Advertisement

pp 1-30 | Cite as

mRNA-Based Vaccines and Mode of Action

Chapter
First Online:
Part of the Current Topics in Microbiology and Immunology book series

Abstract

In the past 20 years, the mRNA vaccine technology has evolved from the first proof of concept to the first licensed vaccine against emerging pandemics such as SARS-CoV-2. Two mRNA vaccines targeting SARS-CoV-2 have received emergency use authorization by US FDA, conditional marketing authorization by EMA, as well as multiple additional national regulatory authorities. The simple composition of an mRNA encoding the antigen formulated in a lipid nanoparticle enables a fast adaptation to new emerging pathogens. This can speed up vaccine development in pandemics from antigen and sequence selection to clinical trial to only a few months. mRNA vaccines are well tolerated and efficacious in animal models for multiple pathogens and will further contribute to the development of vaccines for other unaddressed diseases. Here, we give an overview of the mRNA vaccine design and factors for further optimization of this new promising technology and discuss current knowledge on the mode of action of mRNA vaccines interacting with the innate and adaptive immune system.

This is a preview of subscription content, log in to check access.

Notes

Acknowledgements

We thank Igor Splawski and Janine Mühe for critically reading the manuscript.

References

  1. Ahmed F, Benedito VA, Zhao PX (2011) Mining functional elements in messenger RNAs: overview, challenges, and perspectives. Front Plant Sci 2Google Scholar
  2. Alberer M et al (2017) Safety and immunogenicity of a mRNA rabies vaccine in healthy adults: an open-label, non-randomised, prospective, first-in-human phase 1 clinical trial. LancetGoogle Scholar
  3. Allen IC et al (2009) The NLRP3 inflammasome mediates in vivo innate immunity to influenza A virus through recognition of viral RNA. Immunity 30(4):556–565Google Scholar
  4. Anderson BR et al (2010) Incorporation of pseudouridine into mRNA enhances translation by diminishing PKR activation. Nucleic Acids Res 38(17):5884–5892Google Scholar
  5. Anderson BR, Muramatsu H, Jha BK, Silverman RH, Weissman D, Karikó K (2011) Nucleoside modifications in RNA limit activation of 2ʹ-5ʹ-oligoadenylate synthetase and increase resistance to cleavage by RNase L. Nucleic Acids Res 39(21):9329–9338Google Scholar
  6. Andries O et al (2013) Innate immune response and programmed cell death following carrier-mediated delivery of unmodified mRNA to respiratory cells. J Control Release 167(2):157–166Google Scholar
  7. Andries O, Mc Cafferty S, De Smedt SC, Weiss R, Sanders NN, Kitada T (2015) N1-methylpseudouridine-incorporated mRNA outperforms pseudouridine-incorporated mRNA by providing enhanced protein expression and reduced immunogenicity in mammalian cell lines and mice. J Control Release 217:337–344Google Scholar
  8. Bahl K et al (2017) Preclinical and clinical demonstration of immunogenicity by mRNA vaccines against H10N8 and H7N9 influenza viruses. Mol Ther 25(6):1316–1327Google Scholar
  9. Baiersdörfer M et al (2019) A facile method for the removal of dsRNA contaminant from in vitro-transcribed mRNA. Mol Ther Nucleic Acids 15:26–35Google Scholar
  10. Banerjee AK (1980) 5’-terminal cap structure in eucaryotic messenger ribonucleic acids. Microbiol Rev 44(2):175–205Google Scholar
  11. Beddows S et al (2006) Construction and characterization of soluble, cleaved, and stabilized trimeric env proteins Based on HIV type 1 env subtype A. AIDS Res Hum Retroviruses 22(6):569–579Google Scholar
  12. Ben-Asouli Y, Banai Y, Pel-Or Y, Shir A, Kaempfer R (2002) Human interferon-γ mRNA autoregulates its translation through a Pseudoknot that activates the interferon-inducible protein kinase PKR. Cell 108(2):221–232Google Scholar
