title: Adjuvant effects of a sequence-engineered mRNA vaccine: translational profiling demonstrates similar human and murine innate response.
abstract: 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.
authors.affiliation: Sanofi Pasteur, VaxDesign Campus, 2501 Discovery Drive Suite 300, Orlando, FL, USA. darin.edwards@sanofipasteur.com.
authors.forename: Darin K
authors.identifier: 0000-0001-5977-6258
authors.initials: DK
authors.lastname: Edwards
authors.affiliation: CureVac AG, Paul-Ehrlich-Str. 15, 72076, Tübingen, Germany.
authors.forename: Edith
authors.initials: E
authors.lastname: Jasny
authors.affiliation: Sanofi Pasteur, VaxDesign Campus, 2501 Discovery Drive Suite 300, Orlando, FL, USA.
authors.forename: Heesik
authors.initials: H
authors.lastname: Yoon
authors.affiliation: CureVac AG, Paul-Ehrlich-Str. 15, 72076, Tübingen, Germany.
authors.forename: Nigel
authors.initials: N
authors.lastname: Horscroft
authors.affiliation: Sanofi Pasteur, VaxDesign Campus, 2501 Discovery Drive Suite 300, Orlando, FL, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Schanen
authors.affiliation: Sanofi Pasteur, VaxDesign Campus, 2501 Discovery Drive Suite 300, Orlando, FL, USA.
authors.forename: Tanya
authors.initials: T
authors.lastname: Geter
authors.affiliation: CureVac AG, Paul-Ehrlich-Str. 15, 72076, Tübingen, Germany.
authors.forename: Mariola
authors.initials: M
authors.lastname: Fotin-Mleczek
authors.affiliation: CureVac AG, Paul-Ehrlich-Str. 15, 72076, Tübingen, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Petsch
authors.affiliation: Sanofi Pasteur, VaxDesign Campus, 2501 Discovery Drive Suite 300, Orlando, FL, USA.
authors.forename: Vaughan
authors.initials: V
authors.lastname: Wittman
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D001483:Base Sequence; D004306:Dose-Response Relationship, Immunologic; D005786:Gene Expression Regulation / Q000187:drug effects; D053263:Gene Regulatory Networks / Q000187:drug effects; D005818:Genetic Engineering; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects* / Q000235:genetics; D007252:Influenza Vaccines / Q000276:immunology*; D008198:Lymph Nodes / Q000378:metabolism; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000008:administration & dosage*; D057170:Translational Research, Biomedical
chemical_list: D000276:Adjuvants, Immunologic; D007252:Influenza Vaccines; D012333:RNA, Messenger
keywords: Adjuvant; CLRs; Human; In vitro; Innate; MIMIC; Mouse; RLRs; Self-adjuvantation; TLRs; Vaccine; mRNA