{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T12:39:20Z","timestamp":1791895160908,"version":"4.3.4"},"reference-count":39,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,8,26]],"date-time":"2025-08-26T00:00:00Z","timestamp":1756166400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation (SNF)","doi-asserted-by":"publisher","award":["10001271"],"award-info":[{"award-number":["10001271"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Influenza remains a major health threat due to its high contagiousness and global spread, affecting not only humans but also agricultural livestock and wild animals through transmission via migratory birds. Despite over 70 years of vaccination, influenza still creates epidemics and pandemics, and the ongoing use of vaccination is an essential but currently insufficient strategy. In this study, we assessed the immunogenicity and efficacy of an AP205 virus-like particle (VLP) carrying the HA head domain of the A\/PR8\/H1N1 strain, administered intranasally and subcutaneously in mice. For this purpose, the entire head region of A\/PR8\/H1N1 was genetically integrated into a sterically improved version of AP205, which exhibits capsid monomers fused into a dimer, thereby offering inexpensive and scalable production processes. The vaccine induced strong systemic anti-HA IgG and IgA antibodies via both routes, with no significant difference in the levels of IgG. Both immunisation strategies induced protection against a lethal challenge with H1PR8 mouse-adapted influenza virus. The findings demonstrate the potential of the AP205 VLP platform for HA1-based influenza vaccines and its applicability for controlling influenza in both humans and livestock.<\/jats:p>","DOI":"10.3390\/v17091165","type":"journal-article","created":{"date-parts":[[2025,8,27]],"date-time":"2025-08-27T08:19:32Z","timestamp":1756282772000},"page":"1165","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Versatile and Scalable Nanoparticle Vaccine as a Scaffold Against Newly Emerging Influenza Viruses"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-5493-8893","authenticated-orcid":false,"given":"Alessandro","family":"Pardini","sequence":"first","affiliation":[{"name":"Department of BioMedical Research, University of Bern, 3008 Bern, Switzerland"},{"name":"Department of Rheumatology and Immunology, University Hospital Bern, 3008 Bern, Switzerland"},{"name":"Graduate School of Cellular and Biomedical Sciences, University of Bern, 3008 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominik A.","family":"Rothen","sequence":"additional","affiliation":[{"name":"Department of BioMedical Research, University of Bern, 3008 Bern, Switzerland"},{"name":"Department of Rheumatology and Immunology, University Hospital Bern, 3008 Bern, Switzerland"},{"name":"Graduate School of Cellular and Biomedical Sciences, University of Bern, 3008 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7074-3842","authenticated-orcid":false,"given":"Pascal S.","family":"Krenger","sequence":"additional","affiliation":[{"name":"Department of BioMedical Research, University of Bern, 3008 Bern, Switzerland"},{"name":"Department of Rheumatology and Immunology, University Hospital Bern, 3008 Bern, Switzerland"},{"name":"Graduate School of Cellular and Biomedical Sciences, University of Bern, 3008 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Cathrine","family":"Vogt","sequence":"additional","affiliation":[{"name":"Department of BioMedical Research, University of Bern, 3008 Bern, Switzerland"},{"name":"Department of Rheumatology and Immunology, University Hospital Bern, 3008 Bern, Switzerland"},{"name":"Graduate School of Cellular and Biomedical Sciences, University of Bern, 3008 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romano","family":"Josi","sequence":"additional","affiliation":[{"name":"Department of BioMedical Research, University of Bern, 3008 Bern, Switzerland"},{"name":"Department of Rheumatology and Immunology, University Hospital Bern, 3008 Bern, Switzerland"},{"name":"Graduate School of Cellular and Biomedical Sciences, University of Bern, 3008 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuelan","family":"Liu","sequence":"additional","affiliation":[{"name":"International Immunology Centre, Anhui Agricultural University, Hefei 230036, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaspars","family":"Tars","sequence":"additional","affiliation":[{"name":"Latvian Biomedical Research & Study Centre, Ratsupites iela 1, LV 1067 Riga, Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manfred","family":"Kopf","sequence":"additional","affiliation":[{"name":"Institute of Molecular Health Sciences, ETH Zurich, 8093 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5219-4033","authenticated-orcid":false,"given":"Monique","family":"Vogel","sequence":"additional","affiliation":[{"name":"Department of BioMedical Research, University of Bern, 3008 Bern, Switzerland"},{"name":"Department of Rheumatology and Immunology, University Hospital Bern, 3008 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4370-2099","authenticated-orcid":false,"given":"Martin F.","family":"Bachmann","sequence":"additional","affiliation":[{"name":"Department of BioMedical Research, University of Bern, 3008 Bern, Switzerland"},{"name":"Department of Rheumatology and