"CDC (2018, February 12). How Influenza (Flu) Vaccines Are Made, Available online: https:\/\/www.cdc.gov\/flu\/protect\/vaccine\/how-fluvaccine-made.htm."},{"key":"ref_11","unstructured":"Pasteur, S. (2017). Sanofi pasteur: Fluzone quadrivalent (influenza vaccine) package insert. Sanofi Pasteur, Sanofi Pasteur."},{"key":"ref_12","unstructured":"GlaxoSmithKline (2017). Gsk: Fluarix quadrivalent influenza vaccine package insert. GlaxoSmithKline, GlaxoSmithKline."},{"key":"ref_13","unstructured":"Seqirus (2017). Seqirus: Afluria quadrivalent influenza vaccine package insert. Seqirus, Seqirus."},{"key":"ref_14","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_15","unstructured":"Weir, J.P. (2018, February 12). Food and Drug Administration Supplement Approval, Available online: https:\/\/www.fda.gov\/downloads\/BiologicsBloodVaccines\/Vaccines\/ApprovedProducts\/UCM522280.pdf."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"D5","DOI":"10.1016\/j.vaccine.2008.05.076","article-title":"Seasonal inactivated influenza virus vaccines","volume":"26","author":"Couch","year":"2008","journal-title":"Vaccine"},{"key":"ref_17","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_18","doi-asserted-by":"crossref","unstructured":"Krause, J.C., and Crowe, J.E. (2014). Committing the oldest sins in the newest kind of ways-antibodies targeting the influenza virus type a hemagglutinin globular head. Microbiol. Spectr., 2.","DOI":"10.1128\/microbiolspec.AID-0021-2014"},{"key":"ref_19","unstructured":"CDC (2018, February 12). Seasonal Influenza Vaccine Supply & Distribution, Available online: https:\/\/www.cdc.gov\/flu\/about\/qa\/index.htm."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5410","DOI":"10.1016\/j.vaccine.2016.08.019","article-title":"The 2015 global production capacity of seasonal and pandemic influenza vaccine","volume":"34","author":"McLean","year":"2016","journal-title":"Vaccine"},{"key":"ref_21","unstructured":"NCIRD (2018). CDC Vaccine Price List."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"8148","DOI":"10.1038\/ncomms9148","article-title":"Development of high-yield influenza a virus vaccine viruses","volume":"6","author":"Ping","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"E8296","DOI":"10.1073\/pnas.1616530113","article-title":"Development of high-yield influenza B virus vaccine viruses","volume":"113","author":"Ping","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1007\/978-1-61779-621-0_9","article-title":"Influenza virus surveillance, vaccine strain selection and manufacture","volume":"865","author":"Stohr","year":"2012","journal-title":"Methods Mol. Biol."},{"key":"ref_25","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\u20132013 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_26","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/S0042-6822(03)00377-5","article-title":"Receptor-binding properties of modern human influenza viruses primarily isolated in vero and mdck cells and chicken embryonated eggs","volume":"313","author":"Mochalova","year":"2003","journal-title":"Virology"},{"key":"ref_27","unstructured":"World Health Organization (WHO) (2003). Addendum to the Recommended Composition of Influenza Virus Vaccines for Use in the 2003\u20132004 Influenza Season, WHO."},{"key":"ref_28","unstructured":"CDC (2018, February 12). 2003\u20132004 U.S. Influenza Season Summary, Available online: https:\/\/www.cdc.gov\/flu\/weekly\/weeklyarchives2003-2004\/03-04summary.htm."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"12578","DOI":"10.1073\/pnas.1712377114","article-title":"Contemporary H3N2 influenza viruses have a glycosylation site that alters binding of antibodies elicited by egg-adapted vaccine strains","volume":"114","author":"Zost","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.virol.2006.02.020","article-title":"Molecular changes associated with adaptation of human influenza a virus in embryonated chicken eggs","volume":"350","author":"Widjaja","year":"2006","journal-title":"Virology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.tim.2008.01.008","article-title":"Evolving complexities of influenza virus and its receptors","volume":"16","author":"Nicholls","year":"2008","journal-title":"Trends Microbiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.coviro.2012.03.003","article-title":"The role of receptor binding specificity in interspecies transmission of influenza viruses","volume":"2","author":"Imai","year":"2012","journal-title":"Curr. Opin. Virol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.coviro.2016.12.004","article-title":"Immune history and influenza virus susceptibility","volume":"22","author":"Cobey","year":"2017","journal-title":"Curr. Opin. Virol."