RNA Vaccines pp 203-222 | Cite as

The European Regulatory Environment of RNA-Based Vaccines

  • Thomas Hinz
  • Kajo Kallen
  • Cedrik M. Britten
  • Bruno Flamion
  • Ulrich Granzer
  • Axel Hoos
  • Christoph Huber
  • Samir Khleif
  • Sebastian Kreiter
  • Hans-Georg Rammensee
  • Ugur Sahin
  • Harpreet Singh-Jasuja
  • Özlem Türeci
  • Ulrich Kalinke
Protocol
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 

References

  1. 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 4:404–408CrossRefPubMedGoogle Scholar
  2. 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 47:1580–1588CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Wolff JA, Malone RW, Williams P et al (1990) Direct gene transfer into mouse muscle in vivo. Science 247:1465–1468CrossRefPubMedGoogle Scholar
  4. 4.
    Tang DC, DeVit M, Johnston SA (1992) Genetic immunization is a simple method for eliciting an immune response. Nature 356:152–154CrossRefPubMedGoogle Scholar
  5. 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 23:1719–1722CrossRefPubMedGoogle Scholar
  6. 6.
    Conry RM, LoBuglio AF, Wright M et al (1995) Characterization of a messenger RNA polynucleotide vaccine vector. Cancer Res 55:1397–1400PubMedGoogle Scholar
  7. 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 30:1–7CrossRefPubMedGoogle Scholar
  8. 8.
    Pascolo S (2004) Messenger RNA-based vaccines. Expert Opin Biol Ther 4:1285–1294CrossRefPubMedGoogle Scholar
  9. 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 WO2008077592Google Scholar
  10. 10.
    Pardi N, Muramatsu H, Weissman D et al (2013) In vitro transcription of long RNA containing modified nucleosides. Methods Mol Biol 969:29–42CrossRefPubMedGoogle Scholar
  11. 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 23:165–175CrossRefPubMedGoogle Scholar
  12. 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 108:4009–4017CrossRefPubMedGoogle Scholar
  13. 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 16:1833–1840CrossRefPubMedPubMedCentralGoogle Scholar
  14. 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 17:961–971CrossRefPubMedGoogle Scholar
  15. 15.
    Kormann MS, Hasenpusch G, Aneja MK et al (2011) Expression of therapeutic proteins after delivery of chemically modified mRNA in mice. Nat Biotechnol 29:154–157CrossRefPubMedGoogle Scholar
  16. 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 20:948–953CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Schlake T, Thess A, Fotin-Mleczek M et al (2012) Developing mRNA-vaccine technologies. RNA Biol 9:1319–1330CrossRefPubMedPubMedCentralGoogle Scholar
  18. 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 2:10–31CrossRefPubMedPubMedCentralGoogle Scholar
  19. 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 23:1456–1464CrossRefPubMedPubMedCentralGoogle Scholar
  20. 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 8:627–636CrossRefPubMedGoogle Scholar
  21. 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 18:702–708CrossRefPubMedGoogle Scholar
  22. 22.
    Sahin U, Kariko K, Tureci O (2014) mRNA-based therapeutics--developing a new class of drugs. Nat Rev Drug Discov 13:759–780CrossRefPubMedGoogle Scholar
  23. 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 34:1–15CrossRefPubMedGoogle Scholar
  24. 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. 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. 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 14:748CrossRefPubMedPubMedCentralGoogle Scholar
  27. 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 3:26CrossRefPubMedPubMedCentralGoogle Scholar
  28. 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 180:309–318CrossRefPubMedGoogle Scholar
  29. 29.
    Britten CM, Singh-Jasuja H, Flamion B et al (2013) The regulatory landscape for actively personalized cancer immunotherapies. Nat Biotechnol 31:880–882CrossRefPubMedGoogle Scholar
  30. 30.
    Castle JC, Kreiter S, Diekmann J et al (2012) Exploiting the mutanome for tumor vaccination. Cancer Res 72:1081–1091CrossRefPubMedGoogle Scholar
  31. 31.
    Castle JC, Loewer M, Boegel S et al (2014) Mutated tumor alleles are expressed according to their DNA frequency. Sci Rep 4:4743CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Kreiter S, Vormehr M, van de Roemer N et al (2015) Mutant MHC class II epitopes drive therapeutic immune responses to cancer. Nature 520:692–696CrossRefPubMedPubMedCentralGoogle Scholar
  33. 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 16:1170–1180CrossRefPubMedGoogle Scholar
  34. 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 18:5460–5470CrossRefPubMedGoogle Scholar
  35. 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 64:381–388CrossRefPubMedGoogle Scholar
  36. 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 24:2686–2693CrossRefPubMedGoogle Scholar
  37. 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 30:1210–1216CrossRefPubMedGoogle Scholar
  38. 38.
    Geall AJ, Verma A, Otten GR et al (2012) Nonviral delivery of self-amplifying RNA vaccines. Proc Natl Acad Sci U S A 109:14604–14609CrossRefPubMedPubMedCentralGoogle Scholar
