Harnessing trained immunity for next-generation vaccines: from rational adjuvant design to self-adjuvanting antigens

The paradigm of trained immunity (TI), a de facto innate immune memory mediated by metabolic and epigenetic reprogramming of innate leukocytes, has expanded the conceptual framework for rational vaccine adjuvant design. Moving beyond conventional empiricism, TI offers a mechanistic basis that may enhance protection against certain heterologous pathogens, particularly in specific conditions.

This review provides a comprehensive analysis of next-generation adjuvants engineered to induce TI. We outline the core mechanistic foundations encompassing the PI3K/Akt/mTOR/HIF1α-driven immunometabolic switch and ensuing chromatin rewiring, categorize emerging adjuvant strategies from natural TI inducers to synthetic pattern-recognition receptor agonists, direct metabolic-epigenetic modulators, and self-adjuvanting antigens, examine the enabling role of nanotechnology in achieving spatiotemporal control, and discuss translational roadmaps, safety considerations, and pivotal challenges.

TI-inducing adjuvants provide a mechanistic basis for bridging innate and adaptive immunity and represent a promising direction for next-generation vaccine development. Realizing their full potential will require resolving critical challenges in precision-tunability, host heterogeneity, and durability of the trained state, alongside defining validated correlates of protection. The convergence of systems immunology and advanced delivery platforms might accelerate the transition from concept to clinical vaccines, and contribute to the improved preparedness against infectious and noninfectious diseases.