{"paper_id":"1148bad0-efd0-4f96-bf1f-fdbe44f970c8","body_text":"A Human Lymph node-on-a-Chip for Personalized Evaluation of Vaccine Immunogenicity | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article A Human Lymph node-on-a-Chip for Personalized Evaluation of Vaccine Immunogenicity Weiqiang Chen, Fanghao Shi, Dongdong Liu, Yujing Song, John Manoyan, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8951191/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Vaccines have revolutionized public health, yet their development remains hampered by the poor predictive power of animal models, leading to high clinical failure rates and variable efficacy across populations. To bridge this translational gap, we developed a human lymph node-on-a-chip model that biomimetically reproduces key physiological features of human lymph node, including compartmentalized immune cell zones and functional stromal networks. This immunocompetent model recapitulates the complete cascade of vaccine-induced adaptive immune processes in human lymph nodes, from antigen presentation, immune cell differentiation to germinal center formation and antibody secretion, providing a human-relevant platform for preclinical vaccine testing. Using donor-matched immune cells from influenza vaccine trials, we established a personalized clinical-trial-on-chip platform that accurately mirrors individual vaccine responses. Benchmarking on-chip immunogenicity readouts against clinical serological and transcriptomic data confirmed the platform's predictive power for assessing vaccine efficacy across diverse populations. Our study uncovered a key mechanism of vaccine failure in vulnerable populations: age- and comorbidities-related factors impair T follicular helper cell differentiation and disrupt critical T-B cell interactions. Single-cell transcriptomic profiling revealed critical immune signaling networks involving MyD88 in DCs, IL-2/STAT5 balance in T cells, and TACI/BCMA activation in B cells that collectively govern the efficiency of the adaptive immune cascade. These mechanistic insights enabled us to validate clinically actionable strategies, including dose escalation and IL-2 cytokine adjuvant as effective countermeasures to enhance immunogenicity efficiency in immunocompromised individuals. These results demonstrate the potential of this human lymph node-on-a-chip as a transformative precision vaccinology tool for personalized vaccine immunogenicity assessment and optimization. Biological sciences/Biological techniques/Lab-on-a-chip Biological sciences/Immunology/Lymphoid tissues/Lymph node Physical sciences/Engineering/Biomedical engineering Full Text Additional Declarations Yes there is potential Competing Interest. W.C. and F.S. are coinventors on a U.S. provisional patent application (19/214,577) submitted by New York University that covers “Lymph Node on a Chip Device and Method”. The other authors declare that they have no competing interests. Supplementary Files SI20260223.pdf SUPPLEMENTARY INFORMATION Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {\"props\":{\"pageProps\":{\"initialData\":{\"identity\":\"rs-8951191\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":false,\"archivedVersions\":[],\"articleType\":\"Article\",\"associatedPublications\":[],\"authors\":[{\"id\":606811444,\"identity\":\"fd14f00d-9b98-4abe-b77f-78b8c2d32896\",\"order_by\":0,\"name\":\"Weiqiang 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