  13. Berkovits BD, Mayr C (2015) Alternative 3ʹ UTRs act as scaffolds to regulate membrane protein localization. Nature 522(7556):363–367Google Scholar
  14. Bernstein P, Peltz SW, Ross J (1989) The poly(A)-poly(A)-binding protein complex is a major determinant of mRNA stability in vitro. Mol. Cell. Biol. 9(2):659–670Google Scholar
  15. Beverley PCL (2002) Immunology of vaccination. Br Med Bull 62(1):15–28Google Scholar
  16. Beverly M, Hagen C, Slack O (2018) Poly A tail length analysis of in vitro transcribed mRNA by LC-MS. Anal Bioanal Chem 410(6):1667–1677Google Scholar
  17. Borg FA, Isenberg DA (2007) Syndromes and complications of interferon therapy. Curr Opin Rheumatol 19(1):61–66Google Scholar
  18. Bourhy H et al (2007) “Annex 2 Recommendations for inactivated rabies vaccine for human use produced in cell substrates and embryonated eggs. World Heal Organ Tech Rep Ser 941:83–132Google Scholar
  19. Brisse M, Ly H (2019) Comparative structure and function analysis of the RIG-I-like receptors: RIG-I and MDA5. Front Immunol 10Google Scholar
  20. Broos K et al (2016) Particle-mediated Intravenous Delivery of Antigen mRNA Results in Strong Antigen-specific T-cell Responses Despite the Induction of Type I Interferon. Mol. Ther. - Nucleic Acids 5:e326Google Scholar
  21. Burns CC, Diop OM, Sutter RW, Kew OM (2014) Vaccine-derived polioviruses. J Infect Dis 210(suppl 1):S283–S293Google Scholar
  22. Burton DR, Hangartner L (2016) Broadly neutralizing antibodies to HIV and their role in vaccine design. Annu Rev Immunol 34:635–659Google Scholar
  23. Carr MW, Roth SJ, Luther E, Rose SS, Springer TA (1994) Monocyte chemoattractant protein 1 acts as a T-lymphocyte chemoattractant. Proc Natl Acad Sci USA 91(9):3652Google Scholar
  24. Carralot JP et al (2004) Polarization of immunity induced by direct injection of naked sequence-stabilized mRNA vaccines. Cell Mol Life Sci 61(18):2418–2424Google Scholar
  25. Chumakov K, Elzinga N, Wood DJ (2002) Annex 2 Recommendations for the production and control of poliomyelitis vaccine ( inactivated) 1. World Heal Organ Tech Rep Ser (910)Google Scholar
  26. Clarke TF IV, Clark PL (2010) Increased incidence of rare codon clusters at 5ʹ and 3ʹ gene termini: implications for function. BMC Genomics 11:118Google Scholar
  27. Crouse J, Kalinke U, Oxenius A (2015) Regulation of antiviral T cell responses by type I interferons. Nat Rev Immunol 15(4):231–242Google Scholar
  28. De Beuckelaer A et al (2016) Type I interferons interfere with the capacity of mRNA lipoplex vaccines to elicit cytolytic T cell responses. Mol Ther 24(11):2012–2020Google Scholar
  29. De Beuckelaer A, Grooten J, De Koker S (2017) Type I interferons modulate CD8+ T cell immunity to mRNA vaccines. Trends Mol Med 23(3):216–226Google Scholar
  30. Devarkar SC et al (2016) Structural basis for m7G recognition and 2′-O-methyl discrimination in capped RNAs by the innate immune receptor RIG-I. Proc Natl Acad Sci USA 113(3):596Google Scholar
  31. Devoldere J, Dewitte H, De Smedt SC, Remaut K (2016) Evading innate immunity in nonviral mRNA delivery: don’t shoot the messenger. Drug Discov Today 21(1):11–25Google Scholar
  32. Ding Y, Tang Y, Kwok CK, Zhang Y, Bevilacqua PC, Assmann SM (2014) In vivo genome-wide profiling of RNA secondary structure reveals novel regulatory features. Nature 505(7485):696–700Google Scholar
  33. Durbin AF, Wang C, Marcotrigiano J, Gehrke L (2016) RNAs containing modified nucleotides fail to trigger RIG-I conformational changes for innate immune signaling. MBio 7(5)Google Scholar
