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Published January 13, 2021 | Version v1
Journal article Open

A New Era in Vaccine Technology: mRNA-Based Vaccine Design

  • 1. Department of Medical Microbiology, Gulhane Medical Faculty, University of Health Sciences, Ankara, Turkey
  • 2. Department of Medical Microbiology, Gulhane Training and Research Hospital, Ankara, Turkey

Description

Özet

Messenger RNA (mRNA) teknolojisi hem genetik hastalıkların ve kanserlerin tedavisinde (terapötik kanser aşıları) hem de enfeksiyöz hastalıkların yayılımının önlenmesinde gelecek vaat eden yeni nesil bir yaklaşımı temsil eder. mRNA aşı sistemlerinin temel mantığı istenilen bir proteinin viral bir enfeksiyonu taklit ederek vücutta üretilmesini sağlamak ve onun işlevlerinden yararlanmaktır. DNA temelli sistemlerden ve viral vektörlerden farklı olarak üretilmek istenilen proteine ait genetik kodu taşıyan mRNA molekülleri ikinci bir aracı genetik sistem olmaksızın hücrelere doğrudan iletilir ve protein üretimi için gönderilen mesajın sitoplazmaya ulaşması yeterli olduğundan bu moleküller kromozomal yapılara entegre olma riski taşımazlar. mRNA temelli sistemlerin tasarlanmasındaki temel zorluklar bu moleküllerin hücre içi ve hücre dışı enzimlere çok duyarlı olması, stabilizasyon sorunları, doğal immün sistem tarafından tanınarak ortadan kaldırılması gibi sınırlayıcı özelliklerdir. Tüm bu problemlerin üstesinden gelmek ve başarılı mRNA transfeksiyonu elde etmek adına kapak analogları, modifiye nükleotidler, genetik sekans mühendisliği müdahaleleri, taşıyıcı partiküller ve oda sıcaklığına dayanıklı mRNA sistemlerinin geliştirilmesine yönelik alanlarda son 10 yılda önemli ilerlemeler kaydedilmiştir. Bir diğer önemli nokta ise mRNA sistemlerinin immünojenisitesinin optimize edilmesidir; istenilen adjuvan benzeri etkileri belirli bir derecede korurken, otoimmünite veya aşırı duyarlılık reaksiyonlarına neden olabilecek antijenik uyarılardan kaçınma arasındaki dengeyi sağlamak önemlidir. Bu amaçla özel saflaştırma yöntemlerinin seçimi ve ökaryotik mRNA’lara benzer motiflerin kullanılması gibi yaklaşımlar ve ek adjuvanlarla beraber kullanılan sistemler tasarlanmıştır. Replike olabilen mRNA sistemleri adjuvan özelliği sergileyen çift zincirli RNA (dsRNA) gibi kendi adjuvanlarını üretebilmesi ve daha uzun süreli antijen üretimi ile farklı amaçlara yönelik yeni ve düşük üretim maliyetli tasarım sistemleri olarak denenmektedir. Aynı mRNA molekülü üzerinden birden fazla antijenin veya proteinin hücresel ekspresyonu gibi esnek seçenekler de denenmiştir. Bu makalede mRNA temelli sistemlerin alternatif tasarımlarına değinilmiş ve mRNA aşı teknolojisindeki son gelişmelerin bir özeti sunulmuştur.

