Skip to main content
SpringerLink
Log in

mRNA-Based Vaccines and Mode of Action

  • Chapter
  • First Online:
mRNA Vaccines

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 440))

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 via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Ahmed F, Benedito VA, Zhao PX (2011) Mining functional elements in messenger RNAs: overview, challenges, and perspectives. Front Plant Sci 2

    Google Scholar 

  • 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. Lancet

    Google Scholar 

  • 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):556–565

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Anderson BR et al (2010) Incorporation of pseudouridine into mRNA enhances translation by diminishing PKR activation. Nucleic Acids Res 38(17):5884–5892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):9329–9338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):157–166

    Article  CAS  PubMed  Google Scholar 

  • 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 217:337–344

    Google Scholar 

  • Bahl K et al (2017) Preclinical and clinical demonstration of immunogenicity by mRNA vaccines against H10N8 and H7N9 influenza viruses. Mol Ther 25(6):1316–1327

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baiersdörfer M et al (2019) A facile method for the removal of dsRNA contaminant from in vitro-transcribed mRNA. Mol Ther Nucleic Acids 15:26–35

    Article  PubMed  PubMed Central  Google Scholar 

  • Banerjee AK (1980) 5’-terminal cap structure in eucaryotic messenger ribonucleic acids. Microbiol Rev 44(2):175–205

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):569–579

    Article  CAS  PubMed  Google Scholar 

  • 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):221–232

    Article  CAS  PubMed  Google Scholar 

  • Berkovits BD, Mayr C (2015) Alternative 3ʹ UTRs act as scaffolds to regulate membrane protein localization. Nature 522(7556):363–367

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):659–670

    CAS  PubMed  PubMed Central  Google Scholar 

  • Beverley PCL (2002) Immunology of vaccination. Br Med Bull 62(1):15–28

    Article  CAS  PubMed  Google Scholar 

  • 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):1667–1677

    Article  CAS  PubMed  Google Scholar 

  • Borg FA, Isenberg DA (2007) Syndromes and complications of interferon therapy. Curr Opin Rheumatol 19(1):61–66

    Article  CAS  PubMed  Google Scholar 

  • 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 941:83–132

    Google Scholar 

  • Brisse M, Ly H (2019) Comparative structure and function analysis of the RIG-I-like receptors: RIG-I and MDA5. Front Immunol 10

    Google Scholar 

  • 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:e326

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Burns CC, Diop OM, Sutter RW, Kew OM (2014) Vaccine-derived polioviruses. J Infect Dis 210(suppl 1):S283–S293

    Article  PubMed  Google Scholar 

  • Burton DR, Hangartner L (2016) Broadly neutralizing antibodies to HIV and their role in vaccine design. Annu Rev Immunol 34:635–659

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):3652

    Google Scholar 

  • Carralot JP et al (2004) Polarization of immunity induced by direct injection of naked sequence-stabilized mRNA vaccines. Cell Mol Life Sci 61(18):2418–2424

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 

  • Clarke TF IV, Clark PL (2010) Increased incidence of rare codon clusters at 5ʹ and 3ʹ gene termini: implications for function. BMC Genomics 11:118

    Article  PubMed  PubMed Central  Google Scholar 

  • Crouse J, Kalinke U, Oxenius A (2015) Regulation of antiviral T cell responses by type I interferons. Nat Rev Immunol 15(4):231–242

    Article  CAS  PubMed  Google Scholar 

  • 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):2012–2020

    Article  PubMed  PubMed Central  Google Scholar 

  • 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):216–226

    Article  PubMed  Google Scholar 

  • 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):596

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):11–25

    Article  CAS  PubMed  Google Scholar 

  • 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):696–700

    Article  CAS  PubMed  Google Scholar 

  • 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 

  • 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):1

    Google Scholar 

  • 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):958–966

    Article  CAS  PubMed  Google Scholar 

  • 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):7598–7609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fensterl V, Sen GC (2015) Interferon-induced Ifit proteins: their role in viral pathogenesis. J Virol 89(5):2462

