Skip to main content
View expanded cover

RNA Vaccines pp 203–222Cite as

The European Regulatory Environment of RNA-Based Vaccines

Part of the Methods in Molecular Biology book series (MIMB,volume 1499)

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.

Keywords

  • mRNA
  • Vaccines
  • Anticancer vaccination
  • Vaccination against infectious disease
  • Preventive and therapeutic approaches
  • Regulatory framework in the EU
  • Advanced therapy medicinal products (ATMP)
  • Genetically modified medicinal products

* Thomas Hinz and Kajo Kallen contributed equally to this manuscript.

This is a preview of subscription content, access via your institution.

Buying options

Protocol
USD   49.95
Price excludes VAT (USA)
  • DOI: 10.1007/978-1-4939-6481-9_13
  • Chapter length: 20 pages
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
eBook
USD   109.00
Price excludes VAT (USA)
  • ISBN: 978-1-4939-6481-9
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
Softcover Book
USD   139.99
Price excludes VAT (USA)
Hardcover Book
USD   179.99
Price excludes VAT (USA)

Springer Nature is developing a new tool to find and evaluate Protocols. Learn more

References

  1. 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

    CAS  CrossRef  PubMed  Google Scholar 

  2. 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

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  3. Wolff JA, Malone RW, Williams P et al (1990) Direct gene transfer into mouse muscle in vivo. Science 247:1465–1468

    CAS  CrossRef  PubMed  Google Scholar 

  4. Tang DC, DeVit M, Johnston SA (1992) Genetic immunization is a simple method for eliciting an immune response. Nature 356:152–154

    CAS  CrossRef  PubMed  Google Scholar 

  5. 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

    CAS  CrossRef  PubMed  Google Scholar 

  6. Conry RM, LoBuglio AF, Wright M et al (1995) Characterization of a messenger RNA polynucleotide vaccine vector. Cancer Res 55:1397–1400

    CAS  PubMed  Google Scholar 

  7. 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

    CAS  CrossRef  PubMed  Google Scholar 

  8. Pascolo S (2004) Messenger RNA-based vaccines. Expert Opin Biol Ther 4:1285–1294

    CAS  CrossRef  PubMed  Google Scholar 

  9. 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

    Google Scholar 

  10. Pardi N, Muramatsu H, Weissman D et al (2013) In vitro transcription of long RNA containing modified nucleosides. Methods Mol Biol 969:29–42

    CAS  CrossRef  PubMed  Google Scholar 

  11. 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

    CAS  CrossRef  PubMed  Google Scholar 

  12. 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

    CAS  CrossRef  PubMed  Google Scholar 

  13. 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

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  14. 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

    CAS  CrossRef  PubMed  Google Scholar 

  15. 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

    CAS  CrossRef  PubMed  Google Scholar 

  16. 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

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  17. Schlake T, Thess A, Fotin-Mleczek M et al (2012) Developing mRNA-vaccine technologies. RNA Biol 9:1319–1330

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  18. 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

    CrossRef  PubMed  PubMed Central  Google Scholar 

  19. 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

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  20. 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

    CAS  CrossRef  PubMed  Google Scholar 

  21. 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

    CAS  CrossRef  PubMed  Google Scholar 

  22. Sahin U, Kariko K, Tureci O (2014) mRNA-based therapeutics--developing a new class of drugs. Nat Rev Drug Discov 13:759–780

    CAS  CrossRef  PubMed  Google Scholar 

  23. 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

    CAS  CrossRef  PubMed  Google Scholar 

  24. 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)

    Google Scholar 

  25. 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)

    Google Scholar 

  26. 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

    CrossRef  PubMed  PubMed Central  Google Scholar 

  27. 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

    CrossRef  PubMed  PubMed Central  Google Scholar 

  28. 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

    CAS  CrossRef  PubMed  Google Scholar 

  29. Britten CM, Singh-Jasuja H, Flamion B et al (2013) The regulatory landscape for actively personalized cancer immunotherapies. Nat Biotechnol 31:880–882

