Adjuvant effects of a sequence-engineered mRNA vaccine: translational profiling demonstrates similar human and murine innate response
| Autor: | Mariola Fotin-Mleczek, Benjamin Petsch, Nigel Horscroft, Edith Jasny, Tanya Geter, Heesik Yoon, Brian C. Schanen, Darin K. Edwards, Vaughan Wittman |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Chemokine Mouse medicine.medical_treatment mRNA Dose-Response Relationship Immunologic Self-adjuvantation General Biochemistry Genetics and Molecular Biology Translational Research Biomedical 03 medical and health sciences 0302 clinical medicine Immune system In vitro Adjuvants Immunologic medicine Innate Animals Humans Gene Regulatory Networks RNA Messenger TLRs RLRs Adjuvant Medicine(all) Innate immune system CLRs biology Base Sequence Biochemistry Genetics and Molecular Biology(all) Research General Medicine TLR7 TLR8 Acquired immune system Immunity Innate MIMIC Mice Inbred C57BL 030104 developmental biology Gene Expression Regulation Influenza Vaccines 030220 oncology & carcinogenesis TLR3 Immunology biology.protein Lymph Nodes Genetic Engineering Vaccine Human |
| Zdroj: | Journal of Translational Medicine |
| ISSN: | 1479-5876 |
| Popis: | 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. Electronic supplementary material The online version of this article (doi:10.1186/s12967-016-1111-6) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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