Coronavirus Disease Research Community - COVID-19
Published February 4, 2021 | Version v1
Journal article Open

An Overview of the Safety Profile, Advantages and Disadvantages of mRNA Based Vaccines in the SARS-CoV-2 Pandemic

Creators

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

Description

Özet

Haberci ribonükleik asit (mRNA) gen ekspresyonu ve aşı teknolojisinin geleneksel aşı yöntemlerine (canlı attenüe, inaktif, protein subünit) ve yeni nesil sistemlere (DNA- deoksiribonükleik asit- ve viral vektörler) kıyasla belirli avantajları ve dezavantajları vardır. mRNA aşılarında ekspresyon siteminin tek bir bariyeri (hücre membranı) geçip ribozomlara ulaşması yeterli olduğundan bu aşılar tasarım avantajına sahiptir ve ayrıca insersiyonel mutagenez riski taşımamaktadır. mRNA sistemlerinin geçici ekspresyon oluşturması, üretilen antijen ile ilgili ek riskleri minimalize etmektedir. mRNA ekspresyon sistemlerinin en önemli dezavantajlarından biri RNA’nın stabil bir molekül olmaması ve bu aşılar için genellikle soğuk saklama ve transport koşullarının gerekmesidir. mRNA molekülünün in-vitro ve in-vivo stabilitesinin artırılması ve doğal bağışıklığın hücresel sensörlerinden saklanabilmesi için çeşitli teknikler (kapak sistemleri, sekans optimizasyonu, modifiye nükleozitler) geliştirilmiştir. Geleneksel aşılara göre hızlı tasarımı ve ölçeklenebilir üretimi ve düşük doz aşılama ile yüksek immünojenik aktivite sunması bu aşıları özellikle salgınlara müdahalede (SARS-CoV-2, Severe acute respiratory syndrome coronavirus 2, pandemisinde olduğu gibi) güçlü araçlar haline getirmektedir. Antijen üretiminin ve sunumunun doğal koşullara benzer olarak yapılması bu aşıların immün sistemin hücresel ve humoral yolaklarını başarılı bir şekilde aktive etmesini sağlamaktadır. Klinik çalışmalarda, çeşitli bulaşıcı hastalıkları ve kanserleri hedefleyen mRNA aşılarının genellikle güvenli olduğu ve iyi tolere edildiği değerlendirilmekle beraber, SARS-CoV-2 pandemisi sürecinde aşılanan milyonlarca kişiden elde edilecek veriler bu sistemin etkinliğini ve güvenliğini diğer aşı platformları ile karşılaştırma imkanı sunacaktır. mRNA molekülleri hücrelere çıplak olarak veya nanopartikül taşıyıcılar içerisinde iletilebilmektedir. Bazı taşıyıcı partiküller için toksisite ve alerjik reaksiyon riskleri bulunduğu gibi, bu aşıların otoimmün reaksiyonlara neden olabileceğine dair endişeler de vardır, bu nedenle aşı içeriğindeki tüm bileşenler için olası risklerin kapsamlı çalışma verileri ile incelenmesi ve aşıların güvenlik profilinin uzun dönem sonuçlarını sunan izlem çalışmaları ile ortaya konması gerekmektedir. Düşük sıklıkta da olsa, aşılama sonrası anafilaktik reaksiyon riski bulunduğu için aşı yapılan yerlerde anafilaksiye müdahale edebilmek için gerekli malzeme ve ekipmanlar bulundurulmalı, aşı yapan ekip bu konuda farkındalık sahibi olup aşılanan bireyleri bir süre izlemde tutmalıdır.

Abstract

Messenger ribonucleic acid (mRNA) gene expression and vaccine technology has certain advantages and disadvantages compared to traditional vaccine methods (live attenuated, inactive, protein subunit) and new generation systems (DNA-deoxyribonucleic acid- and viral vectors). mRNA vaccines have a design advantage since the expression system needs to cross a single barrier (cell membrane) and reach the ribosomes, also there is no risk of insertional mutagenesis in these vaccines. The transient expression of mRNA systems minimizes the additional risks associated with the antigen produced. One of the most important disadvantages of mRNA expression systems is that RNA is not a stable molecule and generally cold storage and transport conditions are required for these vaccines. Various techniques (cap systems, sequence optimization, modified nucleosides) have been developed to increase the in-vitro and in-vivo stability of the mRNA molecule and to stealth from cellular sensors of innate immunity. Its rapid design and scalable production compared to traditional vaccines and high immunogenic activity with low dose vaccination make these vaccines particularly powerful tools in response to epidemics (as in the current Severe acute respiratory syndrome coronavirus 2, SARS-CoV-2, pandemic). Antigen production and presentation similar to natural conditions enables these vaccines to successfully activate the cellular and humoral pathways of the immune system. In clinical studies, it is evaluated that mRNA vaccines targeting various infectious diseases and cancers are generally safe and well tolerated, however the data to be obtained from millions of people vaccinated during the SARS-CoV-2 pandemic will provide the opportunity to compare the effectiveness and safety of this system with other vaccine platforms. mRNA molecules can be delivered to cells naked or in nanoparticle carriers. There are risks of toxicity and allergic reactions to some carrier particles, as well as concerns that these vaccines may cause autoimmune reactions, therefore, possible risks for all components in the vaccine content should be examined with comprehensive study data and the safety profile of vaccines should be revealed through follow-up studies that present long-term results. Despite the low frequency, since there is a risk of anaphylactic reaction after vaccination, necessary materials and equipment should be available in places where the vaccine is administered, and the vaccinating team should be aware of this issue and keep the vaccinated individuals under follow-up for a while.