    CAS  CrossRef  PubMed  Google Scholar 

  30. Castle JC, Kreiter S, Diekmann J et al (2012) Exploiting the mutanome for tumor vaccination. Cancer Res 72:1081–1091

    CAS  CrossRef  PubMed  Google Scholar 

  31. Castle JC, Loewer M, Boegel S et al (2014) Mutated tumor alleles are expressed according to their DNA frequency. Sci Rep 4:4743

    CrossRef  PubMed  PubMed Central  Google Scholar 

  32. 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

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  33. 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

    CAS  CrossRef  PubMed  Google Scholar 

  34. 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

    CAS  CrossRef  PubMed  Google Scholar 

  35. 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

    CAS  CrossRef  PubMed  Google Scholar 

  36. 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

    CAS  CrossRef  PubMed  Google Scholar 

  37. 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

    CAS  CrossRef  PubMed  Google Scholar 

  38. 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

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  39. 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

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  40. 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

    PubMed  PubMed Central  Google Scholar 

  41. 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

    CrossRef  PubMed  Google Scholar 

  42. 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

    CrossRef  PubMed  PubMed Central  Google Scholar 

  43. Ulmer JB, Mansoura MK, Geall AJ (2015) Vaccines ‘on demand’: science fiction or a future reality. Expert Opin Drug Discov 10(2):101–106

    CAS  CrossRef  PubMed  Google Scholar 

  44. 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

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  45. Geall AJ, Mandl CW, Ulmer JB (2013) RNA: the new revolution in nucleic acid vaccines. Semin Immunol 25:152–159

    CAS  CrossRef  PubMed  Google Scholar 

  46. 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

    CAS  CrossRef  PubMed  Google Scholar 

  47. 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

    CAS  CrossRef  PubMed  Google Scholar 

  48. 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

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  49. 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

    Google Scholar 

  50. 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

    Google Scholar 

  51. 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

    Google Scholar 

  52. 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

    Google Scholar 

  53. EMA, Reflection paper on classification of advanced therapy medicinal products. 20 June 2014. EMA/CAT/600280/2010 Rev.1. Committee for Advanced Therapies (CAT)

    Google Scholar 

  54. EMA, Guideline on the requirements for quality documentation concerning biological investigational medicinal products in clinical trials. EMA/CHMP/534898/2008

    Google Scholar 

  55. EU, Guidelines to Good Manufacturing Practice. Medicinal Products for Human and Veterinary Use. Annex 13. Investigational Medicinal Products

    Google Scholar 

  56. ICH, Harmonised tripartite guideline for good clinical practice E6(R1)

    Google Scholar 

  57. EU, Volume 2B. Notice to applicants. Medicinal products for human use

    Google Scholar 

  58. EMA, Guideline on the risk-based approach according to annex I, part IV of Directive 2001/83/EC applied to advanced therapy medicinal products

    Google Scholar 

  59. EMA, Guideline on the quality, non-clinical and clinical aspects of gene therapy medicinal products. EMA/CAT/80183/2014

    Google Scholar 

  60. EMA, Guideline on human cell-based medicinal products. EMEA/CHMP/410869/2006

    Google Scholar 

  61. EMA, Guideline on quality, non-clinical and clinical aspects of medicinal products containing genetically modified cells. EMA/CAT/GTWP/671639/2008

    Google Scholar 

  62. EU, Good manufacturing practice. Medicinal products for human and veterinary use. Part II: basic requirements for active substances used as starting materials

    Google Scholar 

  63. EMA, Note for guidance on preclinical pharmacological and toxicological testing of vaccines. CPMP/SWP/465/95

    Google Scholar 

  64. EMA, Non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals. ICH M(3)

    Google Scholar 

  65. EMA, Guideline on the evaluation of anticancer medicinal products in man. EMA/CHMP/205/95/Rev.4

    Google Scholar 

  66. EMA, Guideline on clinical evaluation of new vaccines. EMEA/CHMP/VWP/164653/2005

    Google Scholar 

  67. FDA, Guidance for Industry. Clinical Considerations for Therapeutic Cancer Vaccines

    Google Scholar 

Download references

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

Authors

Corresponding authors

Correspondence to Thomas Hinz or Ulrich Kalinke .

Editor information

Editors and Affiliations

Rights and permissions

Reprints 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