mRNA AŞILARINDA GÜNCEL YAKLAŞIMLAR

Yıl 2022, Cilt: 13 Sayı: 1, 1 - 10, 30.04.2022

Kamil Batur , Hakan Yardımcı

https://doi.org/10.38137/vftd.1021843

Öz

Tarihteki ilk aşının 1796 yılında Edward Jenner tarafından geliştirilmesinden günümüze kadar geçen süreçte birçok hastalığa karşı aşı geliştirilmiştir ve etkili olarak kullanılmıştır. Son yıllarda giderek popülerleşen mRNA aşılarının geçmişi 90’lı yıllara kadar dayanmaktadır. Wolf ve arkadaşlarının 1990 yılında lusiferaz ve beta-galaktosidaz enzimlerini kodlayan mRNA’ları farelere kas içi uyguyalarak bu proteinleri in vivo olarak gözlemlemeleri mRNA aşılarının gelişiminde önemli bir basamak olmuştur. mRNA aşıları bir Cap Bölgesi, 5’ ve 3’ translasyona uğramayan bölgeler, açık okuma bölgesi ve Poli A kuyruğundan oluşur. Geleneksel mRNA aşıları ve kendi kendini çoğaltan mRNA aşıları olarak iki gruba ayrılırlar. İki grup da hücre translasyon mekanizmalarını kullanarak antijen üretir. mRNA’nın stabilitesini ve translasyon verimini arttırmak için Cap, UTR, Poli A kuyruğu gibi bölgeler ve nükleotid bazlar optimize edilmelidir. mRNA’nın hücre içine iletimi için viral vektörler, peptid, polimer ve lipid tabanlı vektörler kullanılabilir. Hedef bölge sakansını içeren bir pDNA tasarımı ile başlayan üretim süreci, optimizasyon ve kalıntılardan arındırma ile devam eder. Son ürün bir taşıma sistemi içerisine dahil edilir ve ürünün proteine çevrilme yeteneği test edilir. mRNA aşıları, genome entegre olmaması, nispeten kolay ve hızlı bir şekilde üretilebilmeleri ve güçlü bir bağışıklık yanıtı oluşturmaları gibi avantajları nedeniyle tercih edilen bir aşı platformu olarak karşımıza çıkmaktadır. Bu derlemede mRNA aşıları ve optimizasyonu hakkında genel bilgiler verilmesi amaçlanmıştır.

Anahtar Kelimeler

Aşı, Bağışıklık, mRNA, mRNA Aşıları

CURRENT APPROACHES to mRNA VACCINES

Öz

Since the development of the first vaccine in history by Edward Jenner in 1796, vaccines against many diseases have been developed and used effectively. The history of mRNA vaccines, which has become increasingly popular in recent years, dates back to the 90s. In 1990, Wolf et al. observed these proteins in vivo by intramuscularly administering mRNAs encoding luciferase and beta-galactosidase enzymes to mice, which was an important step in the development of mRNA vaccines. mRNA vaccines consist of a Cap Region, 5’ and 3’ non-translated regions, open reading region, and Poly A tail. They are divided into two groups as conventional mRNA vaccines and self-replicating mRNA vaccines. Both groups produce antigens using cell translational mechanisms. In order to increase the stability and translation efficiency of mRNA, regions such as Cap, UTR, Poly A tail and nucleotide bases should be optimized. Viral vectors, peptide, polymer and lipid-based vectors can be used for intracellular delivery of mRNA. The production process, which starts with a pDNA design containing the target region saccharine, continues with optimization and decontamination. The final product is incorporated into a transport system and the ability of the product to be converted into protein is tested. mRNA vaccines emerge as a preferred vaccine platform due to their advantages such as not being integrated into the genome, being relatively easy and fast to produce, and generating a strong immune response. In this review, it is aimed to give general information about mRNA vaccines and their optimization.

