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Populations that are particularly vulnerable to infections, such as neonates, infants, and older adults, exhibit distinct immunological profiles contributing to sub-optimal responses to conventional vaccines. Historically, vaccine development has relied on animal models; however, these are limited by low-throughput, bioethical concerns, and species-specific biological differences that do not reliably predict human responses. Moreover, conventional methods of adjuvant discovery and development have failed to consider that human immune responses vary by a range of demographic features, especially age, leading to failure of multiple candidate adjuvanted vaccines in clinical trials. Spurred in part by the U.S. Food & Drug Administration Modernization Act 2.0, a paradigm shift in preclinical approaches to drug and vaccine discovery and development is taking place. In recognition of the complexity of the human immune system, there is an increase in the development of age-specific human in vitro platforms, such as primary cell assays, tissue-engineered constructs, and organ-on-a-chip technologies, as an alternative to animal models. Such systems enable high-throughput evaluation of population-specific reactogenicity and immunogenicity of vaccines, facilitating the discovery of age-tailored adjuvant formulations. Specifically, these models can capture primary and trained innate immune responses, antigen-presenting cell (APC) activation, and the complex APC-T and T-B cellular crosstalk that shapes adaptive immunity. Despite their potential, challenges remain in standardizing models to reflect the multi-organ interplay underlying vaccine-induced immune responses. In this review, we highlight key technological advances in age-specific adjuvant discovery, with a primary focus on early life and older adulthood - the periods of greatest immunological vulnerability and distinctiveness. We discuss the successes and current limitations of bench-to-bedside translation and explore the evolving regulatory landscape. Integrating human biology early in the vaccine development pipeline at these critical stages of the lifespan can ensure that next-generation adjuvants are optimized for robust, age-appropriate host defense.