  34. Edwards et al DK (2017) Adjuvant effects of a sequence-engineered mRNA vaccine: translational profiling demonstrates similar human and murine innate response. J Transl Med 15(1):1Google Scholar
  35. Elango N, Elango S, Shivshankar P, Katz MS (2005) Optimized transfection of mRNA transcribed from a d(A/T)100 tail-containing vector. Biochem Biophys Res Commun 330(3):958–966Google Scholar
  36. Elfakess R, Sinvani H, Haimov O, Svitkin Y, Sonenberg N, Dikstein R (2011) Unique translation initiation of mRNAs-containing TISU element. Nucleic Acids Res 39(17):7598–7609Google Scholar
  37. Fensterl V, Sen GC (2015) Interferon-induced Ifit proteins: their role in viral pathogenesis. J Virol 89(5):2462Google Scholar
  38. Ford LP, Bagga PS, Wilusz J (1997) The poly(A) tail inhibits the assembly of a 3ʹ-to-5ʹ exonuclease in an in vitro RNA stability system. Mol Cell Biol 17(1):398–406Google Scholar
  39. Fotin-Mleczek M 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):1–15Google Scholar
  40. Galloway A, Cowling VH (2019) mRNA cap regulation in mammalian cell function and fate. Biochim Biophys Acta Gene Regul Mech 1862(3):270Google Scholar
  41. Geall AJ et al (2012) Nonviral delivery of self-amplifying RNA vaccines. Proc Natl Acad Sci 109(36):14604–14609Google Scholar
  42. Georg P, Sander LE (2019) Innate sensors that regulate vaccine responses. Curr Opin Immunol 59:31–41Google Scholar
  43. Grier AE et al (2016) pEVL: a linear plasmid for generating mRNA IVT templates with extended encoded poly(A) sequences. Mol Ther Nucleic Acids 5(4):e306Google Scholar
  44. Groom JR, Luster AD (2011) CXCR3 ligands: redundant, collaborative and antagonistic functions. Immunol Cell Biol 89(2)Google Scholar
  45. Grudzien-Nogalska E, Jemielity J, Kowalska J, Darzynkiewicz E, Rhoads RE (2007) Phosphorothioate cap analogs stabilize mRNA and increase translational efficiency in mammalian cells. RNA 13(10):1745–1755Google Scholar
  46. Gruys E, Toussaint MJM, Niewold TA, Koopmans SJ (2005) Acute phase reaction and acute phase proteins. J Zhejiang Univ Sci B 6(11):1045–1056Google Scholar
  47. Gustafsson C, Govindarajan S, Minshull J (2004) Codon bias and heterologous protein expression. Trends Biotechnol 22(7):346–353Google Scholar
  48. Haralambieva IH, Kennedy RB, Ovsyannikova IG, Schaid DJ, Poland GA (2019) Current perspectives in assessing humoral immunity after measles vaccination. Expert Rev Vaccines 18(1):75Google Scholar
  49. Hesseling A et al (2009) Disseminated bacille Calmette-Guérin disease in HIV-infected South African infants. Bull World Health Organ 87(7):505Google Scholar
  50. Hickling J, Jones K, Friede M, Zehrung D, Chen D, Kristensen D (2011) Intradermal delivery of vaccines: potential benefits and current challenges. Bull World Health Organ 89(3):221Google Scholar
  51. 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):1–7Google Scholar
  52. Holtkamp S et al (2006) Modification of antigen-encoding RNA increases stability, translational efficacy and T-cell stimularoy capacity of dendritic cells. Blood 108(13)Google Scholar
  54. Iavarone C, O’hagan DT, Yu D, Delahaye NF, Ulmer JB (2017) Mechanism of action of mRNA-based vaccines. Expert Rev Vaccines 16(9):871–881Google Scholar
  55. Innis BL et al (1994) Protection against hepatitis A by an inactivated vaccine. JAMA J Am Med Assoc 271(17):1328Google Scholar
  56. Jackson LA et al (2020) An mRNA vaccine against SARS-CoV-2—preliminary report. N Engl J MedGoogle Scholar
  57. Jan CH, Friedman RC, Ruby JG, Bartel DP (2011) Formation, regulation and evolution of Caenorhabditis elegans 3′ UTRs. Nature 469(7328):97–101Google Scholar
  58. Jemielity J et al (2003) Novel ‘anti-reverse’ cap analogs with superior translational properties. RNA 9(9):1108–1122Google Scholar