},{"key":"ref_34","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_35","doi-asserted-by":"crossref","first-page":"180","DOI":"10.15585\/mmwr.mm6706a2","article-title":"Interim estimates of 2017\u20132018 seasonal influenza vaccine effectiveness\u2014United States, February 2018","volume":"67","author":"Flannery","year":"2018","journal-title":"Morb. Mortal. Wkly. Rep."},{"key":"ref_36","unstructured":"CDC (2018, February 12). Cell-Based Flu Vaccines, Available online: https:\/\/www.cdc.gov\/flu\/protect\/vaccine\/cell-based.htm."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1080\/21645515.2015.1016666","article-title":"Cell culture-based influenza vaccines: A necessary and indispensable investment for the future","volume":"11","author":"Hegde","year":"2015","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"504831","DOI":"10.1155\/2015\/504831","article-title":"Current and emerging cell culture manufacturing technologies for influenza vaccines","volume":"2015","author":"Milian","year":"2015","journal-title":"BioMed Res. Int."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"220","DOI":"10.4049\/jimmunol.1201060","article-title":"Toward animal cell culture-based influenza vaccine design: Viral hemagglutinin N-glycosylation markedly impacts immunogenicity","volume":"190","author":"Hutter","year":"2013","journal-title":"J. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3707","DOI":"10.1021\/pr400329k","article-title":"Comparative glycomics analysis of influenza hemagglutinin (H5N1) produced in vaccine relevant cell platforms","volume":"12","author":"An","year":"2013","journal-title":"J. Proteome Res."},{"key":"ref_41","unstructured":"Branswell, H. (2018, March 10). Flu Vaccine Grown without Eggs Provided Measurably Better Protection This Season, FDA Says. Available online: https:\/\/www.pbs.org\/newshour\/health\/flu-vaccine-grown-without-eggs-provided-measurably-better-protection-this-season-fda-says."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1111\/irv.12447","article-title":"The characteristics and antigenic properties of recently emerged subclade 3c.3a and 3c.2a human influenza a(H3N2) viruses passaged in mdck cells","volume":"11","author":"Lin","year":"2017","journal-title":"Influenza Other Respir. Viruses"},{"key":"ref_43","unstructured":"CDC (2018, March 19). Seasonal Influenza Vaccine Supply for the U.S. 2017\u20132018 Influenza Season, Available online: https:\/\/www.cdc.gov\/flu\/about\/qa\/vaxsupply.htm."},{"key":"ref_44","unstructured":"CDC (2018, February 12). Flublok Seasonal Influenza (Flu) Vaccine, Available online: https:\/\/www.cdc.gov\/flu\/protect\/vaccine\/qa_flublok-vaccine.htm."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"S31","DOI":"10.1016\/j.jip.2011.05.003","article-title":"A fast track influenza virus vaccine produced in insect cells","volume":"107","author":"Cox","year":"2011","journal-title":"J. Invertebr. Pathol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"5496","DOI":"10.1016\/j.vaccine.2014.07.074","article-title":"Technology transfer and scale-up of the flublok recombinant hemagglutinin (ha) influenza vaccine manufacturing process","volume":"32","author":"Buckland","year":"2014","journal-title":"Vaccine"},{"key":"ref_47","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_48","unstructured":"NCIRD (2018, February 22). Archived CDC Vaccine Price List as of 2 February 2017, Available online: https:\/\/www.cdc.gov\/vaccines\/programs\/vfc\/awardees\/vaccine-management\/price-list\/2017\/2017-02-02.html."},{"key":"ref_49","unstructured":"CDC (2018, March 20). Fluad\u2122 Flu Vaccine with Adjuvant, Available online: https:\/\/www.cdc.gov\/flu\/protect\/vaccine\/adjuvant.htm."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1586\/erv.12.140","article-title":"The history of mf59((r)) adjuvant: A phoenix that arose from the ashes","volume":"12","author":"Ott","year":"2013","journal-title":"Expert Rev. Vaccines"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"4341","DOI":"10.1016\/j.vaccine.2011.09.061","article-title":"The mechanism of action of mf59\u2014An innately attractive adjuvant formulation","volume":"30","author":"Ott","year":"2012","journal-title":"Vaccine"},{"key":"ref_52","unstructured":"World Health Organization (WHO) (2018, March 20). Squalene-Based Adjuvants in Vaccines. Available online: http:\/\/www.who.int\/vaccine_safety\/committee\/topics\/adjuvants\/squalene\/questions_and_answers\/en\/."