A roadmap for modernizing vaccine safety assessment: Challenges and opportunities for new approach methodologies

Vaccines are administered to large populations of healthy individuals, including vulnerable groups, making an exceptionally rigorous safety profile a prerequisite for their approval and use. Nonclinical vaccine safety assessment has traditionally relied on standardized animal testing methodologies, which face increasing challenges: the ethical imperative to reduce animal use, the need for faster vaccine development, and the limitations of animal models in predicting human-specific immune responses. The advent of modern vaccine platforms such as mRNA technologies and viral-vector vaccines necessitates a re-evaluation of safety frameworks. This article explores emerging strat­egies to modernize vaccine safety assessment, integrating new approach methodologies (NAMs), including in vitro systems, artificial intelligence, and adverse outcome pathways (AOPs). Ethical refinements to animal husbandry practices, including group housing, humane endpoints, pain man­agement and scaled blood sampling volumes, are also discussed to align with the principles of the 3Rs (replacement, reduction, refinement). The adoption of molecular and omics-based techniques, along with innovative validation strategies, offers opportunities to improve predictive accuracy and mechanistic insight. The article highlights a strategic framework for implementing NAMs across the three stages at which animals are still used – early screening, late nonclinical development, and batch release – while ensuring alignment with regulatory requirements. Implementation must be careful enough to ensure that the use of NAMs in the safety evaluation of vaccines maintains or exceeds current safety assessment standards. By addressing scientific, ethical, and regulatory challenges, NAMs have the potential to transform vaccine safety assessment, enhancing human relevance and accelerating innovation in vaccine development. Plain language summaryThis article examines the evolving landscape of vaccine safety assessment, focusing on opportunities to modernize testing approaches through new approach methodologies (NAMs). Drawing on recent discussions with stakeholders across industry, academia, and regulatory bodies, we outline key chal­lenges and strategic pathways for implementing NAMs in vaccine development while maintaining robust safety standards. Special attention is given to emerging technologies, such as human-relevant test systems, artificial intelligence, and virtual control groups, to the replacement of animal-based potency, pyrogen and adventitious agent tests used for batch release, and to considerations for regu­latory acceptance and implementation strategies.