Info: Zenodo’s user support line is staffed on regular business days between Dec 23 and Jan 5. Response times may be slightly longer than normal.

Coronavirus Disease Research Community - COVID-19
Published January 11, 2021 | Version v1
Journal article Open

Historical Development Process of mRNA Vaccines and SARS-CoV-2 Pandemic

Creators

  • 1. Department of Medical History and Ethics, Gulhane Medical Faculty, University of Health Sciences, Ankara, Turkey
  • 2. Department of Medical Microbiology, Gulhane Institute Of Health Sciences, University of Health Sciences, Ankara, Turkey

Description

Özet

Geleneksel aşıların tarihi 200 yıl öncesine kadar uzanmakla beraber, nükleik asit temelli bir aşı sınıfının üretilebileceğine dair ilk veriler 30 yıl gibi çok daha yakın bir zamanda ortaya çıkmıştır. mRNA’nın (mesajcı ribonükleik asit) yeni bir terapötik ilaç sınıfı olarak kullanılabileceğini gösteren erken çalışma sonuçları ilk olarak 1990’lı yılların başlarında açıklandı. Sonraki süreçte mRNA temelli sistemlerin stabilite ve etkinliği ile ilgili engeller aşılırken, bu yaklaşımın geleneksel aşıların yetersiz kaldığı kanser hastalıklarının tedavisinde ve bilinen aşılarla koruyucu immünite geliştirilemeyen bazı enfeksiyon hastalıklarının önlenmesinde yeni bir umut olabileceği öne sürüldü. Bu aşıların düşük maliyetli olmaları yanında, büyük ölçekli ve hızlı üretim kapasitesi gibi avantajları da dikkate alınarak son 10 yılda mRNA temelli teknolojiler üzerine önemli yatırımlar yapıldı. Standardize edilmiş genel bir çerçeve üzerinden yeni mRNA aşı tasarımlarının kolay bir şekilde yapılabilmesi bu sistemleri yeni ve bilinmeyen bir etkene karşı hızlı bir şekilde aşı geliştirmede öne çıkarmış ve pandemi durumlarında bu özelliğinin yanına yüksek kapasitede hızlı üretim avantajı da eklenince mRNA aşıları yeni ve cazip bir aşı platformları olarak görülmeye başlandı. mRNA temelli teknolojide son 5 yılda yakalanan hızlı ivmenin SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2) pandemisi ile kesişmesi bu teknoloji için bir dönüm noktası oldu. Pandemi sürecinde diğer aşı sistemlerine kıyasla hızlı tasarım ve üretim süreçleri ile güvenlik ve etkinlik çalışmaları mRNA aşıları için kısa sürede tamamlandı. Birkaç mRNA temelli aşı sistemi uluslararası kurumlar tarafından acil kullanım onayları alırken, aşıların milyonlarca kişiye uygulanması sonrası mRNA temelli sistemlerin olası yan etkileri ve güvenlikleri ile ilgili muazzam bir veri elde edileceği beklenmektedir. Sonuç olarak yeni bir teknoloji olmasına rağmen 30 yıllık bir deneyim üzerine kurulan mRNA temelli aşılar için SARS-CoV-2 pandemisi ile birlikte yeni bir çağa giriş yapıldığı söylenebilir. Bu makalede mRNA’nın keşfinden başlayarak, mRNA temelli aşıların ilk onaylarına kadar geçen sürede söz konusu teknolojinin geliştirilmesinde karşılaşılan zorluklar ve dönüm noktası niteliğindeki olayların bir özeti sunulmuştur.

