Adjuvant effects of a sequence-engineered mRNA vaccine: translational profiling demonstrates similar human and murine innate response
Open accessAbstract
BACKGROUND: Prophylactic and therapeutic vaccines often depend upon a strong activation of the innate immune system to drive a potent adaptive immune response, often mediated by a strong adjuvant. For a number of adjuvants immunological readouts may not be consistent across species. METHODS: In this study, we evaluated the innate immunostimulatory potential of mRNA vaccines in both humans and mice, using a novel mRNA-based vaccine encoding influenza A hemagglutinin of the pandemic strain H1N1pdm09 as a model. This evaluation was performed using an in vitro model of human innate immunity and in vivo in mice after intradermal injection. RESULTS: Results suggest that immunostimulation from the mRNA vaccine in humans is similar to that in mice and acts through cellular RNA sensors, with genes for RLRs [ddx58 (RIG-1) and ifih1 (MDA-5)], TLRs (tlr3, tlr7, and tlr8-human only), and CLRs (clec4gp1, clec2d, cledl1) all significantly up-regulated by the mRNA vaccine. The up-regulation of TLR8 and TLR7 points to the involvement of both mDCs and pDCs in the response to the mRNA vaccine in humans. In both humans and mice activation of these pathways drove maturation and activation of immune cells as well as production of cytokines and chemokines known to attract and activate key players of the innate and adaptive immune system. CONCLUSION: This translational approach not only allowed for identification of the basic mechanisms of self-adjuvantation from the mRNA vaccine but also for comparison of the response across species, a response that appears relatively conserved or at least convergent between the in vitro human and in vivo mouse models.
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The RNActive® platform designed by CureVac combines the use of co-delivered RNA and protamine (a polycationic peptide) complex as adjuvant, which has been shown to effectively trigger innate immune responses and enhance vaccine immunogenicity.
“A vaccine platform (RNActive®) was designed by CureVac186 combining the use of co-delivered RNA and protamine (a polycationic peptide) complex as adjuvant, which has been shown to effectively trigger innate immune responses and enhance vaccine immunogenicity.186–189”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [187]
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“Furthermore, mRNA can efficiently transfect nondividing cells (15) and may be engineered and manufactured to provide selfadjuvanticity (16).”
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- Authors
- Edwards, D. K., Jasny, E., Yoon, H., Horscroft, N., Schanen, B., Geter, T., Fotin-Mleczek, M., Petsch, B., & Wittman, V.
- Affiliations
- Institut Pasteur (FR)
- CureVac (Germany) (DE)
- Corresponding author
- Edwards, Darin K.
- Venue
- Journal of Translational Medicine
- Published
- 2017-01-03
- Volume
- 15
- Issue
- 1
- Pages
- 1-1
- ISSN
- 1479-5876 (ISSN-L)
- PMC
- PMC5210268
- OpenAlex
- W2567689582
- Cited by
- 186
- References
- 57
- Citations by year
- 2026: 11 · 2025: 12 · 2024: 20 · 2023: 27 · 2022: 34 · 2021: 44 · 2020: 15 · 2019: 13 · 2018: 6 · 2017: 4
- FWCI
- 4.70
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Journal of Translational Medicine (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Defense Sciences Office, DARPA (HR0011-11-3-0001)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Keywords
- mRNA vaccines, adjuvant effect, innate immunity, influenza A hemagglutinin, H1N1pdm09, RIG-I, MDA5, TLR7, TLR8, TLR3, C-type lectin, dendritic cells, plasmacytoid dendritic cells, cytokine and chemokine production, cross-species comparison, translational profiling
- MeSH terms
- Adjuvants, Immunologic, Animals, Base Sequence, Dose-Response Relationship, Immunologic, Gene Expression Regulation, Genetic Engineering, Humans, Immunity, Innate, Influenza Vaccines, Lymph Nodes, Mice, Inbred C57BL, RNA, Messenger, Gene Regulatory Networks, Translational Research, Biomedical
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