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

Journal of Translational Medicine

Research

Mariola Fotin-Mleczek¹  Edith Jasny¹  Nigel Horscroft¹  Benjamin Petsch¹  Brian Schanen²  Darin K. Edwards²  Vaughan Wittman²  Tanya Geter²  Heesik Yoon² 

[1] CureVac AG, Paul-Ehrlich-Str. 15, 72076, Tübingen, Germany;Sanofi Pasteur, VaxDesign Campus, 2501 Discovery Drive Suite 300, Orlando, FL, USA;

关键词: mRNA;    Vaccine;    Innate;    In vitro;    MIMIC;    Adjuvant;    Human;    Mouse;    RLRs;    CLRs;    TLRs;    Self-adjuvantation;   

DOI  :  10.1186/s12967-016-1111-6

 received in 2016-09-22, accepted in 2016-12-15,  发布年份 2017

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© The Author(s) 2017