  59. Jia J, Yao P, Arif A, Fox PL (2013) Regulation and dysregulation of 3ʹ UTR-mediated translational control. Curr Opin Genet Dev 23(1):29–34Google Scholar
  60. John S et al (2018) Multi-antigenic human cytomegalovirus mRNA vaccines that elicit potent humoral and cell-mediated immunity. Vaccine 36(12):1689–1699Google Scholar
  61. Juskewitch JE, Tapia CJ, Windebank AJ (2010) Lessons from the Salk polio vaccine: methods for and risks of rapid translation. Clin Transl Sci 3(4):182–185Google Scholar
  62. Karikó 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(2):165–175Google Scholar
  63. Karikó K et al (2008) Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Mol Ther 16(11):1833–1840Google Scholar
  64. Karikó K, Muramatsu H, Ludwig J, Weissman D (2011) Generating the optimal mRNA for therapy: HPLC purification eliminates immune activation and improves translation of nucleoside-modified, protein-encoding mRNA. Nucleic Acids Res 39(21):e142Google Scholar
  65. Karikó K, Muramatsu H, Keller JM, Weissman D (2012) Increased erythropoiesis in mice injected with submicrogram quantities of pseudouridine-containing mRNA encoding erythropoietin. Mol Ther 20(5):948–953Google Scholar
  66. Kato H et al (2008) Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-I and melanoma differentiation-associated gene 5. J Exp Med 205(7):1601–1610Google Scholar
  67. Kauffman KJ et al (2016) Efficacy and immunogenicity of unmodified and pseudouridine-modified mRNA delivered systemically with lipid nanoparticles in vivo. Biomaterials 109:78–87Google Scholar
  68. Kaygun H, Marzluff WF (2005) Translation termination is involved in histone mRNA degradation when DNA replication is inhibited. Mol Cell Biol 25(16):6879–6888Google Scholar
  69. Kierzek E, Kierzek R (2003) The thermodynamic stability of RNA duplexes and hairpins containing N6-alkyladenosines and 2-methylthio-N6-alkyladenosines. Nucleic Acids Res 31(15):4472–4480Google Scholar
  70. Kocmik I et al (2018) Modified ARCA analgos providing enhanced properties of capped mRNAs. Cell Cycle 17(13):71–75Google Scholar
  71. Koh WS, Porter JR, Batchelor E (2019) Tuning of mRNA stability through altering 3’-UTR sequences generates distinct output expression in a synthetic circuit driven by p53 oscillations. Sci Rep 9(1):5976Google Scholar
  72. Kore AR, Charles I (2010) Synthesis and evaluation of 2′–O–allyl substituted dinucleotide cap analog for mRNA translation. Bioorganic Med Chem 18(22):8061–8065Google Scholar
  73. Kore AR, Shanmugasundaram M, Charles I, Vlassov AV, Barta TJ (2009) Locked nucleic acid (LNA)-modified dinucleotide mRNA cap analogue: synthesis, enzymatic incorporation, and utilization. J Am Chem Soc 131(18):6364–6365Google Scholar
  74. Kormann MSD et al (2011) Expression of therapeutic proteins after delivery of chemically modified mRNA in mice. Nat Biotechnol 29(2):110–112Google Scholar
  75. Kowalczyk A et al (2016) Self-adjuvanted mRNA vaccines induce local innate immune responses that lead to a potent and boostable adaptive immunity. Vaccine 34(33):3882–3893Google Scholar
  76. Kozak M (2005) Regulation of translation via mRNA structure in prokaryotes and eukaryotes. Gene 361(1–2):13–37Google Scholar
  77. Kozak M (1991a) A short leader sequence impairs the fidelity of initiation by eukaryotic ribosomes. Gene Expr 1(2):111–115Google Scholar
  78. Kozak M (1991b) Effects of long 5ʹ leader sequences on initiation by eukaryotic ribosomes in vitro. Gene Expr 1(2):117–125Google Scholar
  79. Kranz LM et al (2016) Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy. Nature 534Google Scholar
  80. Kuhn AN 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(8):961–971Google Scholar
  81. Kuhn AN, Diken M, Kreiter S, Vallazza B, Türeci Ö, Sahin U (2011) Determinants of intracellular RNA pharmacokinetics: Implications for RNA-based immunotherapeutics. RNA Biol 8(1):35–43Google Scholar
