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Journal of Translational Medicine
Published in: Journal of Translational Medicine 1/2017

Open Access 01-12-2017 | Research

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

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

Published in: Journal of Translational Medicine | Issue 1/2017

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Abstract

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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Literature
1.
Mastelic B, Garcon N, Del Giudice G, Golding H, Gruber M, Neels P, et al. Predictive markers of safety and immunogenicity of adjuvanted vaccines. Biologicals. 2013;41:458–68.CrossRefPubMed
2.
Mestas J, Hughes CC. Of mice and not men: differences between mouse and human immunology. J Immunol. 2004;172:2731–8.CrossRefPubMed
3.
Schroder K, Irvine KM, Taylor MS, Bokil NJ, Le Cao KA, Masterman KA, et al. Conservation and divergence in toll-like receptor 4-regulated gene expression in primary human versus mouse macrophages. Proc Natl Acad Sci USA. 2012;109:944–53.CrossRef
4.
Seok J, Warren HS, Cuenca AG, Mindrinos MN, Baker HV, Xu W, et al. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci USA. 2013;110:3507–12.CrossRefPubMedPubMedCentral
5.
Tameris MD, Hatherill M, Landry BS, Scriba TJ, Snowden MA, Lockhart S, et al. Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trial. Lancet. 2013;381:1021–8.CrossRefPubMed
6.
Takao K, Miyakawa T. Genomic responses in mouse models greatly mimic human inflammatory diseases. Proc Natl Acad Sci USA. 2015;112(4):1167–72.CrossRefPubMed
7.
8.
9.
Morton JJ, Bird G, Refaeli Y, Jimeno A. Humanized mouse xenograft models: narrowing the tumor-microenvironment gap. Cancer Res. 2016;76:6153–8.CrossRefPubMed
10.
Smith DJ, Lin LJ, Moon H, Pham AT, Wang X, Liu S, Ji S, Rezek V, Shimizu S, Ruiz M, Lam J, Janzen DM, Memarzadeh S, Kohn DB, Zack J, Kitchen SG, An DS, Yang L. Propagating humanized BLT mice for the study of human immunology and immunotherapy. Stem Cells Dev. 2016;25:1863–73.CrossRefPubMed
11.
Higbee RG, Byers AM, Dhir V, Drake D, Fahlenkamp HG, Gangur J, et al. An immunologic model for rapid vaccine assessment—a clinical trial in a test tube. Altern Lab Anim. 2009;37(Suppl 1):19–27.PubMed
12.
Hoffmann S, Peterbauer A, Schindler S, Fennrich S, Poole S, Mistry Y, et al. International validation of novel pyrogen tests based on human monocytoid cells. J Immunol Methods. 2005;298:161–73.CrossRefPubMed
13.
Ma Y, Poisson L, Sanchez-Schmitz G, Pawar S, Qu C, Randolph GJ, et al. Assessing the immunopotency of Toll-like receptor agonists in an in vitro tissue-engineered immunological model. Immunology. 2010;130:374–87.CrossRefPubMedPubMedCentral
14.
Schindler S, Spreitzer I, Loschner B, Hoffmann S, Hennes K, Halder M, et al. International validation of pyrogen tests based on cryopreserved human primary blood cells. J Immunol Methods. 2006;316:42–51.CrossRefPubMed
15.
Zaitseva M, Romantseva T, Blinova K, Beren J, Sirota L, Drane D, et al. Use of human MonoMac6 cells for development of in vitro assay predictive of adjuvant safety in vivo. Vaccine. 2012;30:4859–65.CrossRefPubMed
16.
Drake DR III, Singh I, Nguyen MN, Kachurin A, Wittman V, Parkhill R, Kachurina O, Moser JM, Burdin N, Moreau M, Mistretta N, Byers AM, Dhir V, Tapia TM, Vernhes C, Gangur J, Kamala T, Swaminathan N, Warren WL. In vitro biomimetic model of the human immune system for predictive vaccine assessments. Disruptive Sci Technol. 2012;1:28–40.CrossRef
17.
Luna E, Agrawal P, Mehta R, Vernhes C, Viskov C, Amiral J, et al. Evaluation of immunostimulatory potential of branded and US-generic enoxaparins in an in vitro human immune system model. Clin Appl Thromb Hemost. 2015;21:211–22.CrossRefPubMedPubMedCentral