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1080\/21645515.2017.1373227","article-title":"Mf59-adjuvanted influenza vaccine (fluad(r)) elicits higher immune responses than a non-adjuvanted influenza vaccine (fluzone(r)): A randomized, multicenter, phase iii pediatric trial in Mexico","volume":"14","author":"Patel","year":"2018","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_54","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_55","doi-asserted-by":"crossref","first-page":"e00669-17","DOI":"10.1128\/mBio.00669-17","article-title":"Rationally designed influenza virus vaccines that are antigenically stable during growth in eggs","volume":"8","author":"Harding","year":"2017","journal-title":"mBio"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"6763","DOI":"10.1128\/JVI.79.11.6763-6771.2005","article-title":"Improvement of influenza a\/Fujian\/411\/02 (H3N2) virus growth in embryonated chicken eggs by balancing the hemagglutinin and neuraminidase activities, using reverse genetics","volume":"79","author":"Lu","year":"2005","journal-title":"J. Virol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2943","DOI":"10.1016\/j.vaccine.2004.08.054","article-title":"Generation of influenza vaccine viruses on vero cells by reverse genetics: An H5N1 candidate vaccine strain produced under a quality system","volume":"23","author":"Nicolson","year":"2005","journal-title":"Vaccine"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"5366","DOI":"10.1016\/j.vaccine.2017.08.021","article-title":"Novel hemagglutinin nanoparticle influenza vaccine with matrix-m adjuvant induces hemagglutination inhibition, neutralizing and protective responses in ferrets against homologous and drifted a(H3N2) subtypes","volume":"35","author":"Smith","year":"2017","journal-title":"Vaccine"},{"key":"ref_59","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_60","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1080\/14760584.2016.1175942","article-title":"Progress in developing virus-like particle influenza vaccines","volume":"15","author":"Quan","year":"2016","journal-title":"Expert Rev. Vaccines"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"3752","DOI":"10.1016\/j.vaccine.2007.01.111","article-title":"Vaccine adjuvants revisited","volume":"25","author":"Aguilar","year":"2007","journal-title":"Vaccine"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1038\/15058","article-title":"Advances in vaccine adjuvants","volume":"17","author":"Singh","year":"1999","journal-title":"Nat. Biotechnol."},{"key":"ref_63","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_64","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_65","doi-asserted-by":"crossref","first-page":"9588","DOI":"10.1073\/pnas.91.20.9588","article-title":"A potential peptide vaccine against two different strains of influenza virus isolated at intervals of about 10 years","volume":"91","author":"Naruse","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_66","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_67","doi-asserted-by":"crossref","first-page":"286","DOI":"10.3389\/fphar.2015.00286","article-title":"Advances and challenges of liposome assisted drug delivery","volume":"6","author":"Sercombe","year":"2015","journal-title":"Front. Pharmacol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1586\/14760584.2013.811195","article-title":"Influenza virosomes as vaccine adjuvant and carrier system","volume":"12","author":"Moser","year":"2013","journal-title":"Expert Rev. Vaccines"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.jconrel.2016.05.008","article-title":"A novel liposomal recombinant lipoimmunogen enhances anti-tumor immunity","volume":"233","author":"Shen","year":"2016","journal-title":"J. Control. Release"},{"key":"ref_70","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_71","doi-asserted-by":"crossref","first-page":"515","DOI":"10.18388\/abp.2014_1873","article-title":"DNA vaccines against influenza","volume":"61","author":"Stachyra","year":"2014","journal-title":"Acta Biochim. Pol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1002\/wrna.1189","article-title":"Messenger rna-based vaccines: Progress, challenges, applications","volume":"4","author":"Kramps","year":"2013","journal-title":"Wiley Interdiscip. Rev. RNA"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1128\/CMR.8.3.406","article-title":"Nucleic acid vaccines","volume":"8","author":"Vogel","year":"1995","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"6946","DOI":"10.1016\/j.vaccine.2012.02.071","article-title":"Influenza A vaccines using linear expression cassettes delivered via electroporation afford full protection against challenge in a mouse model","volume":"30","author":"Shen","year":"2012","journal-title":"Vaccine"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1016\/S1473-3099(11)70240-7","article-title":"DNA priming and influenza vaccine immunogenicity: Two phase 1 open label randomised clinical trials","volume":"11","author":"Ledgerwood","year":"2011","journal-title":"Lancet Infect. Dis."