  82. Lässig C, Hopfner K-P (2017) Discrimination of cytosolic self and non-self RNA by RIG-I-like receptors. J Biol Chem 292(22):9000–9009Google Scholar
  83. Lawrence JB, Singer RH (1986) Intracellular localization of messenger RNAs for cytoskeletal proteins. Cell 45(3):407–415Google Scholar
  84. Le Bon A et al (2014) Direct stimulation of T cells by type I IFN enhances the CD8+ T cell response during cross-priming. J Immunol 176(8):4682–4689Google Scholar
  85. Lee J, Arun Kumar S, Jhan YY, Bishop CJ (2018) Engineering DNA vaccines against infectious diseases. Acta Biomater 80:31–47Google Scholar
  86. Lemckert AAC et al (2005) Immunogenicity of heterologous prime-boost regimens involving recombinant adenovirus serotype 11 (Ad11) and Ad35 vaccine vectors in the presence of anti-Ad5 immunity. J Virol 79(15):9694–9701Google Scholar
  87. Leppek K, Das R, Barna M (2018) Functional 5′ UTR mRNA structures in eukaryotic translation regulation and how to find them. Nat Rev Mol Cell Biol 19(3):158–174Google Scholar
  88. Liang F et al (2017) Efficient targeting and activation of antigen-presenting cells in vivo after modified mRNA vaccine administration in rhesus macaques. Mol Ther 25(12):2635–2647Google Scholar
  89. Lindgren G et al (2017) Induction of robust B cell responses after influenza mRNA vaccination is accompanied by circulating hemagglutinin-specific ICOS+ PD-1+ CXCR3+ T follicular helper cells. Front Immunol 8:1539Google Scholar
  90. Loomis KH et al (2018) In vitro transcribed mRNA vaccines with programmable stimulation of innate immunity. Bioconjug Chem 29(9):3072–3083Google Scholar
  91. Lutz J et al (2017) Unmodified mRNA in LNPs constitutes a competitive technology for prophylactic vaccines. NPJ Vaccines 2(1):1–9Google Scholar
  92. Mannironi C, Bonner WM, Hatch CL (1989) H2A.X. a histone isoprotein with a conserved C-terminal sequence, is encoded by a novel mRNA with both DNA replication type and polyA 3ʹ processing signals. Nucleic Acids Res 17(22):9113Google Scholar
  93. Mariner JC et al (2012) Rinderpest eradication: appropriate technology and social innovations. Science (80–) 337 (6100):1309–1312Google Scholar
  94. Martinon F et al (1993) Induction of virus-specific cytotoxic T lymphocytesin vivo by liposome-entrapped mRNA. Eur J Immunol 23(7):1719–1722Google Scholar
  95. Marzluff WF (1992) Histone 3ʹ ends: essential and regulatory functions. Gene Expr 2(2)Google Scholar
  96. Mauger DM et al (2019) mRNA structure regulates protein expression through changes in functional half-life. Proc Natl Acad Sci USA 116(48):24075–24083Google Scholar
  97. Mayr C (2008) Regualtion by 3ʹ-untranslated regions. Postgrad Med J 67(791):862–862Google Scholar
  98. McHeyzer-Williams LJ, Pelletier N, Mark L, Fazilleau N, McHeyzer-Williams MG (2009) Follicular helper T cells as cognate regulators of B cell immunity. Curr Opin Immunol 21(3):266–273Google Scholar
  99. McNab F, Mayer-Barber K, Sher A, Wack A, O’Garra A (2015) Type I interferons in infectious disease. Nat Rev Immunol 15(2):87–103Google Scholar
  100. Meis R, Meis JE, Biotechnologies E (2006) Achieve 100 % capping efficiency with the NEW ScriptCapTM m 7 G capping system improve the translation efficiency of any 5ʹ-capped mRNA with the NEW ScriptCapTM 2ʹ–O–Methyltransferase. System 13(4):5–6Google Scholar
  101. Meis JE, Meis R, Biotechnologies E (2016) The new mScript TM mRNA production system—efficient mRNA transcription, capping and tailing for the highest yields of active protein. Epic Biotechnol Forum 14(1):4–5Google Scholar
