Engineering Human Donor Derived Germinal Center‐Like Organoids (GCLOs) for Studying Immune Response to Vaccination

ABSTRACT Germinal centers (GCs) are transient microanatomical structures that coordinate humoral immune responses through dynamic interactions between antigen presenting cells, T follicular helper cells, and B cells. Despite their central importance to immune protection, GC human biology remains difficult to interrogate due to significant inter‐species variability, limited experimental accessibility to primary human tissues, and high interindividual variability. We developed a human immune culture platform that supports spontaneous multicellular organization of human peripheral blood mononuclear cells derived from primary CD19+ B cells, memory CD4+ T cells, and monocyte‐derived dendritic cells into Germinal Center‐like Organoids (GCLOs). These bioengineered GCLOs self‐organize into stable clusters that exhibit stimulus and donor dependent differences in cellular composition and function. We observed the emergence of GC‐like T and B cell subsets, functional IgG output, and the appearance of plasmablast‐like populations. Notably, the age of the donors and the type of stimuli influenced GCLOs architecture, immune subsets, and antibody output. Platform outputs showed correspondence with clinical vaccine responsiveness across human donors, capturing inter‐individual differences in humoral GCLO immune responses to the flu vaccine, including age‐associated trends consistent with immunosenescence. This platform allows scalable investigation of human GC‐associated immune features and provides a tractable framework for studying donor heterogeneity in humoral immunity.