Anahtar Kelimeler

Immunity, mRNA, mRNA Vaccine, Vaccine

Kaynakça

• Akbarzadeh, A., Rezaei-Sadabady, R., Davaran, S., Joo, S. W., Zarghami, N., Hanifehpour, Y., Samiei, M., Kouhi, M., & Nejati-Koshki, K. (2013). Liposome: Classification, preparation, and applications. Nanoscale Research Letters, 8(1), 102.
• Aldrich, C., Leroux–Roels, I., Huang, K. B., Bica, M. A., Loeliger, E., Schoenborn-Kellenberger, O., Walz, L., Leroux-Roels, G., von Sonnenburg, F., & Oostvogels, L. (2021). Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial. Vaccine, 39(8), 1310–1318.
• Deering, R. P., Kommareddy, S., Ulmer, J. B., Brito, L. A., & Geall, A. J. (2014). Nucleic acid vaccines: Prospects for non-viral delivery of mRNA vaccines. In Expert Opinion on Drug Delivery Vol. 11, Issue 6, pp. 885–899. Desmettre P. (2019). Veterinary Vaccines in the Development of Vaccination and Vaccinology. History of Vaccine Development, 30,329-338
• Ehrengruber, M. U., Schlesinger, S., & Lundstrom, K. (2011). Alphaviruses: Semliki forest virus and sindbis virus vectors for gene transfer into neurons. Current Protocols in Neuroscience, Chapter 4(SUPPL.57).
• Feldman, R. A., Fuhr, R., Smolenov, I., (Mick)Ribeiro, A., Panther, L., Watson, M., Senn, J. J., Smith, M., Almarsson, Ӧrn, Pujar, H. S., Laska, M. E., Thompson, J., Zaks, T., & Ciaramella, G. (2019). mRNA vaccines against H10N8 and H7N9 influenza viruses of pandemic potential are immunogenic and well tolerated in healthy adults in phase 1 randomized clinical trials. Vaccine, 37(25), 3326–3334.
• Gary, D. J., Lee, H., Sharma, R., Lee, J. S., Kim, Y., Cui, Z. Y., Jia, D., Bowman, V. D., Chipman, P. R., Wan, L., Zou, Y., Mao, G., Park, K., Herbert, B. S., Konieczny, S. F., & Won, Y. Y. (2011). Influence of nano-carrier architecture on in vitro siRNA delivery performance and in vivo biodistribution: Polyplexes vs micelleplexes. ACS Nano, 5(5), 3493–3505.
• Geall, A. J., Mandl, C. W., & Ulmer, J. B. (2013). RNA: The new revolution in nucleic acid vaccines. In Seminars in Immunology (Vol. 25, Issue 2, pp. 152–159). Academic Press.
• Golombek, S., Pilz, M., Steinle, H., Kochba, E., Levin, Y., Lunter, D., Schlensak, C., Wendel, H. P., & Avci-Adali, M. (2018). Intradermal Delivery of Synthetic mRNA Using Hollow Microneedles for Efficient and Rapid Production of Exogenous Proteins in Skin. Molecular Therapy - Nucleic Acids, 11, 382–392.
• Grudzien-Nogalska, E., Stepinski, J., Jemielity, J., Zuberek, J., Stolarski, R., Rhoads, R. E., & Darzynkiewicz, E. (2007). Synthesis of Anti-Reverse Cap Analogs (ARCAs) and their Applications in mRNA Translation and Stability. In Methods in Enzymology Vol. 431, pp. 203–227.
• Hajj, K. A., & Whitehead, K. A. (2017). Tools for translation: Non-viral materials for therapeutic mRNA delivery. In Nature Reviews Materials (Vol. 2).
• Holtkamp, S., Kreiter, S., Selmi, A., Simon, P., Koslowski, M., Huber, C., Türeci, Ö., & Sahin, U. (2006). Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells. Blood, 108(13), 4009–4017.
• Houseley, J., & Tollervey, D. (2009). The Many Pathways of RNA Degradation. In Cell Vol. 136, Issue 4, pp. 763–776
• Iavarone, C., O’hagan, D. T., Yu, D., Delahaye, N. F., & Ulmer, J. B. (2017). Mechanism of action of mRNA-based vaccines. Expert Review of Vaccines, 16(9), 871–881.
• 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.
• 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 Research, 39(21), 142.
• Koh, K. J., Liu, Y., Lim, S. H., Loh, X. J., Kang, L., Lim, C. Y., & Phua, K. K. L. (2018). Formulation, characterization and evaluation of mRNA-loaded dissolvable polymeric microneedles (RNApatch). Scientific Reports, 8(1).
• Kormann, M. S. D., Hasenpusch, G., Aneja, M. K., Nica, G., Flemmer, A. W., Herber-Jonat, S., Huppmann, M., Mays, L. E., Illenyi, M., Schams, A., Griese, M., Bittmann, I., Handgretinger, R., Hartl, D., Rosenecker, J., & Rudolph, C. (2011). Expression of therapeutic proteins after delivery of chemically modified mRNA in mice. Nature Biotechnology, 29(2), 154–159.