  102. Mockey M, Gonçalves C, Dupuy FP, Lemoine FM, Pichon C, Midoux P (2006) mRNA transfection of dendritic cells: synergistic effect of ARCA mRNA capping with Poly(A) chains in cis and in trans for a high protein expression level. Biochem Biophys Res Commun 340(4):1062–1068Google Scholar
  103. Mogensen TH (2009) Pathogen recognition and inflammatory signaling in innate immune defenses. Clin Microbiol Rev 22(2):240Google Scholar
  104. Mu X, Greenwald E, Ahmad S, Hur S (2018) An origin of the immunogenicity of in vitro transcribed RNA. Nucleic Acids Res 46(10):5239–5249Google Scholar
  105. Muckenthaler MU, Rivella S, Hentze MW, Galy B (2017) A red carpet for iron metabolism. Cell 168(3):344Google Scholar
  106. Mulligan MJ et al (2020) Phase 1/2 study to describe the safety and immunogenicity of a COVID-19 RNA vaccine candidate (BNT162b1) in adults 18 to 55 years of age: interim report. medRxiv  https://doi.org/10.1101/2020.06.30.20142570
  107. Ndhlovu ZM et al (2015) The breadth of expandable memory CD8+ T cells inversely correlates with residual viral loads in HIV elite controllers. J Virol 89(21):10735–10747Google Scholar
  108. Nigg AJ, Walker PL (2009) Overview, prevention, and treatment of rabies. Pharmacotherapy 29(10):1182–1195Google Scholar
  109. Novoa EM, Ribas de Pouplana L (2012) Speeding with control: codon usage, tRNAs, and ribosomes. Trends Genet 28(11):574–581Google Scholar
  110. Orlandini von Niessen AG et al (2019) Improving mRNA-based therapeutic gene delivery by expression-augmenting 3ʹ UTRs identified by cellular library screening. Mol Ther 27(4):824–836Google Scholar
  111. Ozawa S et al (2017) Estimated economic impact of vaccinations in 73 low- and middle-income countries, 2001–2020. Bull World Health Organ 95(9):629Google Scholar
  112. Padilla-Quirarte HO, Lopez-Guerrero DV, Gutierrez-Xicotencatl L, Esquivel-Guadarrama F (2019) Protective antibodies against influenza proteins. Front Immunol 10Google Scholar
  113. Pardi N et al (2017a) Administration of nucleoside-modified mRNA encoding broadly neutralizing antibody protects humanized mice from HIV-1 challenge. Nat Commun 8:14630Google Scholar
  114. Pardi N et al (2017b) Zika virus protection by a single low-dose nucleoside-modified mRNA vaccination. Nature 543(7644):248–251Google Scholar
  115. Pardi N et al (2018) Nucleoside-modified mRNA immunization elicits influenza virus hemagglutinin stalk-specific antibodies. Nat Commun 9(1):3361Google Scholar
  116. Pardi N et al (2018) Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses. J Exp Med 215(6):1571–1588Google Scholar
  117. Pardi N et al (2019) Characterization of HIV-1 nucleoside-modified mRNA vaccines in rabbits and rhesus macaques. Mol Ther Nucleic Acids 15:36–47Google Scholar
  118. Pasquinelli A, Dahlberg J, Elsebet L (1995) Reverse 5’ caps in RNAs made in vitro by phage RNA polymerases. RNA 1(957):110–117Google Scholar
  119. Patinote C et al (2020) Agonist and antagonist ligands of toll-like receptors 7 and 8: ingenious tools for therapeutic purposes. Eur J Med Chem 193:112238Google Scholar
  120. Petrovsky N (2015) Comparative safety of vaccine adjuvants: a summary of current evidence and future needs. Drug Saf 38(11):1059–1074Google Scholar
  121. Petsch B et al (2012) Protective efficacy of in vitro synthesized, specific mRNA vaccines against influenza A virus infection. Nat Biotechnol 30(12):1210–1216Google Scholar
  122. Plotkin S (2014) History of vaccination. Proc Natl Acad Sci USA 111(34):12283Google Scholar
  123. Pollard C et al (2013) Type I IFN counteracts the induction of antigen-specific immune responses by lipid-based delivery of mRNA vaccines. Mol Ther 21(1):251–259Google Scholar
  124. Rabani M, Pieper L, Chew GL, Schier AF (2017) A massively parallel reporter assay of 3′ UTR sequences identifies in vivo rules for mRNA degradation. Mol Cell 68(6):1083-1094.e5Google Scholar
