Corticosteroids and cellulose purification improve, respectively, the in vivo translation and vaccination efficacy of sa-mRNAs
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Abstract
Synthetic mRNAs are an appealing platform with multiple biomedical applications ranging from protein replacement therapy to vaccination. In comparison with conventional mRNA, synthetic self-amplifying mRNAs (sa-mRNAs) are gaining interest because of their higher and longer-lasting expression. However, sa-mRNAs also elicit an innate immune response, which may complicate their clinical application. Approaches to reduce the innate immunity of sa-mRNAs have not been studied in detail. Here we investigated, in vivo, the effect of several innate immune inhibitors and a novel cellulose-based mRNA purification approach on the type I interferon (IFN) response and the translation and vaccination efficacy of our formerly developed sa-mRNA vaccine against Zika virus. Among the investigated inhibitors, we found that corticosteroids and especially topical application of clobetasol at the sa-mRNA injection site was the most efficient in suppressing the type I IFN response and increasing the translation of sa-mRNA. However, clobetasol prevented formation of antibodies against sa-mRNA-encoded antigens and should therefore be avoided in a vaccination context. Residual dsRNA by-products of the in vitro transcription reaction are known inducers of immediate type I IFN responses. We additionally demonstrate a drastic reduction of these dsRNA by-products upon cellulose-based purification, reducing the innate immune response and improving sa-mRNA vaccination efficacy.
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The early and intense type I IFN response induced by saRNA detection hinders replication and antigen expression.
“The early and intense type I IFN response induced by saRNA detection hinders replication and antigen expression, similar to unmodified mRNA5,13–15.”
From Complete substitution with modified nucleotides in self-amplifying RNA suppresses the interferon response and increases potency (2025) · cites this paper as [13]
The Results report that the sa-mRNA vaccine induced a rapid IFN-β response peaking within five hours, and the Introduction says type I IFN can induce enzymes that inhibit mRNA translation. These passages support the early response and its potential to hinder antigen expression, but our copy does not establish that the response hinders sa-mRNA replication. The Discussion instead says the IFN-β peak occurs before replication, addressing what triggers the response rather than whether it inhibits replication. (LLM, conf=0.85)
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Adjuvants, the Elephant in the Room for RNA Vaccines
D’haese, S., den Roover, S., & Aerts, J. L. (2022) · RNA technologies · doi:10.1007/978-3-031-08415-7_12 · Cited by 1 · see citing works
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The strategies and advances of mRNA translation booster
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Status and outlook of mRNA therapeutics for viral diseases
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Self-citationPulmonary Delivery of Self-Amplifying RNA: Balancing Inflammation and Durable Transgene Expression
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Self-citationSelf‐Amplifying RNA‐Based Therapeutics: Advances, Challenges, and Future Perspectives
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Self-citationPrinciples, Optimization, Applications, and Future Prospects of mRNA Vaccine Technology
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- Authors
- Zhong, Z., McCafferty, S., Opsomer, L., Wang, H., Huysmans, H., De Temmerman, J., Lienenklaus, S., Portela Catani, J. P., Combes, F., & Sanders, N. N.
- Affiliations
- Ghent University (BE)
- Medizinische Hochschule Hannover (DE)
- Corresponding author
- Sanders, Niek N.
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2021-04
- Volume
- 29
- Issue
- 4
- Pages
- 1370-1381
- ISSN
- 1525-0016 (ISSN-L)
- PMC
- PMC8058483
- OpenAlex
- W3123562152
- Cited by
- 48
- References
- 50
- Citations by year
- 2026: 12 · 2025: 13 · 2024: 10 · 2023: 2 · 2022: 7 · 2021: 4
- FWCI
- 1.80
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Therapy (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Funders
- Fonds Wetenschappelijk Onderzoek
- China Scholarship Council
- Universiteit Gent
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- self-amplifying mRNA, corticosteroids, clobetasol, type I interferon response, innate immune response, mRNA translation, mRNA vaccines, Zika vaccine, topical application, antibody response
- MeSH terms
- Zika Virus Infection, Zika Virus, Adrenal Cortex Hormones, Cellulose, Clobetasol, Gene Expression Regulation, Humans, Immunity, Innate, Interferon Type I, RNA, Messenger, Protein Biosynthesis, Vaccination
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