    Article  PubMed  Google Scholar 

  • 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):398–406

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):1–15

    Article  CAS  PubMed  Google Scholar 

  • Galloway A, Cowling VH (2019) mRNA cap regulation in mammalian cell function and fate. Biochim Biophys Acta Gene Regul Mech 1862(3):270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Geall AJ et al (2012) Nonviral delivery of self-amplifying RNA vaccines. Proc Natl Acad Sci 109(36):14604–14609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Georg P, Sander LE (2019) Innate sensors that regulate vaccine responses. Curr Opin Immunol 59:31–41

    Article  CAS  PubMed  Google Scholar 

  • 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):e306

    Google Scholar 

  • Groom JR, Luster AD (2011) CXCR3 ligands: redundant, collaborative and antagonistic functions. Immunol Cell Biol 89(2)

    Google Scholar 

  • 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):1745–1755

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gruys E, Toussaint MJM, Niewold TA, Koopmans SJ (2005) Acute phase reaction and acute phase proteins. J Zhejiang Univ Sci B 6(11):1045–1056

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gustafsson C, Govindarajan S, Minshull J (2004) Codon bias and heterologous protein expression. Trends Biotechnol 22(7):346–353

    Article  CAS  PubMed  Google Scholar 

  • 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):75

    Article  CAS  PubMed  Google Scholar 

  • Hesseling A et al (2009) Disseminated bacille Calmette-Guérin disease in HIV-infected South African infants. Bull World Health Organ 87(7):505

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):1–7

    Article  CAS  PubMed  Google Scholar 

  • 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 

  • https://www.who.int/news-room/feature-stories/detail/two-out-of-three-wild-poliovirus-strains-eradicated

  • Iavarone C, O’hagan DT, Yu D, Delahaye NF, Ulmer JB (2017) Mechanism of action of mRNA-based vaccines. Expert Rev Vaccines 16(9):871–881

    Google Scholar 

  • Innis BL et al (1994) Protection against hepatitis A by an inactivated vaccine. JAMA J Am Med Assoc 271(17):1328

    Article  CAS  Google Scholar 

  • Jackson LA et al (2020) An mRNA vaccine against SARS-CoV-2—preliminary report. N Engl J Med

    Google Scholar 

  • Jan CH, Friedman RC, Ruby JG, Bartel DP (2011) Formation, regulation and evolution of Caenorhabditis elegans 3′ UTRs. Nature 469(7328):97–101

    Article  CAS  PubMed  Google Scholar 

  • Jemielity J et al (2003) Novel ‘anti-reverse’ cap analogs with superior translational properties. RNA 9(9):1108–1122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jia J, Yao P, Arif A, Fox PL (2013) Regulation and dysregulation of 3ʹ UTR-mediated translational control. Curr Opin Genet Dev 23(1):29–34

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • John S et al (2018) Multi-antigenic human cytomegalovirus mRNA vaccines that elicit potent humoral and cell-mediated immunity. Vaccine 36(12):1689–1699

    Article  CAS  PubMed  Google Scholar 

  • 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):182–185

    Google Scholar 

  • 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):165–175

    Article  PubMed  Google Scholar 

  • 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):1833–1840

    Article  PubMed  Google Scholar 

  • 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):e142

    Google Scholar 

  • 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):948–953

    Article  PubMed  PubMed Central  Google Scholar 

  • 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):1601–1610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kauffman KJ et al (2016) Efficacy and immunogenicity of unmodified and pseudouridine-modified mRNA delivered systemically with lipid nanoparticles in vivo. Biomaterials 109:78–87

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kaygun H, Marzluff WF (2005) Translation termination is involved in histone mRNA degradation when DNA replication is inhibited. Mol Cell Biol 25(16):6879–6888

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):4472–4480

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kocmik I et al (2018) Modified ARCA analgos providing enhanced properties of capped mRNAs. Cell Cycle 17(13):71–75

    Google Scholar 

  • 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):5976

    Google Scholar 

  • Kore AR, Charles I (2010) Synthesis and evaluation of 2′–O–allyl substituted dinucleotide cap analog for mRNA translation. Bioorganic Med Chem 18(22):8061–8065