  125. Rajan JV, Warren SE, Miao EA, Aderem A (2010) Activation of the NLRP3 inflammasome by intracellular poly I:C. FEBS Lett 584(22):4627–4632Google Scholar
  126. Rauch S, Jasny E, Schmidt KE, Petsch B (2018) New vaccine technologies to combat outbreak situations. Front Immunol 9:1963Google Scholar
  127. Richner JM et al (2017) Modified mRNA vaccines protect against Zika virus infection. Cell 168(6):1114-1125.e10 Google Scholar
  128. Rönnblom LE (1991) Autoimmunity after alpha-interferon therapy for malignant carcinoid tumors. Ann Intern Med 115(3):178 Google Scholar
  129. Rossey I, McLellan JS, Saelens X, Schepens B (2018) Clinical potential of prefusion RSV F-specific antibodies. Trends Microbiol 26(3):209–219Google Scholar
  130. Rydzik AM et al (2017) mRNA cap analogues substituted in the tetraphosphate chain with CX2: identification of O-to-CCl2 as the first bridging modification that confers resistance to decapping without impairing translation. Nucleic Acids Res 45(15):8661–8675Google Scholar
  131. Sadler AJ, Williams BRG (2008) Interferon-inducible antiviral effectors. Nat Rev Immunol 8(7):559–568Google Scholar
  132. Sample PJ et al (2019) Human 5′ UTR design and variant effect prediction from a massively parallel translation assay. Nat Biotechnol 37(7):803Google Scholar
  133. Sanders RW, Moore JP (2017) Native-like env trimers as a platform for HIV-1 vaccine design. Immunol Rev 275(1):161Google Scholar
  134. Scheel B et al (2004) Immunostimulating capacities of stabilized RNA molecules. Eur J Immunol 34(2):537–547Google Scholar
  135. Schlake T, Thess A, Fotin-mleczek M, Kallen K (2012) Developing mRNA-vaccine technologies. RNA Biol 9(November):1–12Google Scholar
  136. Schlake T, Thess A, Thran M, Jordan I (2019) mRNA as novel technology for passive immunotherapy. Cell Mol Life Sci 76(2):301–328Google Scholar
  137. Schmidt A et al (2009) 5′-triphosphate RNA requires base-paired structures to activate antiviral signaling via RIG-I. Proc Natl Acad Sci USA 106(29):12067Google Scholar
  138. Schnee M et al (2016) An mRNA vaccine encoding rabies virus glycoprotein induces protection against lethal infection in mice and correlates of protection in adult and newborn pigs. PLoS Negl Trop Dis 10(6):e0004746Google Scholar
  139. Schnierle BS, Gershon PD, Moss B (1992) Cap-specific mRNA (nucleoside-O2ʹ-)-methyltransferase and poly(A) polymerase stimulatory activities of vaccinia virus are mediated by a single protein. Proc Natl Acad Sci USA 89(7):2897–2901Google Scholar
  140. Shanmugasundaram M, Charles I, Kore AR (2016) Design, synthesis and biological evaluation of dinucleotide mRNA cap analog containing propargyl moiety. Bioorganic Med Chem 24(6):1204–1208Google Scholar
  141. Skowronski DM et al (2014) Low 2012–13 influenza vaccine effectiveness associated with mutation in the egg-adapted H3N2 vaccine strain not antigenic drift in circulating viruses. PLoS ONE 9(3):e92153Google Scholar
  142. Spenkuch F, Motorin Y, Helm M (2014) Pseudouridine: still mysterious, but never a fake (uridine)! RNA Biol 11(12):1540Google Scholar
  143. Stepinski J, Waddell C, Stolarski R, Darzynkiewicz E, Rhoads RE (2001) Synthesis and properties of mRNAs containing the novel ‘anti-reverse’ cap analogs 7-methyl(3’-O-methyl)GpppG and 7-methyl (3’-deoxy)GpppG. RNA 7(10):1486–1495Google Scholar
  144. Stewart M (2019) Polyadenylation and nuclear export of mRNAs. J Biol Chem 294(9):2977–2987Google Scholar
  145. Stitz L et al (2017) A thermostable messenger RNA based vaccine against rabies. PLoS Negl Trop Dis 11(12):1–10Google Scholar