Abstract

Messenger RNA (mRNA) technology represents a promising next-generation approach to both the treatment of genetic diseases and cancers (therapeutic cancer vaccines) and the prevention of the spread of infectious diseases. The basic principle of mRNA vaccine systems is to ensure that a desired protein is produced in the body by mimicking a viral infection and to benefit from its functions. Unlike DNA-based systems and viral vectors, mRNA molecules carrying the genetic code of the desired protein to be produced are directly transmitted to the cells without a second intermediary genetic system, and these molecules do not have the risk of integrating into chromosomal structures, since it is enough for the message sent to reach the cytoplasm for protein production. The main difficulties in designing mRNA-based systems are the limiting features of these molecules, such as being very sensitive to intracellular and extracellular enzymes, stabilization problems, and eliminating them by being recognized by the innate immune system. In order to overcome all these problems and achieve successful mRNA transfection, significant progress has been made in the last 10 years in the fields of cap analogs, modified nucleotides, genetic sequence engineering interventions, carrier particles and the development of room temperature resistant mRNA systems. Another important point is optimizing the immunogenicity of mRNA systems; the balance between avoiding antigenic stimuli that can cause autoimmunity or hypersensitivity reactions and maintaining a certain degree of desired adjuvant-like effects is important. For this purpose, approaches such as the selection of special purification methods and the use of motifs similar to eukaryotic mRNAs and systems used with additional adjuvants have been designed. Self-amplifying mRNA systems are being tested as new and low production cost design systems for different purposes with the ability to produce their own adjuvants, such as double strand RNA (dsRNA) that exhibit adjuvant properties, and with longer antigen production. In this article, alternative designs of mRNA-based systems are discussed and a summary of recent developments in mRNA vaccine technology is presented.

