Self-amplifying RNA vaccines give equivalent protection against influenza to mRNA vaccines but at much lower doses
Open accessAbstract
New vaccine platforms are needed to address the time gap between pathogen emergence and vaccine licensure. RNA-based vaccines are an attractive candidate for this role: they are safe, are produced cell free, and can be rapidly generated in response to pathogen emergence. Two RNA vaccine platforms are available: synthetic mRNA molecules encoding only the antigen of interest and self-amplifying RNA (sa-RNA). sa-RNA is virally derived and encodes both the antigen of interest and proteins enabling RNA vaccine replication. Both platforms have been shown to induce an immune response, but it is not clear which approach is optimal. In the current studies, we compared synthetic mRNA and sa-RNA expressing influenza virus hemagglutinin. Both platforms were protective, but equivalent levels of protection were achieved using 1.25 μg sa-RNA compared to 80 μg mRNA (64-fold less material). Having determined that sa-RNA was more effective than mRNA, we tested hemagglutinin from three strains of influenza H1N1, H3N2 (X31), and B (Massachusetts) as sa-RNA vaccines, and all protected against challenge infection. When sa-RNA was combined in a trivalent formulation, it protected against sequential H1N1 and H3N2 challenges. From this we conclude that sa-RNA is a promising platform for vaccines against viral diseases.
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repRNA acts as its own adjuvant, eliciting more robust immune responses after a single dose relative to conventional mRNA which typically requires multiple, 1,000-fold higher doses.
“As a result, repRNA acts as its own adjuvant, eliciting more robust immune responses after a single dose, relative to conventional mRNA which typically requires multiple, 1,000-fold higher doses (29).”
From An <i>Alphavirus</i> -derived replicon RNA vaccine induces SARS-CoV-2 neutralizing antibody and T cell responses in mice and nonhuman primates (2020) · cites this paper as [29]
The Discussion (page unavailable) says self-amplifying RNA provides additional immune stimuli, consistent with the adjuvant-like part of the claim. But the Results report equivalent protection at a 64-fold lower dose, not a 1,000-fold lower dose, and Figure 1 describes a prime-boost regimen for both RNA vaccines, not a single dose of self-amplifying RNA versus multiple doses of conventional mRNA. (LLM, conf=0.91)
Experimental — accuracy not yet measuredThe self-adjuvanting effect of saRNA triggers a broader immune response, which is considered to have potential to be effective with a single-dose inoculation.
“This triggers a broader immune response, which was also considered to have potential to be effective with a single-dose inoculation.155,156”
From COVID-19 mRNA vaccines: Platforms and current developments (2022) · cites this paper as [156]
saRNA vaccines are inherently self-adjuvanting, as their replicase activity leads to dsRNA and replicon intermediates during transcription that mimic a viral infection.
“saRNA vaccines are inherently self-adjuvanting, as their replicase activity leads to dsRNA and replicon intermediates during transcription mimic a viral infection.”
From COVID-19 mRNA vaccines: Platforms and current developments (2022) · cites this paper as [156]
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- Authors
- Vogel, A. B., Lambert, L., Kinnear, E., Busse, D., Erbar, S., Reuter, K. C., Wicke, L., Perkovic, M., Beissert, T., Haas, H., Reece, S. T., Sahin, U., & Tregoning, J. S.
- Affiliations
- BioNTech (Germany) (DE)
- Imperial College London (GB)
- Translationale Onkologie an der Universitätsmedizin der Johannes Gutenberg-Universität Mainz (DE)
- Corresponding author
- Vogel, Annette B.
- Tregoning, John S.
- ORCID
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2018-02
- Volume
- 26
- Issue
- 2
- Pages
- 446-455
- ISSN
- 1525-0016 (ISSN-L)
- PMC
- PMC5835025
- OpenAlex
- W2775712816
- Cited by
- 501
- References
- 31
- Citations by year
- 2026: 51 · 2025: 66 · 2024: 72 · 2023: 61 · 2022: 81 · 2021: 81 · 2020: 52 · 2019: 24 · 2018: 13
- FWCI
- 19.06
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Molecular Therapy (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Spiral (Imperial College London) (submittedVersion, other-oa)
- Funders
- European Community’s European 7th Framework Program ADITEC (HEALTH-F4-2011-18 280873)
- MRC CASE (MR/J006548/1)
- Topics
- Health Sciences › Medicine › Epidemiology › Influenza Virus Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- self-amplifying RNA vaccine, mRNA vaccines, influenza vaccination, hemagglutinin, vaccine dose reduction, H1N1, H3N2, influenza B, vaccine protection
- MeSH terms
- Animals, Disease Models, Animal, Female, Humans, Immunization, Immunization, Secondary, Influenza, Human, Influenza Vaccines, Influenza A virus, RNA, Messenger, RNA, Viral, T-Lymphocyte Subsets, Hemagglutinin Glycoproteins, Influenza Virus, Mice, Influenza A Virus, H1N1 Subtype
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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