18.
Miranda-Garcia M, Daebritz J, Varga G, Weinhage T, Ehrchen J, Barczyk K, et al. PW03-031—activation-induced cell death of human monocytes. Pediatr Rheumatol. 2013;11:A257.CrossRef
19.
20.
Germain RN, Meier-Schellersheim M, Nita-Lazar A, Fraser ID. Systems biology in immunology: a computational modeling perspective. Annu Rev Immunol. 2011;29:527–85.CrossRefPubMedPubMedCentral
21.
Mastelic B, Lewis DJ, Golding H, Gust I, Sheets R, Lambert PH. Potential use of inflammation and early immunological event biomarkers in assessing vaccine safety. Biologicals. 2013;41:115–24.CrossRefPubMed
22.
23.
Li S, Rouphael N, Duraisingham S, Romero-Steiner S, Presnell S, Davis C, et al. Molecular signatures of antibody responses derived from a systems biology study of five human vaccines. Nat Immunol. 2014;15:195–204.CrossRefPubMed
24.
25.
26.
Jones TR, Obaldia N III, Gramzinski RA, Charoenvit Y, Kolodny N, Kitov S, Davis HL, Krieg AM, Hoffman SL. Synthetic oligodeoxynucleotides containing CpG motifs enhance immunogenicity of a peptide malaria vaccine in Aotus monkeys. Vaccine. 1999;17:3065–71.CrossRefPubMed
27.
McCluskie MJ, Davis HL. Oral, intrarectal, and intranasal immunizations using CpG and non-CpG oligodeoxynucleotides as adjuvants. Vaccine. 2000;19:413–22.CrossRefPubMed
28.
McCluskie MJ, Weeratna RD, Krieg AM, Davis HL. CpG DNA is an effective oral adjuvant to protein antigens in mice. Vaccine. 2000;19:950–7.CrossRefPubMed
29.
Verthelyi D, Kenney RT, Seder RA, Gam AA, Friedag B, Klinman DM. CpG oligodeoxynucleotides as vaccine adjuvants in primates. J Immunol. 2002;168:1659–63.CrossRefPubMed
30.
Medzhitov R, Preston Hurlburt P, Janeway CA. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature. 1997;388:394–7.CrossRefPubMed
31.
Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, Akira S, et al. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science. 2004;303:1526–9.CrossRefPubMed
32.
33.
Gorden KB, Gorski KS, Gibson SJ, Kedl RM, Kieper WC, Qiu X, Tomai MA, Alkan SS, Vasilakos JP. Synthetic TLR agonists reveal functional differences between human TLR7 and TLR8. J Immunol. 2005;174:1259–68.CrossRefPubMed
34.
Yoneyama M, Fujita T. Structural mechanism of RNA recognition by the RIG-I-like receptors. Immunity. 2008;29:178–81.CrossRefPubMed
35.
Agrawal S, Gupta S. TLR1/2, TLR7, and TLR9 signals directly activate human peripheral blood naive and memory B cell subsets to produce cytokines, chemokines, and hematopoietic growth factors. J Clin Immunol. 2011;31:89–98.CrossRefPubMed
36.
O’Mahony DS, Pham U, Iyer R, Hawn TR, Liles WC. Differential constitutive and cytokine-modulated expression of human Toll-like receptors in primary neutrophils, monocytes, and macrophages. Int J Med Sci. 2008;5:1–8.CrossRefPubMedPubMedCentral
37.
Reddy M, Eirikis E, Davis C, Davis HM, Prabhakar U. Comparative analysis of lymphocyte activation marker expression and cytokine secretion profile in stimulated human peripheral blood mononuclear cell cultures: an in vitro model to monitor cellular immune function. J Immunol Methods. 2004;293:127–42.CrossRefPubMed
38.
Rintahaka J, Wiik D, Kovanen PE, Alenius H, Matikainen S. Cytosolic antiviral RNA recognition pathway activates caspases 1 and 3. J Immunol. 2008;180:1749–57.CrossRefPubMed
39.
Lorenz C, Fotin-Mleczek M, Roth G, Becker C, Dam TC, Verdurmen WP, et al. Protein expression from exogenous mRNA: uptake by receptor-mediated endocytosis and trafficking via the lysosomal pathway. RNA Biol. 2011;8:627–36.CrossRefPubMed
40.
41.
Fotin-Mleczek M, Zanzinger K, Heidenreich R, Lorenz C, Thess A, Duchardt KM, et al. Highly potent mRNA based cancer vaccines represent an attractive platform for combination therapies supporting an improved therapeutic effect. J Gene Med. 2012;14:428–39.CrossRefPubMed
