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

Darin K Edwards,Tanya Geter,Vaughan Wittman,Heesik Yoon,Edith Jasny,Nigel Horscroft,Benjamin Petsch,Brian Schanen,Mariola Fotin-Mleczek

doi:10.1186/s12967-016-1111-6

Darin K Edwards, Tanya Geter + Show 7 more

Open Access

https://doi.org/10.1186/s12967-016-1111-6

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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.

Highlights

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
Dose‐driven innate response to messenger ribonucleic acid (mRNA) vaccine stimulation in human MIMIC®‐Peripheral Tissue Equivalent Assay The purpose of the first phase of this study was to evaluate the immune-stimulatory potential of different concentrations of mRNA vaccine in humans
Human cell-based MIMIC®-Peripheral Tissue Equivalent model (PTE) modules were used and were either left untreated or were treated with benchmark influenza vaccine (Fluzone®, 2012–13), the TLR7/8 agonist R848, or 6 increasing concentrations of mRNA vaccine (5–50 μg/106 cells). 24 h after the application of treatment human immune cells were harvested from the modules and analyzed for phenotypic markers associated with activation using conventional flow cytometry

Summary

Introduction

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. New in vitro technologies for the pre-clinical assessment of innate response to vaccines or adjuvants have been developed These include new human-based assays that utilize human monocytoid cell lines or primary immune cells to detect the innate response and safety profile of pyrogens, toxic compounds, adjuvants, and vaccines [11,12,13,14,15]. Two distinct modules of the MIMIC®, the Peripheral Tissue Equivalent model (PTE) and Transwell Peripheral Tissue Equivalent model (TW-PTE), are biomimetic modules designed to simulate innate immune response as it occurs in peripheral tissues such as the skin following an encounter with a vaccine or a pathogen, and can be used to examine human responses against vaccines or vaccine adjuvants They utilize primary human immune cells coupled with naturally occurring signaling processes to replicate the development of cells responsible for much of the innate immune response. In the vein of translational science, this technology can be applied to the evaluation of vaccine adjuvants in pre-clinical assessments including both in vivo models [e.g. murine, non-human primates (NHP)] and in vitro models (e.g. MIMIC®), the results of which have direct applications to later clinical evaluations in humans

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