Abstract
As described in the introduction, key foundational assumptions (Fig. 1.1) have guided the approval and large-scale deployment of mRNA vaccines. Arguably, they were most influential in their fast approval, and they shaped decision making and public understanding. Many of them have been widely broadcasted by mainstream media and give the impression of being rooted in clear and detailed modeling, a sound comprehension of underlying biological mechanisms, and supported by clinical experience.
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References
Abbasi J (2020) Covid-19 and mRNA vaccines-first large test for a new approach. JAMA 324(12):1125–1127
Baiersdörfer M, Boros G, Muramatsu H, Mahiny A, Vlatkovic I, Sahin U, Karikó K (2019) A facile method for the removal of dsRNA contaminant from in vitro-transcribed mRNA. Mol Therapy Nucl Acids 15:26–35
Barabasi AL, Oltvai ZN (2004) Network biology: understanding the cell’s functional organization. Nat Rev Genet 5(2):101–113
Bartoszewski R, Sikorski AF (2019) Editorial focus: understanding off-target effects as the key to successful RNAi therapy. Cell Mol Biol Lett 24(1):1–23
Beissert T, Perkovic M, Vogel A, Erbar S, Walzer KC, Hempel T, Brill S, Haefner E, Becker R, Türeci Ö, et al (2020) A trans-amplifying RNA vaccine strategy for induction of potent protective immunity. Molecular Therapy 28(1):119–128
Blakney AK, McKay PF, Shattock RJ (2018) Structural components for amplification of positive and negative strand veev splitzicons. Front Mol Biosci 5:71
Bloom K, van den Berg F, Arbuthnot P (2020) Self-amplifying RNA vaccines for infectious diseases. Gene Therapy, 1–13
Braun KA, Young ET (2014) Coupling mRNA synthesis and decay. Mol Cell Biol 34(22):4078–4087
Bregman A, Avraham-Kelbert M, Barkai O, Duek L, Guterman A, Choder M (2011) Promoter elements regulate cytoplasmic mRNA decay. Cell 147(7):1473–1483. https://doi.org/10.1016/j.cell.2011.12.005, http://www.sciencedirect.com/science/article/pii/S0092867411015030
Buschmann MD, Carrasco MJ, Alishetty S, Paige M, Alameh MG, Weissman D (2021) Nanomaterial delivery systems for mRNA vaccines. Vaccines 9(1):65
Carthew RW, Sontheimer EJ (2009) Origins and mechanisms of miRNAs and siRNAs. Cell 136(4):642–655
Chandramouly G, Zhao J, McDevitt S, Rusanov T, Hoang T, Borisonnik N, Treddinick T, Lopezcolorado FW, Kent T, Siddique LA, et al (2021) Polθ reverse transcribes RNA and promotes RNA-templated DNA repair. Science Advances 7(24):eabf1771
Chen CYA, Shyu AB (2011) Mechanisms of deadenylation-dependent decay. Wiley Interdisciplinary Reviews: RNA 2(2):167–183
Cheng MH, Zhang S, Porritt RA, Rivas MN, Paschold L, Willscher E, Binder M, Arditi M, Bahar I (2020) Superantigenic character of an insert unique to SARS-CoV-2 spike supported by skewed tcr repertoire in patients with hyperinflammation. Proc Natl Acad Sci
Collart MA, Reese JC (2014) Gene expression as a circular process: cross-talk between transcription and mRNA degradation in eukaryotes; International University of Andalusia (unia) Baeza, Spain
Coppin L, Leclerc J, Vincent A, Porchet N, Pigny P (2018) Messenger RNA life-cycle in cancer cells: emerging role of conventional and non-conventional RNA-binding proteins? Int J Mol Sci 19(3):650
Crick F (1970) Central dogma of molecular biology. Nature 227(5258):561–563
Crick FH (1958) On protein synthesis. In: Symp Soc Exp Biol, vol 12, p 8
Crouse J, Kalinke U, Oxenius A (2015) Regulation of antiviral t cell responses by type i interferons. Nat Rev Immunol 15(4):231–242
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
