Human Organoids in Infectious Disease Research: From Host–Pathogen Interactions to Vaccine Development

Background/Objectives: Human organoids have emerged as physiologically relevant models bridging conventional two-dimensional cultures and animal models. This review summarizes advances in their application to infectious disease modeling and vaccine research, with emphasis on host–pathogen interactions, immune responses, and translational potential. Methods: A narrative review was conducted using targeted searches of PubMed, Scopus, Web of Science Core Collection, and ScienceDirect. Publications from January 2000 to June 2026 were considered, and relevant evidence was qualitatively synthesized according to established applications, proof-of-concept studies, and prospective uses. Results: Human organoids have advanced the study of viral, bacterial, parasitic, and fungal infections by enabling investigation of pathogen entry, tissue tropism, barrier integrity, and immune responses in human-relevant systems. Immune and tonsil-derived organoids have also demonstrated applications in evaluating vaccine-induced immunity, comparing vaccine formulations, investigating mechanisms of immunogenicity, and identifying potential correlates of protection. Integration with single-cell and spatial omics, advanced imaging, and computational approaches is further expanding their utility. However, incomplete immune and vascular complexity, inter-model variability, limited standardization, scalability constraints, and insufficient validation against in vivo and clinical outcomes remain important challenges. Conclusions: Human organoids represent complementary human-relevant platforms with substantial potential for mechanistic and translational vaccinology. Further standardization and prospective validation are required to establish their predictive value for vaccine development.