  39. 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 146:312–326CrossRefPubMedPubMedCentralGoogle Scholar
  40. 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 PubMedPubMedCentralGoogle Scholar
  41. 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 211:947–955CrossRefPubMedGoogle Scholar
  42. 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:e52CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Ulmer JB, Mansoura MK, Geall AJ (2015) Vaccines ‘on demand’: science fiction or a future reality. Expert Opin Drug Discov 10(2):101–106CrossRefPubMedGoogle Scholar
  44. 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 111:1469–1475CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Geall AJ, Mandl CW, Ulmer JB (2013) RNA: the new revolution in nucleic acid vaccines. Semin Immunol 25:152–159CrossRefPubMedGoogle Scholar
  46. 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 124:1070–1077CrossRefPubMedGoogle Scholar
  47. 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 10:703–707CrossRefPubMedGoogle Scholar
  48. 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 31:898–907CrossRefPubMedPubMedCentralGoogle Scholar
  49. 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/ECGoogle Scholar
  50. 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 AgencyGoogle Scholar
  51. 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 726/2004Google Scholar
  52. 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 productsGoogle Scholar
  53. 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. 54.
    EMA, Guideline on the requirements for quality documentation concerning biological investigational medicinal products in clinical trials. EMA/CHMP/534898/2008Google Scholar
  55. 55.
    EU, Guidelines to Good Manufacturing Practice. Medicinal Products for Human and Veterinary Use. Annex 13. Investigational Medicinal ProductsGoogle Scholar
  56. 56.
    ICH, Harmonised tripartite guideline for good clinical practice E6(R1)Google Scholar
  57. 57.
    EU, Volume 2B. Notice to applicants. Medicinal products for human useGoogle Scholar
  58. 58.
    EMA, Guideline on the risk-based approach according to annex I, part IV of Directive 2001/83/EC applied to advanced therapy medicinal productsGoogle Scholar
  59. 59.
    EMA, Guideline on the quality, non-clinical and clinical aspects of gene therapy medicinal products. EMA/CAT/80183/2014Google Scholar
  60. 60.
    EMA, Guideline on human cell-based medicinal products. EMEA/CHMP/410869/2006Google Scholar
  61. 61.
    EMA, Guideline on quality, non-clinical and clinical aspects of medicinal products containing genetically modified cells. EMA/CAT/GTWP/671639/2008Google Scholar
  62. 62.
    EU, Good manufacturing practice. Medicinal products for human and veterinary use. Part II: basic requirements for active substances used as starting materialsGoogle Scholar
  63. 63.
    EMA, Note for guidance on preclinical pharmacological and toxicological testing of vaccines. CPMP/SWP/465/95Google Scholar
  64. 64.
    EMA, Non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals. ICH M(3)Google Scholar
  65. 65.
    EMA, Guideline on the evaluation of anticancer medicinal products in man. EMA/CHMP/205/95/Rev.4Google Scholar
  66. 66.
    EMA, Guideline on clinical evaluation of new vaccines. EMEA/CHMP/VWP/164653/2005Google Scholar
  67. 67.
    FDA, Guidance for Industry. Clinical Considerations for Therapeutic Cancer VaccinesGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Thomas Hinz
    • 1
  • Kajo Kallen
    • 2
  • Cedrik M. Britten
    • 3
  • Bruno Flamion
    • 4
  • Ulrich Granzer
    • 5
  • Axel Hoos
    • 6
  • Christoph Huber
    • 7
  • Samir Khleif
    • 8
  • Sebastian Kreiter
    • 7
  • Hans-Georg Rammensee
    • 9
    • 10
  • Ugur Sahin
    • 11
    • 12
    • 16
  • Harpreet Singh-Jasuja
    • 13
  • Özlem Türeci
    • 14
  • Ulrich Kalinke
    • 15
  1. 1.Section for Therapeutic Vaccines, Division for ImmunologyPaul-Ehrlich-InstitutLangenGermany
  2. 2.Kallen ConsultingKöln/FrechenGermany
  3. 3.R&D OncologyGlaxo Smith KlineStevenageUK
  4. 4.URPhyM, NARILISUniversity of NamurNamurBelgium
  5. 5.Granzer, Regulatory Consulting & ServicesMunichGermany
  6. 6.Glaxo Smith KlineCollegevilleUSA
  7. 7.Association for Cancer ImmunotherapyMainzGermany
  8. 8.GHSU Cancer CenterAugustaUSA
  9. 9.Department of Immunology, Institute for Cell BiologyUniversity of TübingenTübingenGermany
  10. 10.German Cancer ConsortiumDKFZ Partner SiteTübingenGermany
  11. 11.TRON – Translational Oncology at the University Medical CenterJohannes Gutenberg UniversityMainzGermany
  12. 12.Biopharmaceutical New Technologies (BioNTech) CorporationMainzGermany
  13. 13.Immatics Biotechnologies GmbHTübingenGermany
  14. 14.CI3, Cluster for individualized Immune InterventionMainzGermany
  15. 15.Institute for Experimental Infection Research, TwincoreCentre for Experimental and Clinical Infection Research a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection ResearchHannoverGermany
  16. 16.Research Center for Immunotherapy (FZI)MainzGermany

Personalised recommendations