{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T20:17:37Z","timestamp":1770063457515,"version":"3.49.0"},"reference-count":49,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2020,7,15]],"date-time":"2020-07-15T00:00:00Z","timestamp":1594771200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004836","name":"Independent Research Fund Denmark","doi-asserted-by":"publisher","award":["6110-00177B"],"award-info":[{"award-number":["6110-00177B"]}],"id":[{"id":"10.13039\/501100004836","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012774","name":"Innovation fund Denmark","doi-asserted-by":"publisher","award":["8088-00032B"],"award-info":[{"award-number":["8088-00032B"]}],"id":[{"id":"10.13039\/100012774","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>Due to constant antigenic drift and shift, current influenza-A vaccines need to be redesigned and administered annually. A universal flu vaccine (UFV) that provides long-lasting protection against both seasonal and emerging pandemic influenza strains is thus urgently needed. The hemagglutinin (HA) stem antigen is a promising target for such a vaccine as it contains neutralizing epitopes, known to induce cross-protective IgG responses against a wide variety of influenza subtypes. In this study, we describe the development of a UFV candidate consisting of a HAstem trimer displayed on the surface of rigid capsid-like particles (CLP). Compared to soluble unconjugated HAstem trimer, the CLP-HAstem particles induced a more potent, long-lasting immune response and were able to protect mice against both homologous and heterologous H1N1 influenza challenge, even after a single dose.<\/jats:p>","DOI":"10.3390\/vaccines8030389","type":"journal-article","created":{"date-parts":[[2020,7,16]],"date-time":"2020-07-16T10:54:46Z","timestamp":1594896886000},"page":"389","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["A Vaccine Displaying a Trimeric Influenza-A HA Stem Protein on Capsid-Like Particles Elicits Potent and Long-Lasting Protection in Mice"],"prefix":"10.3390","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6596-3527","authenticated-orcid":false,"given":"Susan","family":"Thrane","sequence":"first","affiliation":[{"name":"Department of Immunology and Microbiology, University of Copenhagen, 2200 Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0068-7733","authenticated-orcid":false,"given":"Kara-Lee","family":"Aves","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, University of Copenhagen, 2200 Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6007-5918","authenticated-orcid":false,"given":"Ida E. M","family":"Uddb\u00e4ck","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, University of Copenhagen, 2200 Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6529-9355","authenticated-orcid":false,"given":"Christoph M.","family":"Janitzek","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, University of Copenhagen, 2200 Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3402-2609","authenticated-orcid":false,"given":"Julianna","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuhe R.","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7153-3769","authenticated-orcid":false,"given":"Andrew B.","family":"Ward","sequence":"additional","affiliation":[{"name":"Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thor G.","family":"Theander","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, University of Copenhagen, 2200 Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2668-4992","authenticated-orcid":false,"given":"Morten A.","family":"Nielsen","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, University of Copenhagen, 2200 Copenhagen, Denmark"},{"name":"AdaptVac Aps, Agern Alle 1, 2970 H\u00f8rsholm, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ali","family":"Salanti","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, University of Copenhagen, 2200 Copenhagen, Denmark"},{"name":"AdaptVac Aps, Agern Alle 1, 2970 H\u00f8rsholm, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2392-9803","authenticated-orcid":false,"given":"Allan R.","family":"Thomsen","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, University of Copenhagen, 2200 Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4299-9479","authenticated-orcid":false,"given":"Jan P.","family":"Christensen","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, University of Copenhagen, 2200 Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8782-7830","authenticated-orcid":false,"given":"Adam F.","family":"Sander","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, University of Copenhagen, 2200 Copenhagen, Denmark"},{"name":"AdaptVac Aps, Agern Alle 1, 2970 H\u00f8rsholm, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,15]]},"reference":[{"key":"ref_1","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":"Luliano","year":"2018","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1089\/vim.2017.0141","article-title":"Influenza Virus: Dealing with a Drifting and Shifting Pathogen","volume":"31","author":"Kim","year":"2018","journal-title":"Viral Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/nature14460","article-title":"Global circulation patterns of seasonal influenza viruses vary with antigenic drift","volume":"523","author":"Bedford","year":"2015","journal-title":"Nature"},{"key":"ref_4","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_5","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1093\/infdis\/jiy633","article-title":"Influenza Vaccines: Good, but We Can Do Better","volume":"219","author":"Paules","year":"2019","journal-title":"J. Infect. Dis."