Abstract

Although the history of traditional vaccines goes back 200 years, the first data that a class of nucleic acid-based vaccines can be produced has emerged much more recently, as early as 30 years. First, in the 1990s, early study results were announced showing that mRNA (messenger ribonucleic acid) could be used as a new class of therapeutic drugs. In the next period, while obstacles related to the stability and efficiency of mRNA-based systems were overcome, It has been suggested that this approach could be a new hope in the treatment of cancer diseases where traditional vaccines were insufficient and in the prevention of some infectious diseases where protective immunity could not be developed with known vaccines. Considering the low cost of these vaccines as well as their other advantages such as large scale and rapid production capacity, significant investments have been made in mRNA-based technologies in the last 10 years. The ease of designing new mRNA vaccines over a standardized general framework has made these systems stand out in the rapid development of vaccines against a new and unknown agent and in pandemic situations, mRNA vaccines have begun to be seen as a new and attractive vaccine platforms when the advantage of rapid production in high capacity is added to this feature. The intersection of the rapid acceleration captured in the last 5 years in mRNA-based technology with the SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2) pandemic was a turning point for this technology. During the pandemic process, compared to other vaccine systems, fast design and production processes and safety and effectiveness studies were completed in a short time for mRNA vaccines. While several mRNA-based vaccine systems have received emergency use approvals by international institutions, it is expected that enormous data will be obtained on the possible side effects and safety of mRNA-based systems after vaccines are administered to millions of people. As a result, although it is a new technology, it can be said that a new era has entered with the SARS-CoV-2 pandemic for mRNA-based vaccines based on 30 years of experience. In this article, a summary of the difficulties and milestone events encountered in the development of the technology from the discovery of mRNA to the first approval of mRNA-based vaccines is presented.

Notes

mRNA Aşılarının Tarihsel Gelişim Süreci ve SARS-CoV-2 Pandemisi

Files

jmvi.2020.15.pdf

Files (283.6 kB)

Name Size Download all
md5:f585c43fae139b071703135366697803
283.6 kB Preview Download

