Induction of an IFN-mediated antiviral response by a self-amplifying RNA vaccine: implications for vaccine design
Open accessAbstract
RNA-based vaccines have recently emerged as a promising alternative to the use of DNA-based and viral vector vaccines, in part because of the potential to simplify how vaccines are made and facilitate a rapid response to newly emerging infections. SAM vaccines are based on engineered self-amplifying mRNA (SAM) replicons encoding an Ag, and formulated with a synthetic delivery system, and they induce broad-based immune responses in preclinical animal models. In our study, in vivo imaging shows that after the immunization, SAM Ag expression has an initial gradual increase. Gene expression profiling in injection-site tissues from mice immunized with SAM-based vaccine revealed an early and robust induction of type I IFN and IFN-stimulated responses at the site of injection, concurrent with the preliminary reduced SAM Ag expression. This SAM vaccine-induced type I IFN response has the potential to provide an adjuvant effect on vaccine potency, or, conversely, it might establish a temporary state that limits the initial SAM-encoded Ag expression. To determine the role of the early type I IFN response, SAM vaccines were evaluated in IFN receptor knockout mice. Our data indicate that minimizing the early type I IFN responses may be a useful strategy to increase primary SAM expression and the resulting vaccine potency. RNA sequence modification, delivery optimization, or concurrent use of appropriate compounds might be some of the strategies to finalize this aim.
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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 [14]
The Abstract (page unavailable) reports an early response to self-amplifying RNA and says type I IFN may inhibit replicon amplification and antigen expression. The antigen-expression effect is supported by the section “SAM-driven Ag expression is enhanced in IFNAR KO and MAR1-5A3-treated mice” (page unavailable), but the paper presents inhibition of replication as a possibility, not an established result. (LLM, conf=0.83)
Experimental — accuracy not yet measuredOne copy of saRNA produces multiple copies of RNA transcripts by the above-described mechanism to initiate self-amplification of antigen genes in the cell.
“As a result, one copy of saRNA produces multiple copies of RNA transcripts by the above-described mechanism to initiate self-amplification of antigen genes in the cell.35,195,196”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [195]
Owing to its self-replicative nature, lower doses of saRNA seem to be required to reach the same translational level compared with non-replicative mRNAs.
“Moreover, owing to its self-replicative nature, in which the encoded replicase enables multiple copies of the antigen-encoding RNA, lower doses seem to be required to reach the same translational level compared with non-replicative mRNAs.153,154”
From COVID-19 mRNA vaccines: Platforms and current developments (2022) · cites this paper as [153]
The type I IFN activity of mRNA vaccines can prematurely stop mRNA translation, thereby reducing antigen availability and diminishing the vaccine's efficacy to obtain adaptive immune responses.
“the type I IFN activity of mRNA vaccines can prematurely stop mRNA-translation, thereby reducing antigen availability and diminishing the vaccine's efficacy to obtain adaptive immune responses [63,64]”
From The dawn of mRNA vaccines: the COVID-19 case (2021) · cites this paper as [63]
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- Authors
- Pepini, T., Pulichino, A.-M., Carsillo, T., Carlson, A. L., Sari-Sarraf, F., Ramsauer, K., Debasitis, J. C., Maruggi, G., Otten, G. R., Geall, A. J., Yu, D., Ulmer, J. B., & Iavarone, C.
- Affiliations
- GlaxoSmithKline (United States) (US)
- Novartis Vaccines and Diagnostics , Cambridge, MA 02139
- Novartis Institute for BioMedical Research , Cambridge, MA 02139
- Corresponding author
- Pepini, Timothy
- Maruggi, Giulietta
- Yu, Dong
- Iavarone, Carlo
- ORCID
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2017-05
- Volume
- 198
- Issue
- 10
- Pages
- 4012-4024
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- PMC
- PMC5421303
- OpenAlex
- W2610471486
- Cited by
- 208
- References
- 45
- Citations by year
- 2026: 18 · 2025: 27 · 2024: 28 · 2023: 22 · 2022: 32 · 2021: 31 · 2020: 25 · 2019: 14 · 2018: 10 · 2017: 1
- FWCI
- 6.18
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- GlaxoSmithKline
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- self-amplifying mRNA vaccine, type I interferon, IFN-stimulated genes, antiviral response, vaccine adjuvants, vaccine design
- MeSH terms
- Adjuvants, Immunologic, Animals, Antibodies, Viral, Antigens, Interferon Type I, Respiratory Syncytial Viruses, RNA, Messenger, RNA, Viral, Vaccination, Viral Vaccines, Drug Design, Imaging, Three-Dimensional, Mice, Vaccine Potency
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