Self-amplifying RNA (saRNA) and circular RNA (circRNA) vaccines: Progress, evidence gaps, and translational pathways for durable and scalable immunization

Abstract

Self-amplifying RNA (saRNA) and circular RNA (circRNA) are emerging vaccine modalities that extend conventional, non-replicating mRNA platforms. Self-amplifying RNA encodes a replicase that amplifies intracellular RNA templates, enabling high antigen expression at substantially lower doses than non-replicating mRNA. Circular RNA has a covalently closed topology that confers resistance to exonucleases and supports sustained translation through cap-independent initiation. The evidence base remains asymmetric: saRNA has progressed through multiple human studies, including phase 3 evaluations of COVID-19 vaccines, and has received regulatory authorization in several jurisdictions, whereas circRNA vaccines remain largely preclinical, with limited publicly available human data. This review integrates clinical, animal, and mechanistic evidence, proposes a ‘3D’ framework (durability, dose-sparing, and deployability) and identifies key barriers to robust cross-platform comparison, encompassing delivery systems, innate immune sensing, and chemistry, manufacturing and controls (CMC).