Abstract
A variety of different mRNA-based drugs are currently in development. This became possible, since major breakthroughs in RNA research during the last decades allowed impressive improvements of translation, stability and delivery of mRNA. This article focuses on antigen-encoding RNA-based vaccines that are either directed against tumors or pathogens. mRNA-encoded vaccines are developed both for preventive or therapeutic purposes. Most mRNA-based vaccines are directly administered to patients. Alternatively, primary autologous cells from cancer patients are modified ex vivo by the use of mRNA and then are adoptively transferred to patients. In the EU no regulatory guidelines presently exist that specifically address mRNA-based vaccines. The existing regulatory framework, however, clearly defines that mRNA-based vaccines in most cases have to be centrally approved. Interestingly, depending on whether RNA-based vaccines are directed against tumors or infectious disease, they are formally considered gene therapy products or not, respectively. Besides an overview on the current clinical use of mRNA vaccines in various therapeutic areas a detailed discussion of the current regulatory situation is provided and regulatory perspectives are discussed.
* Thomas Hinz and Kajo Kallen contributed equally to this manuscript.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Matthaei H, Nirenberg MW (1961) The dependence of cell-free protein synthesis in E. coli upon RNA prepared from ribosomes. Biochem Biophys Res Commun 4:404–408
Matthaei JH, Nirenberg MW (1961) Characteristics and stabilization of DNAase-sensitive protein synthesis in E.coli extracts. Proc Natl Acad Sci U S A 47:1580–1588
Wolff JA, Malone RW, Williams P et al (1990) Direct gene transfer into mouse muscle in vivo. Science 247:1465–1468
Tang DC, DeVit M, Johnston SA (1992) Genetic immunization is a simple method for eliciting an immune response. Nature 356:152–154
Martinon F, Krishnan S, Lenzen G et al (1993) Induction of virus-specific cytotoxic T lymphocytes in vivo by liposome-entrapped mRNA. Eur J Immunol 23:1719–1722
Conry RM, LoBuglio AF, Wright M et al (1995) Characterization of a messenger RNA polynucleotide vaccine vector. Cancer Res 55:1397–1400
Hoerr I, Obst R, Rammensee HG, Jung G (2000) In vivo application of RNA leads to induction of specific cytotoxic T lymphocytes and antibodies. Eur J Immunol 30:1–7
Pascolo S (2004) Messenger RNA-based vaccines. Expert Opin Biol Ther 4:1285–1294
Ketterer T, von der Mülbe F, Reidel L et al (2008) Method for purifying RNA on a preparative scale by means of hplc. Patent WO2008077592
Pardi N, Muramatsu H, Weissman D et al (2013) In vitro transcription of long RNA containing modified nucleosides. Methods Mol Biol 969:29–42
Kariko K, Buckstein M, Ni H, Weissman D (2005) Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. Immunity 23:165–175
Holtkamp S, Kreiter S, Selmi A et al (2006) Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells. Blood 108:4009–4017
Kariko K, Muramatsu H, Welsh FA et al (2008) Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Mol Ther 16:1833–1840
Kuhn AN, Diken M, Kreiter S et al (2010) Phosphorothioate cap analogs increase stability and translational efficiency of RNA vaccines in immature dendritic cells and induce superior immune responses in vivo. Gene Ther 17:961–971
Kormann MS, Hasenpusch G, Aneja MK et al (2011) Expression of therapeutic proteins after delivery of chemically modified mRNA in mice. Nat Biotechnol 29:154–157
Kariko K, Muramatsu H, Keller JM et al (2012) Increased erythropoiesis in mice injected with submicrogram quantities of pseudouridine-containing mRNA encoding erythropoietin. Mol Ther 20:948–953
Schlake T, Thess A, Fotin-Mleczek M et al (2012) Developing mRNA-vaccine technologies. RNA Biol 9:1319–1330
Kallen K-J, Thess A (2014) A development that may evolve into a revolution in medicine: mRNA as the basis for novel, nucleotide-based vaccines and drugs. Ther Adv Vaccines 2:10–31
Thess A, Grund S, Mui BL et al (2015) Sequence-engineered mRNA without chemical nucleoside modifications enables an effective protein therapy in large animals. Mol Ther 23:1456–1464
