Abstract
The development of effective vaccines against emerging infectious diseases, including avian influenza strains such as H5N1 and H7N9, is hindered by the limited translational fidelity of animal models and the low throughput of traditional preclinical platforms. Human immune organoids are ex vivo, multicellular, lymphoid cultures derived from tonsil, or spleen tissue, offering a physiologically relevant and scalable system to model human germinal center biology and vaccine responses. We describe how tonsil and spleen organoids can support the rationale design of antigen and adjuvant for influenza vaccines. Coupled antigen strategies, which leverage pre-existing memory T cells, can significantly enhance responses to weak antigens, such as avian HA. Moreover, a cytokine screen performed in human immune organoids revealed distinct adjuvanticity profiles and mapped functional axes involving type I interferons and IL-12/IL-21 signaling. We propose a new paradigm: functional systems immunology, combining mechanistic perturbation in human immune organoids with high-dimensional immune profiling. This platform will enable the causal dissection of human immune regulation at a large scale. High-throughput screen of candidates will enable efficient vaccine designs.