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Title:
Adjuvant effects of a sequence-engineered mRNA vaccine: translational profiling demonstrates similar human and murine innate response | Journal of Translational Medicine
Description:
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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cd14low/ccr7high/hla-drhigh/cd40high/cd80high/cd86high c-jun n-terminal kinases c-jun n-terminal kinase mariola fotin-mleczek & benjamin petsch pw03-031—activation-induced cell death hochberg false-discovery-rate method article download pdf rnalater-preserved ln biopsies dose-dependent maturation driven mitogen-activated protein kinase antibody cross-reactivity induced cd14low/hla-drhigh phenotype miscellaneous immune-related genes clear dose-dependent increase rnalater-preserved skin biopsies dose-dependent maturation effect retinoic acid-inducible gene genome-wide transcriptome analysis mimic® tw-pte increases immune cell activation/maturation immune-related gene subset viral single-stranded rna rnalater-preserved biopsy tissues log2-fold change relative mariola fotin-mleczek published manual technique human mimic®-pte modules dose-driven innate response larger-scale manner [47] messenger rna-based vaccines human leukocyte antigen-dr pre-clinical assessments including pro-inflammatory cytokines il-6 activate mimic®-pte cells live-dead aqua negative prr-selective agonists binding rig-i-mediated activity human mimic®-pte apcs enhanced mrna half-life sequence-engineered mrna vaccine yellow fever vaccine developing mrna-vaccine technologies pre-clinical animal studies privacy choices/manage cookies mimic® tw-pte tw-pte modules dose dependent reduction cell viability assessments false discovery rate immune cell populations
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headline:Adjuvant effects of a sequence-engineered mRNA vaccine: translational profiling demonstrates similar human and murine innate response
description: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. 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 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. 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.
datePublished:2017-01-03T00:00:00Z
dateModified:2017-01-03T00:00:00Z
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Vaccine
Innate
In vitro
MIMIC
Adjuvant
Human
Mouse
RLRs
CLRs
TLRs
Self-adjuvantation
Biomedicine
general
Medicine/Public Health
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headline:Adjuvant effects of a sequence-engineered mRNA vaccine: translational profiling demonstrates similar human and murine innate response
description: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. 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 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. 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.
datePublished:2017-01-03T00:00:00Z
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mRNA
Vaccine
Innate
In vitro
MIMIC
Adjuvant
Human
Mouse
RLRs
CLRs
TLRs
Self-adjuvantation
Biomedicine
general
Medicine/Public Health
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