Lorenz C, Fotin-Mleczek M, Roth G et al (2011) Protein expression from exogenous mRNA: uptake by receptor-mediated endocytosis and trafficking via the lysosomal pathway. RNA Biol 8:627–636
Diken M, Kreiter S, Selmi A et al (2011) Selective uptake of naked vaccine RNA by dendritic cells is driven by macropinocytosis and abrogated upon DC maturation. Gene Ther 18:702–708
Sahin U, Kariko K, Tureci O (2014) mRNA-based therapeutics--developing a new class of drugs. Nat Rev Drug Discov 13:759–780
Fotin-Mleczek M, Duchardt KM, Lorenz C et al (2011) Messenger RNA-based vaccines with dual activity induce balanced TLR-7 dependent adaptive immune responses and provide antitumor activity. J Immunother 34:1–15
Sebastian M, von Boehmer L, Zippelius A et al (2011) Messenger RNA vaccination in NSCLC: findings from a phase I/IIa clinical trial. J Clin Oncol 29:(suppl; abstr 2584)
Sebastian M, von Boehmer L, Zippelius A et al (2012) Messenger RNA vaccination and B-cell responses in NSCLC patients. J Clin Oncol 30:(suppl; abstr 2573)
Sebastian M, Papachristofilou A, Weiss C et al (2014) Phase Ib study evaluating a self-adjuvanted mRNA cancer vaccine (RNActive(R)) combined with local radiation as consolidation and maintenance treatment for patients with stage IV non-small cell lung cancer. BMC Cancer 14:748
Kubler H, Scheel B, Gnad-Vogt U et al (2015) Self-adjuvanted mRNA vaccination in advanced prostate cancer patients: a first-in-man phase I/IIa study. J Immunother Cancer 3:26
Kreiter S, Selmi A, Diken M et al (2008) Increased antigen presentation efficiency by coupling antigens to MHC class I trafficking signals. J Immunol 180:309–318
Britten CM, Singh-Jasuja H, Flamion B et al (2013) The regulatory landscape for actively personalized cancer immunotherapies. Nat Biotechnol 31:880–882
Castle JC, Kreiter S, Diekmann J et al (2012) Exploiting the mutanome for tumor vaccination. Cancer Res 72:1081–1091
Castle JC, Loewer M, Boegel S et al (2014) Mutated tumor alleles are expressed according to their DNA frequency. Sci Rep 4:4743
Kreiter S, Vormehr M, van de Roemer N et al (2015) Mutant MHC class II epitopes drive therapeutic immune responses to cancer. Nature 520:692–696
Bonehill A, Tuyaerts S, Van Nuffel AM et al (2008) Enhancing the T-cell stimulatory capacity of human dendritic cells by co-electroporation with CD40L, CD70 and constitutively active TLR4 encoding mRNA. Mol Ther 16:1170–1180
Aarntzen EH, Schreibelt G, Bol K, Lesterhuis WJ et al (2012) Vaccination with mRNA-electroporated dendritic cells induces robust tumor antigen-specific CD4+ and CD8+ T cells responses in stage III and IV melanoma patients. Clin Cancer Res 18:5460–5470
Wilgenhof S, Corthals J, Van Nuffel AM et al (2015) Long-term clinical outcome of melanoma patients treated with messenger RNA-electroporated dendritic cell therapy following complete resection of metastases. Cancer Immunol Immunother 64:381–388
Wilgenhof S, Van Nuffel AMT, Benteyn D et al (2013) Phase IB study on intravenous synthetic mRNA electroporated dendritic cell immunotherapy in pretreated advanced melanoma patients. Ann Oncol 24:2686–2693
Petsch B, Schnee M, Vogel AB et al (2012) Protective efficacy of in vitro synthesized, specific mRNA vaccines against influenza A virus infection. Nat Biotechnol 30:1210–1216
Geall AJ, Verma A, Otten GR et al (2012) Nonviral delivery of self-amplifying RNA vaccines. Proc Natl Acad Sci U S A 109:14604–14609
Lazzaro S, Giovani C, Mangiavacchi S et al (2015) CD8 T-cell priming upon mRNA vaccination is restricted to bone-marrow-derived antigen-presenting cells and may involve antigen transfer from myocytes. Immunology 146:312–326
Brazzoli M, Magini D, Bonci A et al (2015) Induction of broad-based immunity and protective efficacy by self-amplifying mRNA vaccines encoding influenza virus hemagglutinin. J Virol. doi:10.1128/JVI.01786-15
Bogers WM, Oostermeijer H, Mooij P et al (2015) Potent immune responses in rhesus macaques induced by nonviral delivery of a self-amplifying RNA vaccine expressing HIV type 1 envelope with a cationic nanoemulsion. J Infect Dis 211:947–955
Hekele A, Bertholet S, Archer J et al (2013) Rapidly produced SAMH vaccine against H7N9 influenza is immunogenic in mice. Emerg Microbes Infect 2:e52