42.
Kallen KJ, Heidenreich R, Schnee M, Petsch B, Schlake T, Thess A, et al. A novel, disruptive vaccination technology: self-adjuvanted RNActive((R)) vaccines. Hum Vaccines Immunother. 2013;9:2263–76.CrossRef
43.
Fotin-Mleczek M, Duchardt KM, Lorenz C, et al. Messenger RNA-based vaccines with dual activity induce balanced TLR-7 dependent adaptive immune responses and provide antitumor activity. J Immunother. 2011;34:1–15.CrossRefPubMed
44.
Sebastian M, Von Boehmer L, Zippelius A, Mayer F, Reck M, Atanackovic D, et al. Messenger RNA vaccination in NSCLC: findings from a phase I/IIa clinical trial. J Clin Oncol 2011;29.
45.
Petsch B, Schnee M, Vogel AB, Lange E, Hoffmann B, Voss D, Schlake T, Thess A, Kallen KJ, Stitz L, Kramps T. Protective efficacy of in vitro synthesized, specific mRNA vaccines against influenza A virus infection. Nat Biotechnol. 2012;30:1210–6.CrossRefPubMed
46.
Hoerr I, Obst R, Rammensee H, Jung G. In vivo application of RNA leads to induction of specific cytotoxic T lymphocytes and antibodies. Eur J Immunol. 2000;30:1–7.CrossRefPubMed
47.
Schanen BC, Drake DR 3rd. A novel approach for the generation of human dendritic cells from blood monocytes in the absence of exogenous factors. J Immunol Methods. 2008;335:53–64.CrossRefPubMed
48.
Gautier L, Cope L, Bolstad BM, Irizarry RA. affy—analysis of Affymetrix GeneChip data at the probe level. Bioinformatics. 2004;20:307–15.CrossRefPubMed
49.
50.
Smyth GK. Limma: linear models for microarray data. In: Gentlemen R, Carey V, Dudoit S, Irizarry R, Huber W, editors. Bioinformatics and computational biology solutions using r and bioconductor. New York: Springer; 2005. p. 397–420.CrossRef
51.
Smyth GK, Michaud J, Scott HS. Use of within-array replicate spots for assessing differential expression in microarray experiments. Bioinformatics. 2005;21:2067–75.CrossRefPubMed
52.
Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B. 1995;57:289–300.
53.
Caron G, Duluc D, Fremaux I, Jeannin P, David C, Gascan H, Delneste Y. Direct stimulation of human T cells via TLR5 and TLR7/8: flagellin and R-848 up-regulate proliferation and IFN-gamma production by memory CD4+ T cells. J Immunol. 2005;175:1551–7.CrossRefPubMed
54.
Pflanz S, Hibbert L, Mattson J, Rosales R, Vaisberg E, Bazan JF, Phillips JH, McClanahan TK, de Waal Malefyt R, Kastelein RA. WSX-1 and glycoprotein 130 constitute a signal-transducing receptor for IL-27. J Immunol. 2004;172:2225–31.CrossRefPubMed
55.
Pot C, Apetoh L, Awasthi A, Kuchroo VK. Molecular pathways in the induction of interleukin-27-driven regulatory type 1 cells. J Interferon Cytokine Res. 2010;30:381–8.CrossRefPubMedPubMedCentral
56.
Douagi I, Gujer C, Sundling C, Adams WC, Smed-Sorensen A, Seder RA, et al. Human B cell responses to TLR ligands are differentially modulated by myeloid and plasmacytoid dendritic cells. J Immunol. 2009;182:1991–2001.CrossRefPubMed
57.
Smyth C, Logan G, Weinberger RP, Rowe PB, Alexander IE, Smythe JA. Identification of a dynamic intracellular reservoir of cd86 protein in monocytes that is not associated with the golgi complex. J Immunol. 1998;160:5390–6.PubMed
Metadata
Title
Adjuvant effects of a sequence-engineered mRNA vaccine: translational profiling demonstrates similar human and murine innate response
Authors
Darin K. Edwards
Edith Jasny
Heesik Yoon
Nigel Horscroft
Brian Schanen
Tanya Geter
Mariola Fotin-Mleczek
Benjamin Petsch
Vaughan Wittman
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2017
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/s12967-016-1111-6

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