Additional details

References

  • 1. Pardi N, Hogan MJ, Porter FW, Weissman D. mRNA vaccines - a new era in vaccinology. Nat Rev Drug Discov 2018; 17(4): 261-79.
  • 2. Behbehani AM. The smallpox story: life and death of an old disease. Microbiol Rev 1983; 47(4): 455-509.
  • 3. Henderson DA. The eradication of smallpox--an overview of the past, present, and future. Vaccine 2011; 29 Suppl 4: D7-9.
  • 4. Toumi M, Ricciardi W. The Economic Value of Vaccination: Why Prevention is Wealth. J Mark Access Health Policy 2015; 3. eCollection 2015.
  • 5. Verbeke R, Lentacker I, De Smedt SC, Dewitte H. Three decades of messenger RNA vaccine development. Nano Today 2019; 28: 100766.
  • 6. Boczkowski D, Nair SK, Snyder D, Gilboa E. Dendritic cells pulsed with RNA are potent antigen-presenting cells in vitro and in vivo. J Exp Med 1996; 184(2): 465-72.
  • 7. Conry RM, LoBuglio AF, Wright M, Sumerel L, Pike MJ, Johanning F, Benjamin R, Lu D, Curiel DT. Characterization of a messenger RNA polynucleotide vaccine vector. Cancer Res 1995; 55(7): 1397-400.
  • 8. Malone RW, Felgner PL, Verma IM. Cationic liposome-mediated RNA transfection. Proc Natl Acad Sci U S A 1989; 86(16): 6077-81.
  • 9. Wolff JA, Malone RW, Williams P, Chong W, Acsadi G, Jani A, Felgner PL. Direct gene transfer into mouse muscle in vivo. Science 1990; 247 (4949 Pt 1): 1465-8.
  • 10. Jirikowski GF, Sanna PP, Maciejewski-Lenoir D, Bloom FE. Reversal of diabetes insipidus in Brattleboro rats: intrahypothalamic injection of vasopressin mRNA. Science 1992; 255(5047): 996-8.
  • 11. Martinon F, Krishnan S, Lenzen G, Magné R, Gomard E, Guillet JG, et al. Induction of virus-specific cytotoxic T lymphocytes in vivo by liposome-entrapped mRNA. Eur J Immunol 1993; 23(7): 1719-22.
  • 12. World Health Organization (WHO), Geneva, Switzerland. Draft landscape of COVID-19 candidate vaccines. Available at: https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines [Accessed December 28, 2020].
  • 13. Brende B, Farrar J, Gashumba D, Moedas C, Mundel T, Shiozaki Y, et al. CEPI-a new global R&D organisation for epidemic preparedness and response. Lancet 2017; 389(10066): 233-5.
  • 14. Anadolu Ajansı, Ankara, Türkiye. Bulaşıcı hastalık aşılarına 'Acil Kullanım Onayı' verilebilmesi Kovid-19'la mücadeleyi güçlendirecek. Available at: https://www.aa.com.tr/tr/koronavirus/bulasici-hastalik-asilarina-acil-kullanim-onayi-verilebilmesi-kovid-19la-mucadeleyi-guclendirecek/2081554 [Accessed December 28, 2020].
  • 15. Mahase E. Covid-19: UK approves Pfizer and BioNTech vaccine with rollout due to start next week. BMJ 2020; 371: m4714.
  • 16. US Food and Drug Administration (FDA), Silver Spring, Maryland, USA. Pfizer COVID-19 Vaccine EUA Letter of Authorization. Available at: https://www.fda.gov/media/144412/download [Accessed December 29, 2020].
  • 17. Oliver SE, Gargano JW, Marin M, Wallace M, Curran KG, Chamberland M, et al. The Advisory Committee on Immunization Practices' Interim Recommendation for Use of Moderna COVID-19 Vaccine - United States, December 2020. MMWR Morb Mortal Wkly Rep 2021; 69(5152): 1653-6.
  • 18. Jacob F, Monod J. Genetic regulatory mechanisms in the synthesis of proteins. J Mol Biol 1961; 3: 318-56.
  • 19. Steinman RM, Cohn ZA. Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution. J Exp Med 1973; 137(5): 1142-62.
  • 20. Zhou X, Berglund P, Rhodes G, Parker SE, Jondal M, Liljeström P. Self-replicating Semliki Forest virus RNA as recombinant vaccine. Vaccine 1994; 12(16): 1510-4.
  • 21. Johanning FW, Conry RM, LoBuglio AF, Wright M, Sumerel LA, Pike MJ, et al. A Sindbis virus mRNA polynucleotide vector achieves prolonged and high level heterologous gene expression in vivo. Nucleic Acids Res 1995; 23(9): 1495-501.
  • 22. Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA. The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 1996; 86(6): 973-83.
  • 23. Alexopoulou L, Holt AC, Medzhitov R, Flavell RA. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 2001; 413(6857): 732-8.
  • 24. Heiser A, Coleman D, Dannull J, Yancey D, Maurice MA, Lallas CD, et al. Autologous dendritic cells transfected with prostate-specific antigen RNA stimulate CTL responses against metastatic prostate tumors. J Clin Invest 2002; 109(3): 409-17.
  • 25. Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, Akira S, et al. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 2004; 303(5663): 1526-9.
  • 26. Yoneyama M, Kikuchi M, Natsukawa T, Shinobu N, Imaizumi T, Miyagishi M, et al. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat Immunol 2004; 5(7): 730-7.
