{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T08:43:18Z","timestamp":1781599398919,"version":"3.54.5"},"reference-count":30,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T00:00:00Z","timestamp":1756857600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Swiss National Science Foundation (SNF)","award":["10001271"],"award-info":[{"award-number":["10001271"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>Introduction: Dengue virus (DENV) remains a global health threat, with four distinct serotypes (DENV1-4) that complicate vaccine development due to low-affinity, cross-reactive antibodies that increase the risk of antibody-dependent enhancement (ADE). Objective: To address the challenge of inducing strictly serotype-specific immune responses, this study explored the use of targeting individual lymph nodes (LNs) for the creation of simultaneous but independent immune responses as a targeted approach to reduce cross-reactivity and improve vaccine specificity. Methods: In the initial experiments, targeting individual LN successfully induced specific germinal centers (GCs) for different antigens in distinct LNs, highlighting its potential to enhance immune specificity. This approach was further tested using two virus-like particle (VLP)-based vaccines based on AP205 for DENV1 and DENV4, selected due to their genetic divergence and to probe the potential to minimize cross-reactive immune responses. In this setup, AP205-DV1 and AP205-DV4 were administered in targeted separate LNs, and the specificity of the immune response was compared to subcutaneous administration of a mixture of both vaccines. Results: Our data show that targeting distinct LNs elicited antibodies with significantly higher avidity, which is a critical factor in determining the neutralizing capacity of the immune response. Avidity measurements confirmed that this segregation approach results in a more refined selection of high-affinity B cells. Neutralization experiments demonstrated that targeting distinct LNs with individual vaccines induced a more potent and serotype-specific neutralizing response, compared to the injection of a vaccine mixture. Conclusions: These findings suggest that targeting individual LNs could be a promising method for enhancing both the specificity and potency of immune responses, particularly for flaviviruses. Targeting distinct LNs by direct administration of individual vaccines into distinct watersheds rather than individual lymph nodes will offer the opportunity to facilitate the approach in humans.<\/jats:p>","DOI":"10.3390\/vaccines13090941","type":"journal-article","created":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T09:18:57Z","timestamp":1756977537000},"page":"941","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Targeted Lymph Node Immunization with Serotype-Specific Dengue VLP Vaccines Enhances Antibody Avidity and Specificity"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-3048-4478","authenticated-orcid":false,"given":"Dominik","family":"Rothen","sequence":"first","affiliation":[{"name":"Department of BioMedical Research, University of Bern, 3008 Bern, Switzerland"},{"name":"Department of Immunology RIA, University Hospital Bern, 3010 Bern, Switzerland"},{"name":"Graduate School of Cellular and Biomedical Sciences, University of Bern, 3012 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5493-8893","authenticated-orcid":false,"given":"Alessandro","family":"Pardini","sequence":"additional","affiliation":[{"name":"Department of BioMedical Research, University of Bern, 3008 Bern, Switzerland"},{"name":"Department of Immunology RIA, University Hospital Bern, 3010 Bern, Switzerland"},{"name":"Graduate School of Cellular and Biomedical Sciences, University of Bern, 3012 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-4991-6640","authenticated-orcid":false,"given":"Sudip","family":"Dutta","sequence":"additional","affiliation":[{"name":"Artemis Bioservices, 2629 JD Delft, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascal","family":"Krenger","sequence":"additional","affiliation":[{"name":"Department of BioMedical Research, University of Bern, 3008 Bern, Switzerland"},{"name":"Department of Immunology RIA, University Hospital Bern, 3010 Bern, Switzerland"},{"name":"Graduate School of Cellular and Biomedical Sciences, University of Bern, 3012 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 Immunology RIA, University Hospital Bern, 3010 Bern, Switzerland"},{"name":"Graduate School of Cellular and Biomedical Sciences, University of Bern, 3012 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 Immunology RIA, University Hospital Bern, 3010 Bern, Switzerland"},{"name":"Graduate School of Cellular and Biomedical Sciences, University of Bern, 3012 Bern, 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 Immunology RIA, University Hospital Bern, 3010 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3409-512X","authenticated-orcid":false,"given":"Paul","family":"Engeroff","sequence":"additional","affiliation":[{"name":"Department of BioMedical Research, University of Bern, 3008 Bern, Switzerland"},{"name":"Department of Immunology RIA, University Hospital Bern, 3010 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mona","family":"Mohsen","sequence":"additional","affiliation":[{"name":"Department of BioMedical Research, University of Bern, 3008 Bern, Switzerland"},{"name":"Department of Immunology RIA, University Hospital Bern, 3010 Bern, Switzerland"},{"name":"Tajarub Research & Development, Doha P.O. Box 12627, Qatar"}],"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":"Byron","family":"Martina","sequence":"additional","affiliation":[{"name":"Artemis Bioservices, 2629 JD Delft, The Netherlands"},{"name":"Curacao Biomedical & Health Research Institute, Pater Eeuwensweg 36, Willemstad, Cura\u00e7ao"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4370-2099","authenticated-orcid":false,"given":"Martin","family":"Bachmann","sequence":"additional","affiliation":[{"name":"Department of BioMedical Research, University of Bern, 3008 Bern, Switzerland"},{"name":"Department of Immunology RIA, University Hospital Bern, 3010 Bern, Switzerland"},{"name":"Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1038\/nature12060","article-title":"The global distribution and burden of dengue","volume":"496","author":"Bhatt","year":"2013","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1038\/s41564-019-0392-y","article-title":"Antibody responses to viral infections: A structural perspective across three different enveloped viruses","volume":"4","author":"Murin","year":"2019","journal-title":"Nat. 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