• Kowalski, P. S., Rudra, A., Miao, L., & Anderson, D. G. (2019). Delivering the Messenger: Advances in Technologies for Therapeutic mRNA Delivery. In Molecular Therapy Vol. 27, Issue 4, pp. 710–728.
• Kramps, T., & Elbers, K. (2017). Introduction to RNA vaccines. In Methods in Molecular Biology
• Kreiter, S., Selmi, A., Diken, M., Sebastian, M., Osterloh, P., Schild, H., Huber, C., Türeci, Ö., & Sahin, U. (2008). Increased Antigen Presentation Efficiency by Coupling Antigens to MHC Class I Trafficking Signals. The Journal of Immunology, 180(1), 309–318.
• Lacroix, C., Humanes, A., Coiffier, C., Gigmes, D., Verrier, B., & Trimaille, T. (2020). Polylactide-Based Reactive Micelles as a Robust Platform for mRNA Delivery. Pharmaceutical Research, 37(2).
• Li, Y., & Kiledjian, M. (2010). Regulation of mRNA decapping. Wiley Interdisciplinary Reviews: RNA, 1(2), 253–265. Martin, S. A., & Moss, B. (1975). Modification of RNA by mRNA guanylyltransferase and mRNA (guanine 7) methyltransferase from vaccinia virions. Journal of Biological Chemistry, 250(24), 9330–9335.
• Maruggi, G., Zhang, C., Li, J., Ulmer, J. B., & Yu, D. (2019). mRNA as a Transformative Technology for Vaccine Development to Control Infectious Diseases. Molecular Therapy, 27(4), 757–772.
• McCaffrey, A. P. (2019). RNA Epitranscriptome: Role of the 5’ Cap. Genetic Engineering and Biotechnology News, 39(5).
• Mu, X., Greenwald, E., Ahmad, S., & Hur, S. (2018). An origin of the immunogenicity of in vitro transcribed RNA. Nucleic Acids Research, 46(10), 5239–5249.
• Mugridge, J. S., Coller, J., & Gross, J. D. (2018). Structural and molecular mechanisms for the control of eukaryotic 5′–3′ mRNA decay. Nature Structural and Molecular Biology, 25(12), 1077–1085.
• Mukherjee, A., Waters, A. K., Kalyan, P., Achrol, A. S., Kesari, S., & Yenugonda, V. M. (2019). Lipid-polymer hybrid nanoparticles as a nextgeneration drug delivery platform: State of the art, emerging technologies, and perspectives. In International Journal of Nanomedicine Vol. 14, pp. 1937–1952.
• Muralidhara, B. K., Baid, R., Bishop, S. M., Huang, M., Wang, W., & Nema, S. (2016). Critical considerations for developing nucleic acid macromolecule based drug products. In Drug Discovery Today Vol. 21, Issue 3, pp. 430–444.
• Nakanishi, M., & Otsu, M. (2012). Development of Sendai Virus Vectors and their Potential Applications in Gene Therapy and Regenerative Medicine. Current Gene Therapy, 12(5), 410–416.
• National Library of Medicine (2021). A Study to Evaluate the Efficacy, Safety, and Immunogenicity of mRNA-1647 Cytomegalovirus (CMV) Vaccine in Healthy Participants 16 to 40 Years of Age. Erişim tarihi: 21 Aralık 2021, https://clinicaltrials.gov/ct2/show/NCT05085366
• Pardi, N., Muramatsu, H., Weissman, D., & Karikó, K. (2013). In vitro transcription of long RNA containing modified nucleosides. Methods in Molecular Biology, 969, 29–42.
• Pascolo, S. (2004). Messenger RNA-based vaccines. In Expert Opinion on Biological Therapy Vol. 4, Issue 8, pp. 1285–1294.
• Pollard, C., Rejman, J., De Haes, W., Verrier, B., Van Gulck, E., Naessens, T., De Smedt, S., Bogaert, P., Grooten, J., Vanham, G., & De Koker, S. (2013). Type i IFN counteracts the induction of antigen-specific immune responses by lipid-based delivery of mRNA vaccines. Molecular Therapy, 21(1), 251–259.
• Ramamoorth, M., & Narvekar, A. (2015). Non viral vectors in gene therapy - An overview. In Journal of Clinical and Diagnostic Research Vol. 9, Issue 1, pp. 01–06.
• Richner, J. M., Himansu, S., Dowd, K. A., Butler, S. L., Salazar, V., Fox, J. M., Julander, J. G., Tang, W. W., Shresta, S., Pierson, T. C., Ciaramella, G., & Diamond, M. S. (2017). Modified mRNA Vaccines Protect against Zika Virus Infection. Cell, 169(1), 176.
• Riley, L. E. (2021). mRNA Covid-19 Vaccines in Pregnant Women. New England Journal of Medicine, 384(24), 2342–2343.
