Human vaccines & immunotherapeuticsApr 22, 2026

Progress and challenges of self-amplifying and circular RNA vaccines for long-lasting and scalable protection

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jun 27, 2026

Abstract

Essence

Self-amplifying and circular RNA vaccines aim to extend mRNA vaccination through dose-sparing amplification or more durable RNA stability.

Evidence

This review integrates clinical, animal, and mechanistic evidence, with saRNA supported by multiple human studies including phase 3 COVID-19 evaluations and circRNA remaining largely preclinical.

Caveat

The evidence base is uneven, and delivery systems, innate immune sensing, and CMC differences still limit robust cross-platform comparison.

Simplified

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).