Notes

Aşı Teknolojisinde Yeni Bir Dönem: mRNA Temelli Aşı Tasarımı

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References

  • 1. Şahiner M, Yurdakul ES, Şahiner F. The 150-Year History of Scientific Discoveries as Milestones in the Development Process of Molecular Biology Techniques. J Mol Virol Immunol 2020; 1(1); 43-56.
  • 2. Jacob F, Monod J. Genetic regulatory mechanisms in the synthesis of proteins. J Mol Biol 1961; 3: 318-56.
  • 3. Pardi N, Hogan MJ, Porter FW, Weissman D. mRNA vaccines - a new era in vaccinology. Nat Rev Drug Discov 2018; 17(4): 261-79.
  • 4. Verbeke R, Lentacker I, De Smedt SC, Dewitte H. Three decades of messenger RNA vaccine development. Nano Today 2019; 28: 100766.
  • 5. Xu S, Yang K, Li R, Zhang L. mRNA Vaccine Era-Mechanisms, Drug Platform and Clinical Prospection. Int J Mol Sci 2020; 21(18): 6582.
  • 6. Hekele A, Bertholet S, Archer J, Gibson DG, Palladino G, Brito LA, et al. Rapidly produced SAM(®) vaccine against H7N9 influenza is immunogenic in mice. Emerg Microbes Infect 2013; 2(8): e52.
  • 7. ViralZone, Swiss Institute of Bioinformatics, Switzerland. Host-virus interactions. Available at: https://viralzone.expasy.org/886 [Accessed April 18, 2020].
  • 8. Zhang Y, Zeng X, Jiao Y, Li Z, Liu Q, Ye J, et al. Mechanisms involved in the development of thrombocytopenia in patients with COVID-19. Thromb Res 2020; 193: 110-15.
  • 9. Azkur AK, Akdis M, Azkur D, Sokolowska M, van de Veen W, Brüggen MC, et al. Immune response to SARS-CoV-2 and mechanisms of immunopathological changes in COVID-19. Allergy 2020; 75(7): 1564-81.
  • 10. Magini D, Giovani C, Mangiavacchi S, Maccari S, Cecchi R, Ulmer JB, et al. Self-Amplifying mRNA Vaccines Expressing Multiple Conserved Influenza Antigens Confer Protection against Homologous and Heterosubtypic Viral Challenge. PLoS One 2016; 11(8): e0161193.
  • 11. 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.
  • 12. Fleeton MN, Chen M, Berglund P, Rhodes G, Parker SE, Murphy M, et al. Self-replicative RNA vaccines elicit protection against influenza A virus, respiratory syncytial virus, and a tickborne encephalitis virus. J Infect Dis 2001; 183(9): 1395-8.
  • 13. Beissert T, Perkovic M, Vogel A, Erbar S, Walzer KC, Hempel T, et al. A Trans-amplifying RNA Vaccine Strategy for Induction of Potent Protective Immunity. Mol Ther 2020; 28(1): 119-28.
  • 14. Blakney AK, McKay PF, Shattock RJ. Structural Components for Amplification of Positive and Negative Strand VEEV Splitzicons. Front Mol Biosci 2018; 5: 71.
  • 15. Pardi N, Hogan MJ, Weissman D. Recent advances in mRNA vaccine technology. Curr Opin Immunol 2020; 65: 14-20.
  • 16. Moya-Ramírez I, Bouton C, Kontoravdi C, Polizzi K. High resolution biosensor to test the capping level and integrity of mRNAs. Nucleic Acids Res 2020; 48(22): e129.
  • 17. Sk MF, Jonniya NA, Roy R, Poddar S, Kar P. Computational Investigation of Structural Dynamics of SARS-CoV-2 Methyltransferase-Stimulatory Factor Heterodimer nsp16/nsp10 Bound to the Cofactor SAM. Front Mol Biosci 2020; 7: 590165.
  • 18. Vaidyanathan S, Azizian KT, Haque AKMA, Henderson JM, Hendel A, Shore S, et al. Uridine Depletion and Chemical Modification Increase Cas9 mRNA Activity and Reduce Immunogenicity without HPLC Purification. Mol Ther Nucleic Acids 2018; 12: 530-42.
  • 19. Orlandini von Niessen AG, Poleganov MA, Rechner C, Plaschke A, Kranz LM, Fesser S, et al. Improving mRNA-Based Therapeutic Gene Delivery by Expression-Augmenting 3' UTRs Identified by Cellular Library Screening. Mol Ther 2019; 27(4): 824-36.
  • 20. Holtkamp S, Kreiter S, Selmi A, Simon P, Koslowski M, Huber C, et al. Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells. Blood 2006; 108(13): 4009-17.
  • 21. Chen YH, Coller J. A Universal Code for mRNA Stability? Trends Genet 2016; 32(11): 687-8.
  • 22. Li J, Wang W, He Y, Li Y, Yan EZ, Zhang K, et al. Structurally Programmed Assembly of Translation Initiation Nanoplex for Superior mRNA Delivery. ACS Nano 2017; 11(3): 2531-44.
  • 23. Karikó K, Muramatsu H, Ludwig J, Weissman D. Generating the optimal mRNA for therapy: HPLC purification eliminates immune activation and improves translation of nucleoside-modified, protein-encoding mRNA. Nucleic Acids Res 2011; 39(21): e142.
  • 24. 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.
  • 25. Scheel B, Teufel R, Probst J, Carralot JP, Geginat J, Radsak M, et al. Toll-like receptor-dependent activation of several human blood cell types by protamine-condensed mRNA. Eur J Immunol 2005; 35(5): 1557-66.
  • 26. 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.
  • 27. Aligholipour Farzani T, Földes K, Hanifehnezhad A, Yener Ilce B, Bilge Dagalp S, Amirzadeh Khiabani N, et al. Bovine Herpesvirus Type 4 (BoHV-4) Vector Delivering Nucleocapsid Protein of Crimean-Congo Hemorrhagic Fever Virus Induces Comparable Protective Immunity against Lethal Challenge in IFNα/β/γR-/- Mice Models. Viruses 2019; 11(3): 237.
  • 28. 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].
  • 29. Anadolu Ajansı, Ankara, Türkiye. Selçuk Üniversitesi'nde geliştirilen Türkiye'nin ilk mRNA aşısının yazın kullanıma sunulması planlanıyor. Available at: https://www.aa.com.tr/tr/koronavirus/selcuk-universitesinde-gelistirilen-turkiyenin-ilk-mrna-asisinin-yazin-kullanima-sunulmasi-planlaniyor/2105643 [Accessed December 28, 2020].