Ulmer JB, Mansoura MK, Geall AJ (2015) Vaccines ‘on demand’: science fiction or a future reality. Expert Opin Drug Discov 10(2):101–106
Boisguerin V, Castle JC, Loewer M et al (2014) Translation of genomics-guided RNA-based personalised cancer vaccines: towards the bedside. Br J Cancer 111:1469–1475
Geall AJ, Mandl CW, Ulmer JB (2013) RNA: the new revolution in nucleic acid vaccines. Semin Immunol 25:152–159
Roesler E, Weiss R, Weinberger EE et al (2009) Immunize and disappear-safety-optimized mRNA vaccination with a panel of 29 allergens. J Allergy Clin Immunol 124:1070–1077
Weiss R, Scheiblhofer S, Thalhamer J (2014) Allergens are not pathogens: why immunization against allergy differs from vaccination against infectious diseases. Hum Vaccin Immunother 10:703–707
Zangi L, Lui KO, von Gise A et al (2013) Modified mRNA directs the fate of heart progenitor cells and induces vascular regeneration after myocardial infarction. Nat Biotechnol 31:898–907
EU, Regulation (EU) No 536/2014 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC
EC, Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency
EC, Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004
EU, COMMISSION DIRECTIVE 2009/120/EC of 14 September 2009 amending Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use as regards advanced therapy medicinal products
EMA, Reflection paper on classification of advanced therapy medicinal products. 20 June 2014. EMA/CAT/600280/2010 Rev.1. Committee for Advanced Therapies (CAT)
EMA, Guideline on the requirements for quality documentation concerning biological investigational medicinal products in clinical trials. EMA/CHMP/534898/2008
EU, Guidelines to Good Manufacturing Practice. Medicinal Products for Human and Veterinary Use. Annex 13. Investigational Medicinal Products
ICH, Harmonised tripartite guideline for good clinical practice E6(R1)
EU, Volume 2B. Notice to applicants. Medicinal products for human use
EMA, Guideline on the risk-based approach according to annex I, part IV of Directive 2001/83/EC applied to advanced therapy medicinal products
EMA, Guideline on the quality, non-clinical and clinical aspects of gene therapy medicinal products. EMA/CAT/80183/2014
EMA, Guideline on human cell-based medicinal products. EMEA/CHMP/410869/2006
EMA, Guideline on quality, non-clinical and clinical aspects of medicinal products containing genetically modified cells. EMA/CAT/GTWP/671639/2008
EU, Good manufacturing practice. Medicinal products for human and veterinary use. Part II: basic requirements for active substances used as starting materials
EMA, Note for guidance on preclinical pharmacological and toxicological testing of vaccines. CPMP/SWP/465/95
EMA, Non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals. ICH M(3)
EMA, Guideline on the evaluation of anticancer medicinal products in man. EMA/CHMP/205/95/Rev.4
EMA, Guideline on clinical evaluation of new vaccines. EMEA/CHMP/VWP/164653/2005
FDA, Guidance for Industry. Clinical Considerations for Therapeutic Cancer Vaccines
Acknowledgements
This chapter was issued as a joint effort by the Regulatory Research Group (RRG). The RRG was founded within the Association for Cancer Immunotherapy (CIMT) in 2008 as an independent group of experts focusing on regulatory aspects of drug development. CIMT was founded in 2002 by physicians and researchers from different fields of clinical and theoretical medicine as an independent nonprofit organization (www.cimt.eu).
Author information
Authors and Affiliations
Corresponding authors
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2017 Springer Science+Business Media New York
About this protocol
Cite this protocol
Hinz, T. et al. (2017). The European Regulatory Environment of RNA-Based Vaccines. In: Kramps, T., Elbers, K. (eds) RNA Vaccines. Methods in Molecular Biology, vol 1499. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-6481-9_13
Download citation
DOI: https://doi.org/10.1007/978-1-4939-6481-9_13
Published:
Publisher Name: Humana Press, New York, NY
Print ISBN: 978-1-4939-6479-6
Online ISBN: 978-1-4939-6481-9
eBook Packages: Springer Protocols