Immunology, University Hospital Bern, 3008 Bern, Switzerland"},{"name":"Nuffield Department of Medicine, Centre for Cellular and Molecular Physiology (CCMP), The Jenner Institute, University of Oxford, Oxford OX3 7DQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1038\/s41572-018-0006-7","article-title":"Influenza","volume":"4","author":"Krammer","year":"2018","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1016\/S0140-6736(22)00982-5","article-title":"Influenza","volume":"400","author":"Uyeki","year":"2022","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3199","DOI":"10.1016\/j.vaccine.2018.04.063","article-title":"Estimating the annual attack rate of seasonal influenza among unvaccinated individuals: A systematic review and meta-analysis","volume":"36","author":"Somes","year":"2018","journal-title":"Vaccine"},{"key":"ref_4","unstructured":"WHO (2022). Vaccines Against Influenza: WHO Position Paper\u2014May 2022. Wkly. Epidemiol. Rec., 97, 185\u2013208. Available online: https:\/\/iris.who.int\/bitstream\/handle\/10665\/354264\/WER9719-eng-fre.pdf?sequence=1."},{"key":"ref_5","unstructured":"CDC (2024, July 15). Flu Symptoms & Complications | CDC, Available online: https:\/\/archive.cdc.gov\/www_cdc_gov\/flu\/symptoms\/symptoms.htm."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"126408","DOI":"10.1016\/j.vaccine.2024.126408","article-title":"Advancing influenza vaccines: A review of next-generation candidates and their potential for global health impact","volume":"42","author":"Taaffe","year":"2024","journal-title":"Vaccine"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1016\/S1473-3099(23)00117-2","article-title":"Being ready for the next influenza pandemic?","volume":"23","author":"Kuiken","year":"2023","journal-title":"Lancet Infect. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"European Food Safety Authority (EFSA), European Centre for Disease Prevention and Control (ECDC), Melidou, A., Enkirch, T., Willgert, K., Adlhoch, C., Alm, E., Lamb, F., Marangon, S., and Monne, I. (2024). Drivers for a pandemic due to avian influenza and options for One Health mitigation measures. EFSA J., 22, e8735.","DOI":"10.2903\/j.efsa.2024.8735"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Dou, D., Revol, R., \u00d6stbye, H., Wang, H., and Daniels, R. (2018). Influenza A Virus Cell Entry, Replication, Virion Assembly and Movement. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.01581"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1038\/289366a0","article-title":"Structure of the haemagglutinin membrane glycoprotein of influenza virus at 3 \u00c5 resolution","volume":"289","author":"Wilson","year":"1981","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1038\/296115a0","article-title":"Molecular mechanisms of variation in influenza viruses","volume":"296","author":"Webster","year":"1982","journal-title":"Nature"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1038\/s41573-019-0056-x","article-title":"Next-generation influenza vaccines: Opportunities and challenges","volume":"19","author":"Wei","year":"2020","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Skibinski, D.A.G., Hanson, B.J., Lin, Y., von Messling, V., Jegerlehner, A., Tee, J.B.S., Chye, D.H., Wong, S.K.K., Ng, A.A.P., and Lee, H.Y. (2013). Enhanced Neutralizing Antibody Titers and Th1 Polarization from a Novel Escherichia coli Derived Pandemic Influenza Vaccine. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0076571"},{"key":"ref_14","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_15","doi-asserted-by":"crossref","unstructured":"Chen, J., Wang, J., Zhang, J., and Ly, H. (2021). Advances in Development and Application of Influenza Vaccines. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.711997"},{"key":"ref_16","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_17","doi-asserted-by":"crossref","unstructured":"Vogt, A.-C.S., J\u00f6rg, L., Martina, B., Krenger, P.S., Chang, X., Zeltins, A., Vogel, M., Mohsen, M.O., and Bachmann, M.F. (2022). Virus-Like Particles Are Efficient Tools for Boosting mRNA-Induced Antibodies. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.864718"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1111\/all.15897","article-title":"Influence of antigen density and TLR ligands on preclinical efficacy of a VLP-based vaccine against peanut allergy","volume":"79","author":"Krenger","year":"2023","journal-title":"Allergy Eur. J. Allergy Clin. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1038\/s41541-024-01006-8","article-title":"Probing novel epitopes on the Plasmodium falciparum circumsporozoite protein for vaccine development","volume":"9","author":"Krenger","year":"2024","journal-title":"NPJ Vaccines"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Rothen, D.A., Dutta, S.K., Krenger, P.S., Vogt, A.-C.S., Lieknina, I., Sobczak, J.M., Osterhaus, A.D.M.E., Mohsen, M.O., Vogel, M., and Martina, B. (2024). Preclinical Evaluation of Novel Sterically Optimized VLP-Based Vaccines against All Four DENV Serotypes. Vaccines, 12.","DOI":"10.3390\/vaccines12080874"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"109439","DOI":"10.1016\/j.isci.2024.109439","article-title":"A tetravalent nanovaccine that inhibits growth of HPV-associated head and neck carcinoma via dendritic and T cell activation","volume":"27","author":"Josi","year":"2024","journal-title":"iScience"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Josi, R., Pardini, A., Haindrich, A., Marar, S.V., Vogt, A.