ArticleScience translational medicine2025
Incorporation of 5-methylcytidine alleviates RIG-I-mediated innate immune responses to a self-amplifying RNA vaccine.
Article in Science translational medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
18 citing papers in PubMed.
- Bioengineering strategies for improving the immunogenicity of mRNA vaccines.Signal transduction and targeted therapy · 2026Review
- Sindbis virus self-amplifying replicon is compatible with modified nucleotides mediating expression and vaccine responsesMolecular therapy. Advances · 2026Article
- Pulmonary Delivery of Self-Amplifying RNA: Balancing Inflammation and Durable Transgene Expression.ACS nano · 2026Article
- Heterologous Prime-Boost Vaccination with GRA35-Encoding DNA and mRNA Vaccines Enhances Protective Immunity AgainstMicroorganisms · 2026Article
- A comprehensive analysis of the use of nucleoside analogues in RNA therapeutics.Journal of translational medicine · 2026Review
- Self-amplifying RNA-based CAR T cell therapy with enhanced duration and multi-genic logic functions.bioRxiv : the preprint server for biology · 2026Article
- Safety, immunogenicity, and optimal dosing of VLPCOV-02, a SARS-CoV-2 saRNA vaccine with modified 5-methylcytosine base.iScience · 2026Article
- Immunology of RNA-based vaccines: The critical interplay between inflammation and expression.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Review
- The Interplay Between Therapeutic Self-Amplifying RNA and the Innate Immune System: Balancing Efficiency and Reactogenicity.International journal of molecular sciences · 2025Review
- Delivering the Message: Translating mRNA Therapy for Liver Inherited Metabolic Diseases.Journal of inherited metabolic disease · 2025Review
- Research progress of mRNA vaccines for infectious diseases.European journal of medical research · 2025Review
- Co-expression of HSV-1 ICP34.5 enhances the expression of gene delivered by self-amplifying RNA and mitigates its immunogenicity.FEBS open bio · 2025Article
- Reverse-phase chromatography removes double-stranded RNA, fragments, and residual template to decrease immunogenicity and increase cell potency of mRNA and saRNA.Molecular therapy. Nucleic acids · 2025Article
- Complete substitution with modified nucleotides in self-amplifying RNA suppresses the interferon response and increases potency.Nature biotechnology · 2025Article
- Enhancing RNA vaccine safety through localized delivery strategies.Vaccine insights · 2025Article
- Review
- Review
- Safety and immunogenicity of VLPCOV-02, a SARS-CoV-2 self-amplifying RNA vaccine with a modified base, 5-methylcytosine.iScience · 2024Article
Corrections and comments
- Update of
Authors and funding
20 authors.
Funding
Abstract
To improve existing synthetic RNA-based vaccines, we previously developed a self-amplifying RNA (saRNA)-based vaccine expressing a membrane-anchored (TM) receptor binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein (S-RBD-TM) and demonstrated that a low dose of this saRNA vaccine elicits robust immune responses. Moreover, a recent clinical trial with an saRNA vaccine incorporating 5-methylcytidine (5mC) (saRNA-5mC) has demonstrated reduced vaccine reactogenicity while maintaining robust humoral responses. In this study, we investigate the mechanisms by which 5mC incorporation attenuates adverse effects while maintaining immunogenicity. We found that incorporation of 5mC into the saRNA platform led to prolonged and robust expression of antigen and attenuated induction of type I interferon, a key driver of reactogenicity, specifically in plasmacytoid dendritic cells (pDCs). As a result, saRNA-5mC alleviated excessive innate immune responses in vivo without impairing B cell and T cell responses against the SARS-CoV-2 RBD. Mechanistically, we demonstrated that the detection of unmodified saRNA in pDCs was mediated by a host cytosolic RNA sensor, RIG-I, and this sensing was abolished with 5mC incorporation. In contrast, saRNA-5mC induced robust innate activation in professional antigen-presenting cells, such as macrophages, in a RIG-I-independent manner, highlighting distinct host sensing mechanisms for synthetic RNAs. Our study provides support for the potential clinical use of saRNA-5mC vaccine platforms.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.