Notes

SARS-CoV-2 Pandemisinde mRNA Aşılarının Güvenlik Profili, Avantaj ve Dezavantajlarına Genel Bakış

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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. Henderson DA. The eradication of smallpox--an overview of the past, present, and future. Vaccine 2011; 29 Suppl 4: D7-9.
  • 3. Şahiner F, Cebeci İ. Hepatit C Virusu: Genetik Özellikleri, Aşı Geliştirme Çalışmalarında İlerlemeler ve Güncel Zorluklar. J Mol Virol Immunol 2020; 1(1): 1-13.
  • 4. Alameh MG, Weissman D, Pardi N. Messenger RNA-Based Vaccines Against Infectious Diseases. Curr Top Microbiol Immunol 2020. [Epub ahead of print]
  • 5. Sahin U, Türeci Ö. Personalized vaccines for cancer immunotherapy. Science 2018; 359(6382): 1355-60.
  • 6. 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.
  • 7. Verbeke R, Lentacker I, De Smedt SC, Dewitte H. Three decades of messenger RNA vaccine development. Nano Today 2019; 28: 100766.
  • 8. Anadolu Ajansı, Ankara, Türkiye. AB ile AstraZeneca arasındaki anlaşmazlık büyüyor. Available at: https://www.aa.com.tr/tr/dunya/ab-ile-astrazeneca-arasindaki-anlasmazlik-buyuyor/2124719 [Accessed January 27, 2021].
  • 9. 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].
  • 10. 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].
  • 11. 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].
  • 12. Mahase E. Covid-19: UK approves Pfizer and BioNTech vaccine with rollout due to start next week. BMJ 2020; 371: m4714.
  • 13. 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.
  • 14. 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.
  • 15. Matsukura S, Kokubu F, Kurokawa M, Kawaguchi M, Ieki K, Kuga H, et al. Role of RIG-I, MDA-5, and PKR on the expression of inflammatory chemokines induced by synthetic dsRNA in airway epithelial cells. Int Arch Allergy Immunol 2007;143 Suppl 1:80-3.
  • 16. Heidenreich R, Jasny E, Kowalczyk A, Lutz J, Probst J, Baumhof P, et al. A novel RNA-based adjuvant combines strong immunostimulatory capacities with a favorable safety profile. Int J Cancer 2015; 137(2): 372-84.
  • 17. Kallen KJ, Heidenreich R, Schnee M, Petsch B, Schlake T, Thess A, et al. A novel, disruptive vaccination technology: self-adjuvanted RNActive(®) vaccines. Hum Vaccin Immunother 2013; 9(10): 2263-76.
  • 18. 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.
  • 19. John S, Yuzhakov O, Woods A, Deterling J, Hassett K, Shaw CA, et al. Multi-antigenic human cytomegalovirus mRNA vaccines that elicit potent humoral and cell-mediated immunity. Vaccine 2018; 36(12): 1689-99.
  • 20. McCaffrey A. Design and Manufacturing of Messenger RNA Therapeutics. Education Session from the American Society of Gene & Cell Therapy's 22nd Annual Meeting, April 29 - May 2, 2019. Washington Hilton, Washington DC, USA. Available at: https://www.youtube.com/watch?v=8j33dGRZ_S4&list=LL&index=3 [Accessed December 28, 2020].
  • 21. Güzel Tanoğlu E. Production and Distribution of mRNA Vaccines: SARS-CoV-2 Experience. J Mol Virol Immunol 2020; 1(3): 27-34.
  • 22. 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.
  • 23. Jones KL, Drane D, Gowans EJ. Long-term storage of DNA-free RNA for use in vaccine studies. Biotechniques 2007; 43(5): 675-81.
  • 24. Probst J, Brechtel S, Scheel B, Hoerr I, Jung G, Rammensee HG, et al. Characterization of the ribonuclease activity on the skin surface. Genet Vaccines Ther 2006; 4: 4.
  • 25. Pardi N, Hogan MJ, Weissman D. Recent advances in mRNA vaccine technology. Curr Opin Immunol 2020; 65: 14-20.
  • 26. Ishino S, Ishino Y. DNA polymerases as useful reagents for biotechnology - the history of developmental research in the field. Front Microbiol 2014; 5: 465.