-C.S., Gessler, A., Rentsch, D., Cherubini, P., Bachmann, M.F., and Mohsen, M.O. (2024). Green Routes: Exploring Protein-Based Virus-like Nanoparticle Transport and Immune Activation in Nicotiana benthamiana for Biotechnological Applications. Vaccines, 12.","DOI":"10.3390\/vaccines12080831"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Rothen, D.A., Dutta, S.K., Krenger, P.S., Pardini, A., Vogt, A.-C.S., Josi, R., Lieknina, I., Osterhaus, A.D.M.E., Mohsen, M.O., and Vogel, M. (2024). Preclinical Development of a Novel Zika Virus-like Particle Vaccine in Combination with Tetravalent Dengue Virus-like Particle Vaccines. Vaccines, 12.","DOI":"10.3390\/vaccines12091053"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1038\/s41423-022-00897-8","article-title":"Virus-like particle vaccinology, from bench to bedside","volume":"19","author":"Mohsen","year":"2022","journal-title":"Cell. Mol. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.smim.2017.08.014","article-title":"Major findings and recent advances in virus\u2013like particle (VLP)-based vaccines","volume":"34","author":"Mohsen","year":"2017","journal-title":"Semin. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1515\/BC.2008.064","article-title":"The coming of age of virus-like particle vaccines","volume":"389","author":"Jennings","year":"2008","journal-title":"Biol. Chem."},{"key":"ref_27","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_28","doi-asserted-by":"crossref","first-page":"4267","DOI":"10.1016\/j.jmb.2016.08.025","article-title":"Structure of AP205 Coat Protein Reveals Circular Permutation in ssRNA Bacteriophages","volume":"428","author":"Shishovs","year":"2016","journal-title":"J. Mol. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Liu, X., Chang, X., Rothen, D., Derveni, M., Krenger, P., Roongta, S., Wright, E., Vogel, M., Tars, K., and Mohsen, M.O. (2021). AP205 VLPs Based on Dimerized Capsid Proteins Accommodate RBM Domain of SARS-CoV-2 and Serve as an Attractive Vaccine Candidate. Vaccines, 9.","DOI":"10.3390\/vaccines9040403"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Sun, F., Xiao, G., and Qu, Z. (2017). Murine Bronchoalveolar Lavage. Bio-Protocol, 7.","DOI":"10.21769\/BioProtoc.2287"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"85","DOI":"10.5501\/wjv.v5.i2.85","article-title":"Determination of 50% endpoint titer using a simple formula","volume":"5","author":"Ramakrishnan","year":"2016","journal-title":"World J. Virol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Chan, L., Alizadeh, K., Alizadeh, K., Fazel, F., Kakish, J.E., Karimi, N., Knapp, J.P., Mehrani, Y., Minott, J.A., and Morovati, S. (2021). Review of Influenza Virus Vaccines: The Qualitative Nature of Immune Responses to Infection and Vaccination Is a Critical Consideration. Vaccines, 9.","DOI":"10.3390\/vaccines9090979"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3338","DOI":"10.1038\/s41467-019-11296-5","article-title":"Repeat vaccination reduces antibody affinity maturation across different influenza vaccine platforms in humans","volume":"10","author":"Khurana","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2446","DOI":"10.1111\/all.15311","article-title":"Intranasal administration of a virus like particles-based vaccine induces neutralizing antibodies against SARS-CoV-2 and variants of concern","volume":"77","author":"Rothen","year":"2022","journal-title":"Allergy Eur. J. Allergy Clin. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3788","DOI":"10.4049\/jimmunol.0804004","article-title":"Alveolar Macrophages and Lung Dendritic Cells Sense RNA and Drive Mucosal IgA Responses","volume":"183","author":"Bessa","year":"2009","journal-title":"J. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"8053","DOI":"10.1038\/s41467-023-43842-7","article-title":"Early mucosal events promote distinct mucosal and systemic antibody responses to live attenuated influenza vaccine","volume":"14","author":"Thwaites","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1038\/s41577-021-00583-2","article-title":"Mucosal vaccines\u2014Fortifying the frontiers","volume":"22","author":"Lavelle","year":"2021","journal-title":"Nat. Rev. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/j.jconrel.2010.08.012","article-title":"Administration routes affect the quality of immune responses: A cross-sectional evaluation of particulate antigen-delivery systems","volume":"147","author":"Mohanan","year":"2010","journal-title":"J. Control. Release"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1038\/nri1777","article-title":"Mucosal vaccines: The promise and the challenge","volume":"6","author":"Neutra","year":"2006","journal-title":"Nat. Rev. Immunol."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/17\/9\/1165\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:33:24Z","timestamp":1760034804000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/17\/9\/1165"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,26]]},"references-count":39,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["v17091165"],"URL":"https:\/\/doi.org\/10.3390\/v17091165","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,26]]}}}