de Lorenzo V (2014) From the selfish gene to selfish metabolism: revisiting the central dogma. Bioessays 36(3):226–235
Desfarges S, Ciuffi A (2012) Viral integration and consequences on host gene expression. In: Viruses: essential agents of life. Springer, pp 147–175
Doench JG, Petersen CP, Sharp PA (2003) siRNAs can function as miRNAs. Genes Dev 17(4):438–442
Dori-Bachash M, Shalem O, Manor YS, Pilpel Y, Tirosh I (2012) Widespread promoter-mediated coordination of transcription and mRNA degradation. Genome Biology 13(12):R114
Enssle J, Kugler W, Hentze MW, Kulozik AE (1993) Determination of mRNA fate by different RNA polymerase ii promoters. Proc Natl Acad Sci 90(21):10091–10095
Ferrell Jr JE (2002) Self-perpetuating states in signal transduction: positive feedback, double-negative feedback and bistability. Curr Opin Cell Biol 14(2):140–148
Franco-Serrano L, Huerta M, Hernández S, Cedano J, Perez-Pons J, Piñol J, Mozo-Villarias A, Amela I, Querol E (2018) Multifunctional proteins: involvement in human diseases and targets of current drugs. Protein J 37(5):444–453
Franklin S, Vondriska TM (2011) Genomes, proteomes, and the central dogma. Circ Cardiovasc Genet 4(5):576–576
Fung TS, Liu DX (2018) Post-translational modifications of coronavirus proteins: roles and function. Future Virology 13(6):405–430
Garneau NL, Wilusz J, Wilusz CJ (2007) The highways and byways of mRNA decay. Nat Rev Mol Cell Biol 8(2):113–126
Gerstberger S, Hafner M, Tuschl T (2014) A census of human RNA-binding proteins. Nat Rev Genet 15(12):829–845
Gholamalipour Y, Karunanayake MA, Martin CT (2018) 3’ end additions by T7 RNA polymerase are RNA self-templated, distributive and diverse in character-RNA-Seq analyses. Nucl Acids Res 46(18):9253–9263. https://doi.org/10.1093/nar/gky796, https://academic.oup.com/nar/article-pdf/46/18/9253/26001463/gky796.pdf
Gorgoni B, Gray NK (2004) The roles of cytoplasmic poly (a)-binding proteins in regulating gene expression: a developmental perspective. Brief Funct Genomics 3(2):125–141
Goswami R, Awasthi A (2020) Editorial: T cell differentiation and function in tissue inflammation. Front Immunol 11:289. https://doi.org/10.3389/fimmu.2020.00289, https://www.frontiersin.org/article/10.3389/fimmu.2020.00289
Grant OC, Montgomery D, Ito K, Woods RJ (2020) Analysis of the SARS-CoV-2 spike protein glycan shield: implications for immune recognition. bioRxiv
Haimovich G, Choder M, Singer RH, Trcek T (2013) The fate of the messenger is pre-determined: a new model for regulation of gene expression. Biochim Biophys Acta (BBA)-Gene Regul Mech 1829(6-7):643–653
Heinemann JA (2019) Should dsRNA treatments applied in outdoor environments be regulated? Environment International 132:104856
Hornung V, Ellegast J, Kim S, Brzózka K, Jung A, Kato H, Poeck H, Akira S, Conzelmann KK, Schlee M, et al (2006) 5’-triphosphate RNA is the ligand for RIG-I. Science 314(5801):994–997
Hütter J, Rödig JV, Höper D, Seeberger PH, Reichl U, Rapp E, Lepenies B (2013) Toward animal cell culture-based influenza vaccine design: viral hemagglutinin n-glycosylation markedly impacts immunogenicity. J Immunol 190(1):220–230
Iyer LM, Koonin EV, Aravind L (2003) Evolutionary connection between the catalytic subunits of DNA-dependent RNA polymerases and eukaryotic RNA-dependent RNA polymerases and the origin of RNA polymerases. BMC Struct Biol 3(1):1–23
Jackson NA, Kester KE, Casimiro D, Gurunathan S, DeRosa F (2020) The promise of mRNA vaccines: A biotech and industrial perspective. NPJ Vaccines 5(1):1–6