  • 27. 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.
  • 28. Baiersdörfer M, Boros G, Muramatsu H, Mahiny A, Vlatkovic I, Sahin U, Karikó K. A Facile Method for the Removal of dsRNA Contaminant from In Vitro-Transcribed mRNA. Mol Ther Nucleic Acids 2019; 15: 26-35.
  • 29. Knuf M, Faber J, Barth I, Habermehl P. A combination vaccine against measles, mumps, rubella and varicella. Drugs Today (Barc) 2008; 44(4): 279-92.
  • 30. Mandl CW, Aberle JH, Aberle SW, Holzmann H, Allison SL, Heinz FX. In vitro-synthesized infectious RNA as an attenuated live vaccine in a flavivirus model. Nat Med 1998; 4(12): 1438-40.
  • 31. Oliver SE, Gargano JW, Marin M, Wallace M, Curran KG, Chamberland Met 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.
  • 32. 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; 383(27): 2603-15.
  • 33. 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].
  • 34. Gümral R. In-vivo Delivery of mRNA-Based Vaccines and Administration Routes, J Mol Virol Immunol 2020; 1(3): 18-26.
  • 35. Theofilopoulos AN, Baccala R, Beutler B, Kono DH. Type I interferons (alpha/beta) in immunity and autoimmunity. Annu Rev Immunol 2005; 23: 307-36.
  • 36. Nestle FO, Conrad C, Tun-Kyi A, Homey B, Gombert M, Boyman O, et al. Plasmacytoid predendritic cells initiate psoriasis through interferon-alpha production. J Exp Med 2005; 202(1): 135-43.
  • 37. Fischer S, Gerriets T, Wessels C, Walberer M, Kostin S, Stolz E, et al. Extracellular RNA mediates endothelial-cell permeability via vascular endothelial growth factor. Blood 2007; 110(7): 2457-65.
  • 38. Kannemeier C, Shibamiya A, Nakazawa F, Trusheim H, Ruppert C, Markart P, et al. Extracellular RNA constitutes a natural procoagulant cofactor in blood coagulation. Proc Natl Acad Sci U S A 2007; 104(15): 6388-93.
  • 39. US Food and Drug Administration (FDA), Silver Spring, Maryland, USA. Vaccines and Related Biological Products Advisory Committee December 17, 2020 Meeting Presentation - FDA Review of Efficacy and Safety of Moderna COVID-19 Vaccine Emergency Use Authorization Request. Available at: https://www.fda.gov/media/144585/download [Accessed December 29, 2020].
  • 40. US Food and Drug Administration (FDA), Silver Spring, Maryland, USA. Vaccines and Related Biological Products Advisory Committee Meeting December 10, 2020 FDA Briefing Document Pfizer-BioNTech COVID-19 Vaccine. Available at: https://www.fda.gov/media/144245/download [Accessed December 29, 2020].
  • 41. Krammer F, Srivastava K, PARIS team, Simon V. Robust spike antibody responses and increased reactogenicity in seropositive individuals after a single dose of SARS-CoV-2 mRNA vaccine. medRxiv 2021.01.29.21250653.
  • 42. Ortega Rodríguez NR, Audícana Berasategui MT, de la Hoz Caballer B, Valero Santiago A. The century of mRNA vaccines: COVID-19 vaccines and allergy. J Investig Allergol Clin Immunol 2021. [Epub ahead of print]
  • 43. Bruusgaard-Mouritsen MA, Johansen JD, Garvey LH. Clinical manifestations and impact on daily life of allergy to polyethylene glycol (PEG) in ten patients. Clin Exp Allergy 2021. [Epub ahead of print].
  • 44. Banerji A, Wickner PG, Saff R, Stone CA Jr, Robinson LB, Long AA, et al. mRNA Vaccines to Prevent COVID-19 Disease and Reported Allergic Reactions: Current Evidence and Suggested Approach. J Allergy Clin Immunol Pract 2020: S2213-2198(20)31411-2.
  • 45. CDC COVID-19 Response Team; Food and Drug Administration. Allergic Reactions Including Anaphylaxis After Receipt of the First Dose of Pfizer-BioNTech COVID-19 Vaccine - United States, December 14-23, 2020. MMWR Morb Mortal Wkly Rep 2021; 70(2): 46-51.