Development of a Human Lymph node-on a Chip Microphysiological System for Evaluation of Vaccine Effectiveness against Infectious Diseases - PROJECT SUMMARY Vaccines play an essential role in controlling and preventing infectious diseases in humans. The efficacy of vaccine depends on the extent to which the vaccine enhances the adaptive immune response in the body, which remembers and eliminates the foreign invader. However, the lack of reliable preclinical model for human adaptive immunity modeling and vaccine assessment have frequently led to vaccine products failing in clinical trials. Interspecies differences between current animal models and humans hinder accurate replication of human immune responses for vaccine assessment. Adaptive immune response to vaccine is mainly initiated in lymph nodes (LNs), which serve as vital hubs for various types of adaptive immune-related lymphocytes. LNs are highly structured secondary lymphoid organs with essential functions reliant on the unique spatial arrangement of lymphocytes and stromal cells as well as chemokines that drive the signaling cascades underlying the adaptive immune response. After vaccination, vaccines drain to the LNs, where antigen- presenting cells recognize and phagocytize vaccine antigens to induce T cell and naïve B cell activation and differentiation for antibody secretion that sustain long-term immune responses. Changes in the LN niche such as depletion of CD4+ T cells, reduced germinal centers, and LN extracellular matrix (ECM) fibrosis due to genetic variation, disease, aging, or chronic inflammation can lead to delayed immune responses affecting vaccine efficacy across populations. Developing models of LNs that accurately replicate their intact immune niche, describing the dynamics and organization of LNs, is a significant challenge in human adaptive immunity research. To date, no reliable in vitro model of LNs has been able to simulate the complete dynamic process of adaptive immunity for vaccine assessment. In this work we aim to develop a human “Lymph node-on-a-Chip” microphysiological system with microanatomic organization of key functional compartments (paracortex, follicle, subcapsular sinus, lymphatic and blood vessels) with full spectrum of LN cell types (dendritic cells, T cells, B cells, fibroblasts) and continuous lymph fluid perfusion to replicate the in vivo physiology of human LN microenvironment. These underscores the pressing importance of devising more clinically relevant vaccine testing models. The human Lymph node-on-a-Chip will serve as a unique precision medicine platform that provides a more accurate representation of adaptive immune responses than traditional animal models for vaccine effectiveness evaluation. This technology with a novel “clinical trials on a chip” protocol allows an accurate assessment of vaccines and adjuvants against emerging infectious diseases, thus aids in optimizing vaccination strategies for optimal protection for different populations.