},{"key":"ref_6","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_7","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1056\/NEJMp1714916","article-title":"Chasing seasonal influenza-The need for a universal influenza vaccine","volume":"378","author":"Paules","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1586\/14760584.2016.1115352","article-title":"Strategies towards universal pandemic influenza vaccines","volume":"15","author":"He","year":"2016","journal-title":"Expert Rev. Vaccines"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.it.2017.08.003","article-title":"From Original Antigenic Sin to the Universal Influenza Virus Vaccine","volume":"39","author":"Henry","year":"2018","journal-title":"Trends Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1","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_11","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1126\/science.aac7263","article-title":"A stable trimeric influenza hemagglutinin stem as a broadly protective immunogen","volume":"349","author":"Impagliazzo","year":"2015","journal-title":"Science"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2350","DOI":"10.3389\/fimmu.2018.02350","article-title":"Mini-HA Is Superior to Full Length Hemagglutinin Immunization in Inducing Stem-Specific Antibodies and Protection Against Group 1 Influenza Virus Challenges in Mice","volume":"9","author":"Verspuij","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_13","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_14","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.virol.2018.10.005","article-title":"Development of a universal influenza vaccine using hemagglutinin stem protein produced from Pichia pastoris","volume":"526","author":"Wang","year":"2019","journal-title":"Virology"},{"key":"ref_15","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_16","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1016\/j.vaccine.2017.12.053","article-title":"A virus-like particle vaccine candidate for influenza A virus based on multiple conserved antigens presented on hepatitis B tandem core particles","volume":"36","author":"Ramirez","year":"2018","journal-title":"Vaccine"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.1080\/21645515.2017.1290018","article-title":"Fc or not Fc; that is the question: Antibody Fc-receptor interactions are key to universal influenza vaccine design","volume":"13","author":"Jegaskanda","year":"2017","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1172\/JCI84428","article-title":"Broadly neutralizing anti-influenza antibodies require Fc receptor engagement for in vivo protection","volume":"126","author":"DiLillo","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Kirsteina, A., Akopjana, I., Bogans, J., Lieknina, I., Jansons, J., Skrastina, D., Kazaka, T., Tars, K., Isakova-Sivak, I., and Mezhenskaya, D. (2020). Construction and Immunogenicity of a Novel Multivalent Vaccine Prototype Based on Conserved Influenza Virus Antigens. Vaccines, 8.","DOI":"10.3390\/vaccines8020197"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1172\/JCI123366","article-title":"Subdominance and poor intrinsic immunogenicity limit humoral immunity targeting influenza HA stem","volume":"129","author":"Tan","year":"2019","journal-title":"J. Clin. Investig."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1038\/nri2868","article-title":"Vaccine delivery: A matter of size, geometry, kinetics and molecular patterns","volume":"10","author":"Bachmann","year":"2010","journal-title":"Nat. Rev. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3724","DOI":"10.4049\/jimmunol.1103312","article-title":"Innate Immunity Mediates Follicular Transport of Particulate but Not Soluble Protein Antigen","volume":"188","author":"Link","year":"2012","journal-title":"J. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12951-016-0181-1","article-title":"Bacterial superglue enables easy development of efficient virus - like particle based vaccines","volume":"14","author":"Thrane","year":"2016","journal-title":"J. Nanobiotechno."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-019-41522-5","article-title":"A proof-of-concept study for the design of a VLP-based combinatorial HPV and placental malaria vaccine","volume":"9","author":"Janitzek","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/2162402X.2017.1408749","article-title":"Virus-like particle display of HER2 induces potent anti-cancer responses","volume":"7","author":"Palladini","year":"2018","journal-title":"Oncoimmunology"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Aves, K.-L., Goks\u00f8yr, L., and Sander, A.F. (2020). Advantages and Prospects of Tag\/Catcher Mediated Antigen Display on Capsid-Like Particle-Based Vaccines. Viruses, 12.","DOI":"10.3390\/v12020185"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1038\/s41586-019-1250-z","article-title":"Immunization expands B cells specific to HIV-1 V3 glycan in mice and macaques","volume":"570","author":"Escolano","year":"2019","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.3389\/fimmu.2019.01256","article-title":"Pfs230 and Pfs48\/45 Fusion Proteins Elicit Strong Transmission-Blocking Antibody Responses Against Plasmodium falciparum","volume":"10","author":"Singh","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.jsb.2005.03.010","article-title":"Automated molecular microscopy: The new Leginon system","volume":"151","author":"Suloway","year":"2005","journal-title":"J. Struct. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.jsb.2009.01.002","article-title":"Appion: An integrated, database-driven pipeline to facilitate EM image processing","volume":"166","author":"Lander","year":"2009","journal-title":"J. Struct. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/j.jsb.2012.09.006","article-title":"RELION: Implementation of a Bayesian approach to cryo-EM structure determination","volume":"180","author":"Scheres","year":"2012","journal-title":"J. Struct. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4647","DOI":"10.1016\/j.vaccine.2013.07.052","article-title":"A universal virus-like particle-based vaccine for human papillomavirus: Longevity of protection and role of endogenous and exogenous adjuvants","volume":"31","author":"Tumban","year":"2013","journal-title":"Vaccine"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/srep20137","article-title":"Combined local and systemic immunization is essential for durable T-cell mediated heterosubtypic immunity against influenza A virus","volume":"6","author":"Uddback","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1928","DOI":"10.3389\/fimmu.2017.01928","article-title":"Seasonal Influenza Split Vaccines Confer Partial Cross-Protection against Heterologous Influenza Virus in Ferrets When Combined with the CAF01 Adjuvant","volume":"8","author":"Christensen","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1016\/j.cell.2016.05.073","article-title":"Structure and Function Analysis of an Antibody Recognizing All Influenza A Subtypes","volume":"166","author":"Kallewaard","year":"2016","journal-title":"Cell"},{"key":"ref_36","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_37","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/j.chom.2018.09.010","article-title":"Recurring and Adaptable Binding Motifs in Broadly Neutralizing Antibodies to Influenza Virus Are Encoded on the D3-9 Segment of the Ig Gene","volume":"24","author":"Wu","year":"2018","journal-title":"Cell Host Microbe"},{"key":"ref_38","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_39","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_40","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/j.chom.2019.01.002","article-title":"Influenza Virus Vaccination Elicits Poorly Adapted B Cell Responses in Elderly Individuals","volume":"25","author":"Henry","year":"2019","journal-title":"Cell Host Microbe"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"6367","DOI":"10.1016\/j.vaccine.2006.07.021","article-title":"A global pandemic influenza vaccine action plan","volume":"24","author":"Kieny","year":"2006","journal-title":"Vaccine"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1080\/14760584.2019.1578216","article-title":"Immunological basis for enhanced immunity of nanoparticle vaccines","volume":"18","author":"Kelly","year":"2019","journal-title":"Expert Rev. Vaccines"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-017-03798-3","article-title":"Nanoassembly routes stimulate conflicting antibody quantity and quality for transmission-blocking malaria vaccines","volume":"7","author":"Leneghan","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Gomes, A.C., Roesti, E.S., El-Turabi, A., and Bachmann, M.F. (2019). Type of RNA Packed in VLPs Impacts IgG Class Switching\u2014Implications for an Influenza Vaccine Design. Vaccines, 7.","DOI":"10.3390\/vaccines7020047"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"6358","DOI":"10.1016\/j.vaccine.2009.06.090","article-title":"Antibody quantity versus quality after influenza vaccination","volume":"27","author":"Feng","year":"2009","journal-title":"Vaccine"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1038\/nm.3443","article-title":"Broadly neutralizing hemagglutinin stalk-specific antibodies require FcR interactions for protection against influenza virus in vivo","volume":"20","author":"Dilillo","year":"2014","journal-title":"Nat. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1002\/eji.201041225","article-title":"Universal vaccine against influenza virus: Linking TLR signaling to anti-viral protection","volume":"42","author":"Schmitz","year":"2012","journal-title":"Eur. J. Immunol."},{"key":"ref_48","first-page":"1","article-title":"Hierarchical and Redundant Roles of Activating Fc\u03b3Rs in Protection against Influenza Disease by M2e-Specific IgG1 and IgG2a Antibodies","volume":"91","author":"Ehrhardt","year":"2017","journal-title":"J. Virol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/j.immuni.2018.07.009","article-title":"Electron-Microscopy-Based Epitope Mapping Defines Specificities of Polyclonal Antibodies Elicited during HIV-1 BG505 Envelope Trimer Immunization","volume":"49","author":"Bianchi","year":"2018","journal-title":"Immunity"}],"container-title":["Vaccines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-393X\/8\/3\/389\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:48:52Z","timestamp":1760176132000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-393X\/8\/3\/389"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,15]]},"references-count":49,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2020,9]]}},"alternative-id":["vaccines8030389"],"URL":"https:\/\/doi.org\/10.3390\/vaccines8030389","relation":{},"ISSN":["2076-393X"],"issn-type":[{"value":"2076-393X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,7,15]]}}}