    Article  CAS  Google Scholar 

  • 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):6364–6365

    Article  CAS  PubMed  Google Scholar 

  • Kormann MSD et al (2011) Expression of therapeutic proteins after delivery of chemically modified mRNA in mice. Nat Biotechnol 29(2):110–112

    Article  Google Scholar 

  • 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):3882–3893

    Article  CAS  PubMed  Google Scholar 

  • Kozak M (2005) Regulation of translation via mRNA structure in prokaryotes and eukaryotes. Gene 361(1–2):13–37

    Article  CAS  PubMed  Google Scholar 

  • Kozak M (1991a) A short leader sequence impairs the fidelity of initiation by eukaryotic ribosomes. Gene Expr 1(2):111–115

    CAS  PubMed  Google Scholar 

  • Kozak M (1991b) Effects of long 5ʹ leader sequences on initiation by eukaryotic ribosomes in vitro. Gene Expr 1(2):117–125

    CAS  PubMed  Google Scholar 

  • Kranz LM et al (2016) Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy. Nature 534

    Google Scholar 

  • 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):961–971

    Article  CAS  PubMed  Google Scholar 

  • 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):35–43

    Article  CAS  PubMed  Google Scholar 

  • Lässig C, Hopfner K-P (2017) Discrimination of cytosolic self and non-self RNA by RIG-I-like receptors. J Biol Chem 292(22):9000–9009

    Article  PubMed  PubMed Central  Google Scholar 

  • Lawrence JB, Singer RH (1986) Intracellular localization of messenger RNAs for cytoskeletal proteins. Cell 45(3):407–415

    Article  CAS  PubMed  Google Scholar 

  • 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):4682–4689

    Article  Google Scholar 

  • Lee J, Arun Kumar S, Jhan YY, Bishop CJ (2018) Engineering DNA vaccines against infectious diseases. Acta Biomater 80:31–47

    Google Scholar 

  • 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):9694–9701

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):158–174

    Article  CAS  PubMed  Google Scholar 

  • 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):2635–2647

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 8:1539

    Article  PubMed  PubMed Central  Google Scholar 

  • Loomis KH et al (2018) In vitro transcribed mRNA vaccines with programmable stimulation of innate immunity. Bioconjug Chem 29(9):3072–3083

    Article  CAS  PubMed  Google Scholar 

  • Lutz J et al (2017) Unmodified mRNA in LNPs constitutes a competitive technology for prophylactic vaccines. NPJ Vaccines 2(1):1–9

    Google Scholar 

  • 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):9113

    Google Scholar 

  • Mariner JC et al (2012) Rinderpest eradication: appropriate technology and social innovations. Science (80–) 337 (6100):1309–1312

    Google Scholar 

  • Martinon F et al (1993) Induction of virus-specific cytotoxic T lymphocytesin vivo by liposome-entrapped mRNA. Eur J Immunol 23(7):1719–1722

    Article  CAS  PubMed  Google Scholar 

  • Marzluff WF (1992) Histone 3ʹ ends: essential and regulatory functions. Gene Expr 2(2)

    Google Scholar 

  • Mauger DM et al (2019) mRNA structure regulates protein expression through changes in functional half-life. Proc Natl Acad Sci USA 116(48):24075–24083

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mayr C (2008) Regualtion by 3ʹ-untranslated regions. Postgrad Med J 67(791):862–862

    Google Scholar 

  • 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):266–273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McNab F, Mayer-Barber K, Sher A, Wack A, O’Garra A (2015) Type I interferons in infectious disease. Nat Rev Immunol 15(2):87–103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):5–6

    Google Scholar 

  • 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):4–5

    Google Scholar 

  • 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):1062–1068

    Article  CAS  PubMed  Google Scholar 

  • Mogensen TH (2009) Pathogen recognition and inflammatory signaling in innate immune defenses. Clin Microbiol Rev 22(2):240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mu X, Greenwald E, Ahmad S, Hur S (2018) An origin of the immunogenicity of in vitro transcribed RNA. Nucleic Acids Res 46(10):5239–5249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Muckenthaler MU, Rivella S, Hentze MW, Galy B (2017) A red carpet for iron metabolism. Cell 168(3):344