Kanyavuz A, Marey-Jarossay A, Lacroix-Desmazes S, Dimitrov JD (2019) Breaking the law: unconventional strategies for antibody diversification. Nat Rev Immunol 19(6):355–368
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
Kariko 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. Nucl Acids Res 39(21):e142–e142
Lindgren G, Ols S, Liang F, Thompson EA, Lin A, Hellgren F, Bahl K, John S, Yuzhakov O, Hassett KJ, Brito LA, Salter H, Ciaramella G, Loré K (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. https://doi.org/10.3389/fimmu.2017.01539, https://www.frontiersin.org/article/10.3389/fimmu.2017.01539
Lyons-Weiler J (2020) Pathogenic priming likely contributes to serious and critical illness and mortality in covid-19 via autoimmunity. J Translat Autoimmunity 3:100051
Maruggi G, Zhang C, Li J, Ulmer JB, Yu D (2019) mRNA as a transformative technology for vaccine development to control infectious diseases. Molecular Therapy 27(4):757–772
Mu X, Greenwald E, Ahmad S, Hur S (2018) An origin of the immunogenicity of in vitro transcribed RNA. Nucl Acids Res 46(10):5239–5249. https://doi.org/10.1093/nar/gky177, https://academic.oup.com/nar/article-pdf/46/10/5239/24962288/gky177.pdf
Mueller S (2021) Rarely recognized antibody diversification in covid-19 evolution to counteract advanced SARS-CoV-2 evasion strategies, and implications for prophylactic treatment. Front Physiol 12:1186. https://doi.org/10.3389/fphys.2021.624675, https://www.frontiersin.org/article/10.3389/fphys.2021.624675
Nelson DL, Lehninger AL, Cox MM (2008) Lehninger principles of biochemistry. Macmillan
Neumeier J, Meister G (2021) siRNA specificity: Rnai mechanisms and strategies to reduce off-target effects. Front Plant Sci 11:2196. https://doi.org/10.3389/fpls.2020.526455, https://www.frontiersin.org/article/10.3389/fpls.2020.526455
Oostra M, De Haan C, De Groot R, Rottier P (2006) Glycosylation of the severe acute respiratory syndrome coronavirus triple-spanning membrane proteins 3a and m. J Virol 80(5):2326–2336
Organization WH, et al (2020) mRNA vaccines against covid-19: Pfizer-biontech covid-19 vaccine bnt162b2: prepared by the strategic advisory group of experts (sage) on immunization working group on covid-19 vaccines, 22 december 2020. Tech. rep., World Health Organization
Pardi N, Hogan MJ, Naradikian MS, Parkhouse K, Cain DW, Jones L, Moody MA, Verkerke HP, Myles A, Willis E, 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
Pardi N, Hogan MJ, Porter FW, Weissman D (2018) mRNA vaccines-a new era in vaccinology. Nat Rev Drug Discov 17(4):261
Peng W, de Vries RP, Grant OC, Thompson AJ, McBride R, Tsogtbaatar B, Lee PS, Razi N, Wilson IA, Woods RJ, et al (2017) Recent h3n2 viruses have evolved specificity for extended, branched human-type receptors, conferring potential for increased avidity. Cell Host Microbe 21(1):23–34
Pepini T, Pulichino AM, Carsillo T, Carlson AL, Sari-Sarraf F, Ramsauer K, Debasitis JC, Maruggi G, Otten GR, Geall AJ, et al (2017) Induction of an ifn-mediated antiviral response by a self-amplifying RNA vaccine: implications for vaccine design. J Immunol 198(10):4012–4024
Pichlmair A, Schulz O, Tan CP, Näslund TI, Liljeström P, Weber F, e Sousa CR (2006) Rig-i-mediated antiviral responses to single-stranded RNA bearing 5’-phosphates. Science 314(5801):997–1001
Robbiani DF, Deroubaix S, Feldhahn N, Oliveira TY, Callen E, Wang Q, Jankovic M, Silva IT, Rommel PC, Bosque D, et al (2015) Plasmodium infection promotes genomic instability and aid-dependent b cell lymphoma. Cell 162(4):727–737
