Trained Immunity Empowers Vaccine Design and Application

The COVID-19 pandemic has exposed the limitations of traditional vaccine development models: these approaches rely excessively on pathogen-specific antigen design, feature lengthy development cycles, and struggle to address threats from rapidly mutating pathogens and emerging pathogens. Even before the pandemic, certain traditional vaccines (such as BCG) demonstrated "cross-protection" effects beyond their target diseases. The trained immunity (TRIM) theory offers a promising path to develop broad-spectrum, effective, and durable vaccines. This review summarizes core advances in TRIM within vaccinology, systematically outlining vaccine design strategies based on this concept for the first time. These strategies encompass vaccine-mediated cross-protection, methods to enhance vaccine potency and persistence, pathways to achieve broad-spectrum effects, and regulatory characteristics involving immune recognition, antigen delivery, safety, and tolerability. This study explores the synergistic effects and application prospects of TRIM adjuvants such as β-glucan and Toll-like receptor (TLR) agonists. The impact of transgenerational immune effects on offspring immune function provides a crucial direction for future research. It also highlights current limitations in studies regarding persistence, individual variability, and risks of excessive inflammation. Existing vaccines capable of inducing TRIM will inspire next-generation vaccine development. Innovative applications of this vaccine category can propel the advancement of trained immunity-based vaccines (TIbVs). This review proposes an innovative approach─the "Vaccine Immunity Foundation Hypothesis." This lays the groundwork for designing next-generation vaccines and advancing the clinical translation of TRIM therapies, establishing a theoretical foundation for developing broad-spectrum, highly effective, durable, and safe immune protection strategies.