• Rosenkranz, A. A., & Sobolev, A. S. (2015). Polyethylenimine-based polyplex nanoparticles and features of their behavior in cells and tissues. In Russian Chemical Bulletin (Vol. 64, Issue 12, pp. 2749–2755).
• Rozovics, J. M., Chase, A. J., Cathcart, A. L., Chou, W., Gershon, P. D., Palusa, S., Wilusz, J., & Semler, B. L. (2012). Picornavirus modification of a host mRNA decay protein. MBio, 3(6).
• Schlake, T., Thess, A., Fotin-Mleczek, M., & Kallen, K. J. (2012). Developing mRNA-vaccine technologies. RNA Biology, 9(11), 1319–1330.
• Schott, J. W., Morgan, M., Galla, M., & Schambach, A. (2016). Viral and synthetic RNA vector technologies and applications. In Molecular Therapy (Vol. 24, Issue 9, pp. 1513–1527).
• Sharova, L. V., Sharov, A. A., Nedorezov, T., Piao, Y., Shaik, N., & Ko, M. S. H. (2009). Database for mRNA half-life of 19 977 genes obtained by DNA microarray analysis of pluripotent and differentiating mouse embryonic stem cells. DNA Research, 16(1), 45–58.
• Shaw, C., Lee, H., Knightly, C., Kalidindi, S., Zaks, T., Smolenov, I., & Panther, L. (2019). 2754. Phase 1 Trial of an mRNA-Based Combination Vaccine Against hMPV and PIV3. Open Forum Infectious Diseases, 6(Supplement_2), S970–S970.
• Shimabukuro, T. T., Kim, S. Y., Myers, T. R., Moro, P. L., Oduyebo, T., Panagiotakopoulos, L., Marquez, P. L., Olson, C. K., Liu, R., Chang, K. T., Ellington, S. R., Burkel, V. K., Smoots, A. N., Green, C. J., Licata, C., Zhang, B. C., Alimchandani, M., Mba-Jonas, A., Martin, S. W., … Meaney-Delman, D. M. (2021). Preliminary Findings of mRNA Covid-19 Vaccine Safety in Pregnant Persons. New England Journal of Medicine, 384(24), 2273–2282.
• Tavernier, G., Andries, O., Demeester, J., Sanders, N. N., De Smedt, S. C., & Rejman, J. (2011). MRNA as gene therapeutic: How to control protein expression. In Journal of Controlled Release Vol. 150, Issue 3, pp. 238–247.
• Tezel, A., Dokka, S., Kelly, S., Hardee, G. E., & Mitragotri, S. (2004). Topical delivery of anti-sense oligonucleotides using low-frequency sonophoresis. Pharmaceutical Research, 21(12), 2219–2225.
• Tisen, X., Xuegui, L., Dejie, J., Zhaohui, X., & Zhongmin, D. (2015). Mechanism of 5’-to-3’ degradation of eukaryotic and prokaryotic mRNA. In Yi chuan = Hereditas / Zhongguo yi chuan xue hui bian ji (Vol. 37, Issue 3, pp. 250–258).
• Tros de Ilarduya, C., Sun, Y., & Düzgüneş, N. (2010). Gene delivery by lipoplexes and polyplexes. In European Journal of Pharmaceutical Sciences Vol. 40, Issue 3, pp. 159–170.
• Wadhwa, A., Aljabbari, A., Lokras, A., Foged, C., & Thakur, A. (2020). Opportunities and challenges in the delivery of mrna-based vaccines. Pharmaceutics, 12(2).
• Wei, J. (2021). The Development of mRNA Vaccines for Infectious Diseases : Recent Updates. 5271–5285.
• Weissman, D. (2014). mRNA transcript therapy. Expert Review of Vaccines, 14(2), 265–281.
• Yin, H., Kanasty, R. L., Eltoukhy, A. A., Vegas, A. J., Dorkin, J. R., & Anderson, D. G. (2014). Non-viral vectors for gene-based therapy. In Nature Reviews Genetics Vol. 15, Issue 8, pp. 541–555.
• Youn, H., & Chung, J. K. (2015). Modified mRNA as an alternative to plasmid DNA (pDNA) for transcript replacement and vaccination therapy. In Expert Opinion on Biological Therapy Vol. 15, Issue 9, pp. 1337–1348.
• Zhang, R., Men, K., Zhang, X., Huang, R., Tian, Y., Zhou, B., Yu, C., Wang, Y., Ji, X., Hu, Q., & Yang, L. (2018). Delivery of a modified mRNA encoding IL-22 binding protein (IL-22BP) for colon cancer gene therapy. Journal of Biomedical Nanotechnology, 14(7), 1239–1251.
• Zhao, J., Hyman, L., & Moore, C. (1999). Formation of mRNA 3′ Ends in Eukaryotes: Mechanism, Regulation, and Interrelationships with Other Steps in mRNA Synthesis. Microbiology and Molecular Biology Reviews, 63(2), 405–445.
• Zhong, F., Cao, W., Chan, E., Tay, P. N., Cahya, F. F., Zhang, H., & Lu, J. (2005). Deviation from major codons in the Toll-like receptor genes is associated with low Toll-like receptor expression. Immunology, 114(1), 83–93.