Self-Amplifying RNA Vaccines After the First Approvals: Technology, Development Landscape, and Regulatory Science Considerations
4 affiliations
- 1Korea mRNA Vaccine Initiative, Gachon University, Seongnam 13120, Republic of Korea
- 2Department of Health Policy and Management, General Graduate School, Gachon University, Seongnam 13120, Republic of Korea
- 3Department of Microbiology, College of Medicine, Gachon University, Incheon 21199, Republic of Korea
- 4Department of Life Sciences, Gachon University, Seongnam 13120, Republic of Korea
Abstract
Self-amplifying RNA (saRNA) is a next-generation nucleic acid vaccine platform that enhances antigen expression through intracellular amplification of replicon RNA without producing infectious virions. saRNA constructs encode an alphavirus-derived replicase comprising nonstructural proteins nsP1–nsP4 and can elicit robust immune responses at low RNA doses. Replication intermediates may activate RIG-I, MDA5, and endosomal TLR3/7/8, contributing adjuvant-like activity. Kostaive (ARCT-154; zapomeran) became the first saRNA vaccine to receive full marketing approval in Japan in 2023, followed by authorization in the European Union in 2025 and the United Kingdom in 2026, demonstrating the platform’s clinical and regulatory feasibility. Development now extends beyond COVID-19 to seasonal and pandemic influenza, rabies, Crimean–Congo hemorrhagic fever, Nipah virus disease, and individualized cancer vaccines. However, the longer transcripts and additional replicase and subgenomic-promoter elements make in vitro transcription efficiency, full-length RNA content, double-stranded and truncated RNA impurities, lipid nanoparticle encapsulation, and potency testing particularly important. Regulatory assessment increasingly focuses on correct replicase and antigen expression, the magnitude and duration of self-amplification, biodistribution and persistence, and comparability. This review synthesizes the scientific basis, development landscape, manufacturing challenges, and regulatory science considerations of saRNA vaccines.
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BibTeX
@article{yi2026selfamplifying,
title = {{Self-Amplifying RNA Vaccines After the First Approvals: Technology, Development Landscape, and Regulatory Science Considerations}},
author = {Sunghyun Yi and Eunhye Seo and Kee-Jong Hong and Pil-Gu Park},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27219457},
url = {https://www.mdpi.com/1422-0067/27/21/9457},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Self-Amplifying RNA Vaccines After the First Approvals: Technology, Development Landscape, and Regulatory Science Considerations
AU - Sunghyun Yi
AU - Eunhye Seo
AU - Kee-Jong Hong
AU - Pil-Gu Park
PY - 2026
DA - 2026/10/23
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219457
UR - https://www.mdpi.com/1422-0067/27/21/9457
AB - Self-amplifying RNA (saRNA) is a next-generation nucleic acid vaccine platform that enhances antigen expression through intracellular amplification of replicon RNA without producing infectious virions. saRNA constructs encode an alphavirus-derived replicase comprising nonstructural proteins nsP1–nsP4 and can elicit robust immune responses at low RNA doses. Replication intermediates may activate RIG-I, MDA5, and endosomal TLR3/7/8, contributing adjuvant-like activity. Kostaive (ARCT-154; zapomeran) became the first saRNA vaccine to receive full marketing approval in Japan in 2023, followed by authorization in the European Union in 2025 and the United Kingdom in 2026, demonstrating the platform’s clinical and regulatory feasibility. Development now extends beyond COVID-19 to seasonal and pandemic influenza, rabies, Crimean–Congo hemorrhagic fever, Nipah virus disease, and individualized cancer vaccines. However, the longer transcripts and additional replicase and subgenomic-promoter elements make in vitro transcription efficiency, full-length RNA content, double-stranded and truncated RNA impurities, lipid nanoparticle encapsulation, and potency testing particularly important. Regulatory assessment increasingly focuses on correct replicase and antigen expression, the magnitude and duration of self-amplification, biodistribution and persistence, and comparability. This review synthesizes the scientific basis, development landscape, manufacturing challenges, and regulatory science considerations of saRNA vaccines.
SN - 1422-0067
ER -