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

  • 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):10735–10747

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nigg AJ, Walker PL (2009) Overview, prevention, and treatment of rabies. Pharmacotherapy 29(10):1182–1195

    Article  CAS  PubMed  Google Scholar 

  • Novoa EM, Ribas de Pouplana L (2012) Speeding with control: codon usage, tRNAs, and ribosomes. Trends Genet 28(11):574–581

    Article  CAS  Google Scholar 

  • 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):824–836

    Article  CAS  PubMed  Google Scholar 

  • 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):629

    Article  PubMed  PubMed Central  Google Scholar 

  • Padilla-Quirarte HO, Lopez-Guerrero DV, Gutierrez-Xicotencatl L, Esquivel-Guadarrama F (2019) Protective antibodies against influenza proteins. Front Immunol 10

    Google Scholar 

  • Pardi N et al (2017a) Administration of nucleoside-modified mRNA encoding broadly neutralizing antibody protects humanized mice from HIV-1 challenge. Nat Commun 8:14630

    Article  PubMed  PubMed Central  Google Scholar 

  • Pardi N et al (2017b) Zika virus protection by a single low-dose nucleoside-modified mRNA vaccination. Nature 543(7644):248–251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pardi N et al (2018) Nucleoside-modified mRNA immunization elicits influenza virus hemagglutinin stalk-specific antibodies. Nat Commun 9(1):3361

    Article  PubMed  PubMed Central  Google Scholar 

  • 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):1571–1588

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pardi N et al (2019) Characterization of HIV-1 nucleoside-modified mRNA vaccines in rabbits and rhesus macaques. Mol Ther Nucleic Acids 15:36–47

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pasquinelli A, Dahlberg J, Elsebet L (1995) Reverse 5’ caps in RNAs made in vitro by phage RNA polymerases. RNA 1(957):110–117

    Google Scholar 

  • 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 193:112238

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Petrovsky N (2015) Comparative safety of vaccine adjuvants: a summary of current evidence and future needs. Drug Saf 38(11):1059–1074

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Petsch B et al (2012) Protective efficacy of in vitro synthesized, specific mRNA vaccines against influenza A virus infection. Nat Biotechnol 30(12):1210–1216

    Article  CAS  PubMed  Google Scholar 

  • Plotkin S (2014) History of vaccination. Proc Natl Acad Sci USA 111(34):12283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):251–259

    Article  CAS  PubMed  Google Scholar 

  • 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.e5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rajan JV, Warren SE, Miao EA, Aderem A (2010) Activation of the NLRP3 inflammasome by intracellular poly I:C. FEBS Lett 584(22):4627–4632

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rauch S, Jasny E, Schmidt KE, Petsch B (2018) New vaccine technologies to combat outbreak situations. Front Immunol 9:1963

    Article  PubMed  PubMed Central  Google Scholar 

  • Richner JM et al (2017) Modified mRNA vaccines protect against Zika virus infection. Cell 168(6):1114-1125.e10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rönnblom LE (1991) Autoimmunity after alpha-interferon therapy for malignant carcinoid tumors. Ann Intern Med 115(3):178

    Article  PubMed  Google Scholar 

  • Rossey I, McLellan JS, Saelens X, Schepens B (2018) Clinical potential of prefusion RSV F-specific antibodies. Trends Microbiol 26(3):209–219

    Article  CAS  PubMed  Google Scholar 

  • 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):8661–8675

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sadler AJ, Williams BRG (2008) Interferon-inducible antiviral effectors. Nat Rev Immunol 8(7):559–568

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sample PJ et al (2019) Human 5′ UTR design and variant effect prediction from a massively parallel translation assay. Nat Biotechnol 37(7):803

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sanders RW, Moore JP (2017) Native-like env trimers as a platform for HIV-1 vaccine design. Immunol Rev 275(1):161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Scheel B et al (2004) Immunostimulating capacities of stabilized RNA molecules. Eur J Immunol 34(2):537–547

    Article  CAS  PubMed  Google Scholar 

  • Schlake T, Thess A, Fotin-mleczek M, Kallen K (2012) Developing mRNA-vaccine technologies. RNA Biol 9(November):1–12

