A Human Lymph node-on-a-Chip for Personalized Evaluation of Vaccine Immunogenicity.

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.