Integrating immune adverse outcome pathways into vaccine safety evaluation.

Abstract

Adverse outcome pathways (AOPs) have become an internationally recognized framework for chemical risk assessment, linking molecular initiating events (MIEs) to adverse outcomes through measurable key events. Despite their regulatory acceptance in toxicology, no systematic AOPs have yet been developed for vaccines to our knowledge. This commentary argues that extending the AOP paradigm to vaccine adjuvants is both timely and potentially feasible. Adjuvants are chemically defined entities that reproducibly engage innate immune pathways, making them more tractable starting points for immune AOP construction than antigens, which are variable and context-dependent. We illustrate this concept through three exploratory AOP sketches - systemic inflammation, autoimmunity, and hypersensitivity, and provide exemplar biomarker-pathway-adjuvant linkages as a prototype roadmap. Such efforts are not intended to replace existing preclinical, clinical, or pharmacovigilance systems, but to complement them with structured mechanistic context. We propose these as exploratory frameworks to be iteratively refined as evidence accumulates, recognising the complexity and context‑dependence of immune responses. By framing vaccine safety within transparent, testable pathways, immune AOPs could enhance mechanistic understanding of rare adverse events, guide hypothesis-driven use of new approach methodologies (NAMs), and strengthen confidence in vaccine safety science.