Adjuvant effects of a sequence-engineered mRNA vaccine: translational profiling demonstrates similar human and murine innate responseReport as inadecuate




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Journal of Translational Medicine

, 15:1

Immunobiology and immunotherapy

Abstract

BackgroundProphylactic 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.

MethodsIn 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.

ResultsResults 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.

ConclusionThis 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.

KeywordsmRNA Vaccine Innate In vitro MIMIC Adjuvant Human Mouse RLRs CLRs TLRs Self-adjuvantation AbbreviationsmRNAmessenger ribonucleic acid

RLRsRIG-I-like receptors

TLRsToll-like receptors

CLRsC-type lectin receptors

mDCsmyeloid dendritic cells

pDCsplasmacytoid dendritic cells

MIMIC®Modular Immune In vitro Construct

PTEPeripheral Tissue Equivalent

TW-PTETranswell Peripheral Tissue Equivalent

NHPnon-human primate

PRRspattern recognition receptors

ssRNAsingle-stranded RNA

dsRNAdouble-stranded RNA

HIVhuman immunodeficiency virus

ILinterleukin

JNKc-jun N-terminal kinase

DNAdeoxyribonucleic acid

HAhemagglutinin

dLNdraining lymph node

IDintradermal

PBMCsperipheral blood mononuclear cells

APCsantigen presenting cells

CDcluster of differentiation

ANOVAone-way analysis of variance

MHCmajor histocompatibility complex class

ThT helper

Tr1type 1 regulatory

MAP kinasemitogen-activated protein kinase

CXCRCXC chemokine receptor

NLRNOD-like receptors

Electronic supplementary materialThe online version of this article doi:10.1186-s12967-016-1111-6 contains supplementary material, which is available to authorized users.

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Author: Darin K. Edwards - Edith Jasny - Heesik Yoon - Nigel Horscroft - Brian Schanen - Tanya Geter - Mariola Fotin-Mleczek - Ben

Source: https://link.springer.com/







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