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1792","DOI":"10.1128\/CVI.05663-11","article-title":"Influenza virus H5 DNA vaccination is immunogenic by intramuscular and intradermal routes in humans","volume":"19","author":"Ledgerwood","year":"2012","journal-title":"Clin. Vaccine Immunol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2565","DOI":"10.1016\/j.vaccine.2010.01.029","article-title":"Phase 1 clinical trials of the safety and immunogenicity of adjuvanted plasmid DNA vaccines encoding influenza a virus H5 hemagglutinin","volume":"28","author":"Smith","year":"2010","journal-title":"Vaccine"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2506","DOI":"10.1016\/j.vaccine.2009.02.061","article-title":"DNA vaccination protects against an influenza challenge in a double-blind randomised placebo-controlled phase 1b clinical trial","volume":"27","author":"Jones","year":"2009","journal-title":"Vaccine"},{"key":"ref_79","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_80","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1186\/s13073-017-0450-0","article-title":"Advances in the delivery of rna therapeutics: From concept to clinical reality","volume":"9","author":"Kaczmarek","year":"2017","journal-title":"Genome Med."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1038\/gt.2011.17","article-title":"Selective uptake of naked vaccine rna by dendritic cells is driven by macropinocytosis and abrogated upon dc maturation","volume":"18","author":"Diken","year":"2011","journal-title":"Gene Ther."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"627","DOI":"10.4161\/rna.8.4.15394","article-title":"Protein expression from exogenous mrna: Uptake by receptor-mediated endocytosis and trafficking via the lysosomal pathway","volume":"8","author":"Lorenz","year":"2011","journal-title":"RNA Biol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1586\/erv.09.77","article-title":"DNA vaccines in veterinary use","volume":"8","author":"Redding","year":"2009","journal-title":"Expert Rev. Vaccines"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/j.molmed.2009.06.003","article-title":"Cytoplasmic nucleic acid sensors in antiviral immunity","volume":"15","author":"Ranjan","year":"2009","journal-title":"Trends Mol. Med."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1833","DOI":"10.1038\/mt.2008.200","article-title":"Incorporation of pseudouridine into mrna yields superior nonimmunogenic vector with increased translational capacity and biological stability","volume":"16","author":"Kariko","year":"2008","journal-title":"Mol. Ther."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1146\/annurev-med-120611-145115","article-title":"Toward a universal influenza virus vaccine: Prospects and challenges","volume":"64","author":"Pica","year":"2013","journal-title":"Annu. Rev. Med."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/s12985-017-0918-y","article-title":"Towards a universal influenza vaccine: Different approaches for one goal","volume":"15","author":"Sautto","year":"2018","journal-title":"Virol. J."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/j.cmi.2017.02.009","article-title":"Universal influenza virus vaccines and therapeutic antibodies","volume":"23","author":"Nachbagauer","year":"2017","journal-title":"Clin. Microbiol. Infect."}],"container-title":["Vaccines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-393X\/6\/2\/19\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T14:59:05Z","timestamp":1760194745000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-393X\/6\/2\/19"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,3,30]]},"references-count":88,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2018,6]]}},"alternative-id":["vaccines6020019"],"URL":"https:\/\/doi.org\/10.3390\/vaccines6020019","relation":{},"ISSN":["2076-393X"],"issn-type":[{"value":"2076-393X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,3,30]]}}}