    Google Scholar 

  • Schlake T, Thess A, Thran M, Jordan I (2019) mRNA as novel technology for passive immunotherapy. Cell Mol Life Sci 76(2):301–328

    Article  CAS  PubMed  Google Scholar 

  • 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):12067

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):e0004746

    Article  PubMed  PubMed Central  Google Scholar 

  • 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):2897–2901

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):1204–1208

    Article  CAS  Google Scholar 

  • 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):e92153

    Article  PubMed  PubMed Central  Google Scholar 

  • Spenkuch F, Motorin Y, Helm M (2014) Pseudouridine: still mysterious, but never a fake (uridine)! RNA Biol 11(12):1540

    Article  PubMed  Google Scholar 

  • 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):1486–1495

    CAS  PubMed  PubMed Central  Google Scholar 

  • Stewart M (2019) Polyadenylation and nuclear export of mRNAs. J Biol Chem 294(9):2977–2987

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stitz L et al (2017) A thermostable messenger RNA based vaccine against rabies. PLoS Negl Trop Dis 11(12):1–10

    Article  Google Scholar 

  • 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):6023–6036

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):2367–2374

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):4625–4635

    Google Scholar 

  • Thess A et al (2015) Sequence-engineered mRNA without chemical nucleoside modifications enables an effective protein therapy in large animals. Mol Ther 23(9):1456–1464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):69–79

    PubMed  Google Scholar 

  • 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):507–518

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tuller T, Zur H (2015) Multiple roles of the coding sequence 5′ end in gene expression regulation. Nucleic Acids Res 43(1):13

    Article  CAS  PubMed  Google Scholar 

  • 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):5845–5850

    Google Scholar 

  • Uchida S, Kataoka K, Itaka K (2015) Screening of mRNA chemical modification to maximize protein expression with reduced immunogenicity. Pharmaceutics 7(3):137–151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vaidyanathan S et al (2018) Uridine depletion and chemical modification increase Cas9 mRNA activity and reduce immunogenicity without HPLC purification. Mol Ther Nucleic Acids 12:530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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. 3382–3392

    Google Scholar 

  • Venkatesan S, Gershowitz A, Moss B (1980) Modification of the 5ʹ end of mRNA. J Biol Chem 255(3):903–908

    Article  CAS  PubMed  Google Scholar 

  • 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):1908–1917

    Article  CAS  PubMed  Google Scholar 

  • 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):4552–4560

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):722–727

    Article  CAS  PubMed  Google Scholar 

  • Wolff JA et al (1990) Direct gene transfer into mouse muscle in vivo. Science 247(4949 Pt 1):1465–1468

    Article  CAS  PubMed  Google Scholar 

  • Wolpe SD, Cerami A (1989) Macrophage inflammatory proteins 1 and 2: members of a novel superfamily of cytokines. FASEB J 3(14)

    Google Scholar 

  • World Health Organization (1980) World Health Assembly, 33. Declaration of global eradication of smallpox

    Google Scholar 

  • www.cleancapmrna.com

  • Zhang L, Wang W, Wang S (2015) Effect of vaccine administration modality on immunogenicity and efficacy. Expert Rev Vaccines 14(11):1509–1523

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):12578–12583

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

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

Author information

Authors and Affiliations

  1. CureVac AG, Tübingen, Germany

    Janina Gergen & Benjamin Petsch

Authors
  1. Janina Gergen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Benjamin Petsch
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Benjamin Petsch .

Editor information

Editors and Affiliations

  1. Senior Vice President of Research, Dynavax Technologies, Emeryville, CA, USA

    Dong Yu

  2. CureVac AG, Tübingen, Germany

    Benjamin Petsch

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Gergen, J., Petsch, B. (2020). mRNA-Based Vaccines and Mode of Action. In: Yu, D., Petsch, B. (eds) mRNA Vaccines. Current Topics in Microbiology and Immunology, vol 440. Springer, Cham. https://doi.org/10.1007/82_2020_230

Download citation

Publish with us

Policies and ethics

Search

Navigation