  • 27. Scheel B, Braedel S, Probst J, Carralot JP, Wagner H, Schild H, et al. Immunostimulating capacities of stabilized RNA molecules. Eur J Immunol 2004; 34(2): 537-47.
  • 28. Carralot JP, Probst J, Hoerr I, Scheel B, Teufel R, Jung G, et al. Polarization of immunity induced by direct injection of naked sequence-stabilized mRNA vaccines. Cell Mol Life Sci 2004; 61(18): 2418-24.
  • 29. Karikó K, Buckstein M, Ni H, Weissman D. Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. Immunity 2005; 23(2): 165-75.
  • 30. Probst J, Weide B, Scheel B, Pichler BJ, Hoerr I, Rammensee HG, et al. Spontaneous cellular uptake of exogenous messenger RNA in vivo is nucleic acid-specific, saturable and ion dependent. Gene Ther 2007; 14(15): 1175-80. Erratum in: Gene Ther 2009; 16(5): 706.
  • 31. Karikó K, Muramatsu H, Welsh FA, Ludwig J, Kato H, Akira S, et al. Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Mol Ther 2008; 16(11): 1833-40.
  • 32. Weide B, Carralot JP, Reese A, Scheel B, Eigentler TK, Hoerr I, et al. Results of the first phase I/II clinical vaccination trial with direct injection of mRNA. J Immunother 2008; 31(2): 180-8.
  • 33. Weide B, Pascolo S, Scheel B, Derhovanessian E, Pflugfelder A, Eigentler TK, et al. Direct injection of protamine-protected mRNA: results of a phase 1/2 vaccination trial in metastatic melanoma patients. J Immunother 2009; 32(5): 498-507.
  • 34. Kreiter S, Selmi A, Diken M, Koslowski M, Britten CM, Huber C, et al. Intranodal vaccination with naked antigen-encoding RNA elicits potent prophylactic and therapeutic antitumoral immunity. Cancer Res 2010; 70(22): 9031-40.
  • 35. Petsch B, Schnee M, Vogel AB, Lange E, Hoffmann B, Voss D, et al. Protective efficacy of in vitro synthesized, specific mRNA vaccines against influenza A virus infection. Nat Biotechnol 2012; 30(12): 1210-6.
  • 36. Sahin U, Derhovanessian E, Miller M, Kloke BP, Simon P, Löwer M, et al. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature 2017; 547(7662): 222-6.
  • 37. Pardi N, Hogan MJ, Pelc RS, Muramatsu H, Andersen H, DeMaso CR, et al. Zika virus protection by a single low-dose nucleoside-modified mRNA vaccination. Nature 2017; 543(7644): 248-51.
  • 38. Bahl K, Senn JJ, Yuzhakov O, Bulychev A, Brito LA, Hassett KJ, et al. Preclinical and Clinical Demonstration of Immunogenicity by mRNA Vaccines against H10N8 and H7N9 Influenza Viruses. Mol Ther 2017; 25(6): 1316-27.
  • 39. Alberer M, Gnad-Vogt U, Hong HS, Mehr KT, Backert L, Finak G, et al. 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 2017; 390(10101): 1511-20.
  • 40. US Food and Drug Administration (FDA), Silver Spring, Maryland, USA. Proprietary name: OnpattroTM (patisiran). Center For Drug Evaluation and Research Application Number: 210922Orig1s000. 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210922Orig1s000MultiR.pdf [Accessed December 29, 2020].
  • 41. Aligholipour Farzani T, Földes K, Ergünay K, Gurdal H, Bastug A, Ozkul A. Immunological Analysis of a CCHFV mRNA Vaccine Candidate in Mouse Models. Vaccines (Basel) 2019; 7(3): 115.
  • 42. Baden LR, El Sahly HM, Essink B, Kotloff K, Frey S, Novak R, et al.; COVE Study Group. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N Engl J Med 2020; [Online ahead of print].
  • 43. Polack FP, Thomas SJ, Kitchin N, Absalon J, Gurtman A, Lockhart S, et al.; C4591001 Clinical Trial Group. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med 2020; NEJMoa2034577.
  • 44. European Medicines Agency (EMA), Amsterdam, Netherlands. EMA recommends first COVID-19 vaccine for authorisation in the EU. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/comirnaty [Accessed December 29, 2020].
  • 45. US Food and Drug Administration (FDA), Silver Spring, Maryland, USA. Moderna COVID-19 Vaccine EUA Letter of Authorization. Available at: https://www.fda.gov/media/144636/download [Accessed December 29, 2020].
  • 46. Ozdarendeli A, Ku S, Rochat S, Williams GD, Senanayake SD, Brian DA. Downstream sequences influence the choice between a naturally occurring noncanonical and closely positioned upstream canonical heptameric fusion motif during bovine coronavirus subgenomic mRNA synthesis. J Virol 2001; 75(16): 7362-74.
  • 47. Pavel STI, Yetiskin H, Aydin G, Holyavkin C, Uygut MA, Dursun ZB, et al. Isolation and characterization of severe acute respiratory syndrome coronavirus 2 in Turkey. PLoS One 2020; 15(9): e0238614.
  • 48. Anadolu Ajansı, Ankara, Türkiye. Bakan Varank: 4 aşı adayımız hayvan deneylerini başarıyla tamamlamış durumda. Available at: https://www.aa.com.tr/tr/ekonomi/bakan-varank-4-asi-adayimiz-hayvan-deneylerini-basariyla-tamamlamis-durumda/2079890 [Accessed December 28, 2020].