  146. Svitkin YV, Cheng YM, Chakraborty T, Presnyak V, John M, Sonenberg N (2017) N1-methyl-pseudouridine in mRNA enhances translation through eIF2α-dependent and independent mechanisms by increasing ribosome density. Nucleic Acids Res 45(10):6023–6036Google Scholar
  147. Swiecki M, Wang Y, Vermi W, Gilfillan S, Schreiber RD, Colonna M (2011) Type I interferon negatively controls plasmacytoid dendritic cell numbers in vivo. J Exp Med 208(12):2367–2374Google Scholar
  148. Tannenbaum CS, Tubbs R, Armstrong D, Finke JH, Bukowski RM, Hamilton TA (1998) The CXC Chemokines IP-10 and Mig are necessary for IL-12-mediated regression of the mouse RENCA tumor. J Immunol 153(10):4625–4635Google Scholar
  149. Thess A et al (2015) Sequence-engineered mRNA without chemical nucleoside modifications enables an effective protein therapy in large animals. Mol Ther 23(9):1456–1464Google Scholar
  150. Trepotec Z, Aneja MK, Geiger J, Hasenpusch G, Plank C, Rudolph C (2018) Maximizing the translational yield of mRNA therapeutics by minimizing 5′-UTRs. Tissue Eng Part A 25(1–2):69–79Google Scholar
  151. Trepotec Z, Geiger J, Plank C, Aneja MK, Rudolph C (2019) Segmented poly(A) tails significantly reduce recombination of plasmid DNA without affecting mRNA translation efficiency or half-life. RNA 25(4):507–518Google Scholar
  152. Tuller T, Zur H (2015) Multiple roles of the coding sequence 5′ end in gene expression regulation. Nucleic Acids Res 43(1):13Google Scholar
  153. Tusup M, French LE, Guenova E, Kundig T, Pascolo S (2018) Optimizing the functionality of in vitro-transcribed mRNA. Biomed J Sci Tech Res 7(2):5845–5850Google Scholar
  154. Uchida S, Kataoka K, Itaka K (2015) Screening of mRNA chemical modification to maximize protein expression with reduced immunogenicity. Pharmaceutics 7(3):137–151Google Scholar
  155. Vaidyanathan S et al (2018) Uridine depletion and chemical modification increase Cas9 mRNA activity and reduce immunogenicity without HPLC purification. Mol Ther Nucleic Acids 12:530Google Scholar
  156. Vanblargan LA et al (2018) An mRNA vaccine protects mice against multiple article an mRNA vaccine protects mice against multiple tick-transmitted flavivirus infections, pp. 3382–3392Google Scholar
  157. Venkatesan S, Gershowitz A, Moss B (1980) Modification of the 5ʹ end of mRNA. J Biol Chem 255(3):903–908Google Scholar
  158. Vivinus S et al (2001) An element within the 5′ untranslated region of human Hsp70 mRNA which acts as a general enhancer of mRNA translation. Eur J Biochem 268(7):1908–1917Google Scholar
  159. Wang Z, Day N, Trifillis P, Kiledjian M (1999) An mRNA stability complex functions with poly(A)-binding protein to stabilize mRNA in vitro. Mol Cell Biol 19(7):4552–4560Google Scholar
  160. Wills RJ, Dennis S, Spiegel HE, Gibson DM, Nadler PI (1984) Interferon kinetics and adverse reactions after intravenous, intramuscular, and subcutaneous injection. Clin Pharmacol Ther 35(5):722–727Google Scholar
  161. Wolff JA et al (1990) Direct gene transfer into mouse muscle in vivo. Science 247(4949 Pt 1):1465–1468Google Scholar
  162. Wolpe SD, Cerami A (1989) Macrophage inflammatory proteins 1 and 2: members of a novel superfamily of cytokines. FASEB J 3(14)Google Scholar
  163. World Health Organization (1980) World Health Assembly, 33. Declaration of global eradication of smallpoxGoogle Scholar
  165. Zhang L, Wang W, Wang S (2015) Effect of vaccine administration modality on immunogenicity and efficacy. Expert Rev Vaccines 14(11):1509–1523Google Scholar
  166. Zost SJ et al (2017) Contemporary H3N2 influenza viruses have a glycosylation site that alters binding of antibodies elicited by egg-adapted vaccine strains. Proc Natl Acad Sci USA 114(47):12578–12583Google Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.CureVac AGTübingenGermany

Personalised recommendations