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The human immune system is a complex network of coordinated components that are crucial for health and disease. Animal models, commonly used to study immunomodulatory agents, are limited by species-specific differences, low throughput, and ethical concerns. In contrast, in vitro modeling of human immune responses can enable species- and population-specific mechanistic studies and translational development within the same study participant. Translational accuracy of in vitro models is enhanced by accounting for genetic, epigenetic, and demographic features such as age, sex, and comorbidity. This review explores various human in vitro immune models, considers evidence that they may resemble human in vivo responses, and assesses their potential to accelerate and de-risk vaccine discovery and development.