Roy B, Robb G (2018) Use of thermostable RNA polymerases to produce RNAs having reduced immunogenicity. US Patent 10,034,951
Roy B, Wu MZ (2019) Understanding and overcoming the immune response from synthetic mRNAs: New england biolabs focuses on formation and detection of dsRNA byproducts during in vitro transcription. Genet Eng Biotechnol News 39(12):56–58
Sahin U, Karikó K, Türeci Ö (2014) mRNA-based therapeutics—developing a new class of drugs. Nat Revi Drug Discov 13(10):759–780
Samanta B, Joyce GF (2017) A reverse transcriptase ribozyme. Elife 6:e31153
Schlee M, Roth A, Hornung V, Hagmann CA, Wimmenauer V, Barchet W, Coch C, Janke M, Mihailovic A, Wardle G, et al (2009) Recognition of 5’ triphosphate by rig-i helicase requires short blunt double-stranded RNA as contained in panhandle of negative-strand virus. Immunity 31(1):25–34
Siwaszek A, Ukleja M, Dziembowski A (2014) Proteins involved in the degradation of cytoplasmic mRNA in the major eukaryotic model systems. RNA Biology 11(9):1122–1136
Sørensen B, Susrud A, Dalgleish A (2020) Biovacc-19: A candidate vaccine for covid-19 (sars-cov-2) developed from analysis of its general method of action for infectivity. QRB Discovery, 1–17
Su Y, Ghodke PP, Egli M, Li L, Wang Y, Guengerich FP (2019) Human dna polymerase η has reverse transcriptase activity in cellular environments. J Biol Chem 294(15):6073–6081
Van Hoecke L, Roose K, Ballegeer M, Zhong Z, Sanders NN, De Koker S, Saelens X, Van Lint S (2020) The opposing effect of type i ifn on the t cell response by non-modified mRNA-lipoplex vaccines is determined by the route of administration. Mol Ther-Nucleic Acids 22:373–381
Venkatesan K, Rual JF, Vazquez A, Stelzl U, Lemmens I, Hirozane-Kishikawa T, Hao T, Zenkner M, Xin X, Goh KI, et al (2009) An empirical framework for binary interactome mapping. Nature Methods 6(1):83–90
Verbeke R, Lentacker I, De Smedt SC, Dewitte H (2019) Three decades of messenger RNA vaccine development. Nano Today 28:100766
WHO (2021) The moderna COVID-19 (mRNA-1273) vaccine: what you need to know. https://www.who.int/news-room/feature-stories/detail/the-moderna-covid-19-mrna-1273-vaccine-what-you-need-to-know
Wolff JA, Malone RW, Williams P, Chong W, Acsadi G, Jani A, Felgner PL (1990) Direct gene transfer into mouse muscle in vivo. Science 247(4949):1465–1468
Wu MZ, Asahara H, Tzertzinis G, Roy B (2020) Synthesis of low immunogenicity RNA with high-temperature in vitro transcription. RNA 26(3):345–360
Yoneyama M, Fujita T (2010) Recognition of viral nucleic acids in innate immunity. Rev Med Virol 20(1):4–22
Zamore PD, Haley B (2005) Ribo-gnome: the big world of small RNAs. Science 309(5740):1519–1524
Zhang C, Maruggi G, Shan H, Li J (2019) Advances in mRNA vaccines for infectious diseases. Front Immunol 10:594. https://doi.org/10.3389/fimmu.2019.00594, https://www.frontiersin.org/article/10.3389/fimmu.2019.00594
Zhang L, Richards A, Khalil A, Wogram E, Ma H, Young RA, Jaenisch R (2020) SARS-CoV-2 RNA reverse-transcribed and integrated into the human genome. bioRxiv
Zhang L, Richards A, Barrasa MI, Hughes SH, Young RA, Jaenisch R (2021) Reverse-transcribed sars-cov-2 RNA can integrate into the genome of cultured human cells and can be expressed in patient-derived tissues. Proc Natl Acad Sci 118(21)
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Mueller, S. (2023). Appraisal of Some of the Key Postulates Underlying mRNA Vaccines. In: Challenges and Opportunities of mRNA Vaccines Against SARS-CoV-2. Springer, Cham. https://doi.org/10.1007/978-3-031-18903-6_2
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