SARS-CoV-2’YE KARŞI GELİŞTİRİLEN AŞILAR VE ÜRETİM METOTLARI

Yıl 2021, Cilt: 4 Sayı: 2, 14 - 32, 31.08.2021

Beyza Şerefoğlu , Rabia Çakır Koç , Begüm Kübra Tokyay , Gizem Yolalan , Berrak Gülçin Balaban , Yigit Tanyeri , Sezer İslambey

Öz

Yeni koronavirüs (SARS-CoV-2) virüsünün sebep olduğu Covid-19 pandemisi dünya genelinde 4,3 milyon kişinin ölümüne ve 203 milyon kişinin hastalanmasına sebep olmuştur. Yeni tanımlanan bu virüs, hızlı yayılması ve ciddi hasarlar bırakması sebebiyle hastaneye yatış oranlarını arttırmıştır. Toplum sağlığı ve ülke ekonomileri olumsuz etkilenmiştir. Pandemiyi sonlandırmanın en etkili yolu aşı geliştirilmesi ve etkin aşılamanın yapılmasıdır. Tüm dünyada ve ülkemizde Covid-19’a yönelik aşı geliştirme çalışmaları yapılmaktadır.
Geleneksel bir aşı türü olan inaktif aşılar, uzun yıllar çalışılmış, yan etkileri bilinen, güvenilir aşılardır. İnaktive edilen virüsün immün yanıt oluşturması esasına dayanır. Üretim metodu; virüsün izole edilmesi, hücre kültüründe çoğaltılması, inaktivasyonu ve saflaştırılmasının ve genellikle bir adjuvan ile formülize edilmesidir. Rekombinant protein aşıları, rekombinant DNA teknolojisi ile virüsün viral proteinlerini sentezlemektedir. Üretiminde, SARS-CoV-2 viral proteinlerini kodlayan gen bölgelerinin uygun plazmidler aracılığı ile seçilen in vivo ortamda ekspresyonu, saflaştırılması ve adjuvan ile formülizasyonu yer alır. Virüs benzeri yapılar (VLP) ile oluşturulan aşılar, virüsü taklit ederek antijenik yapıyı tanıtırlar. Üretimlerinde çeşitli konakçı sistemler kullanıldığından, saflaştırma basamakları değişmektedir. Adenovirüs aşılarında viral vektör aracılığı ile immün yanıt oluşturması hedeflenmektedir. Üretiminde antijen kodlayan gen genellikle adenovirüse entegre edilir ve konakçı hücrelerde çoğaltıldıktan sonra hücreler parçalanarak saflaştırılır ve formülize edilir. Sentetik peptit aşıları, patojenin immünojenik bölgesini peptitler ile taklit eden aminoasit dizilerinden oluşur. Aşının üretimi; peptit sentezi, taşıyıcı protein konjugasyonu ve adjuvanlama/formülasyon aşamalarını içerir. mRNA aşılarında ise amaç, viral proteinin insan hücresinde in vivo ekspresyonunu sağlamaktır. Üretimde, mRNA dizilerini içeren plazmidler ile sentezlenen mRNA’ların saflaştırılması ve lipit nanopartiküller ile formülize edilmesini içerir. Bu derlemede, Covid-19’a yönelik geliştirilen aşıların teknolojileri ve üretim metotları avantaj ve dezavantajları ile birlikte değerlendirilmiştir.

Anahtar Kelimeler

Covid-19, Aşı, Üretim, İnaktif, Rekombinant, mRNA, Vektör

Destekleyen Kurum

Türkiye Sağlık Enstitüleri Başkanlığı

Proje Numarası

11548NL

Teşekkür

Türkiye Sağlık Enstitüleri Başkanlığı (TÜSEB) tarafından desteklenen 11548NL numaralı, “SARSCOV-2 Virüsüne Karşı İnaktif Virüs Aşısı ile Rekombinant Aşısı Üretimi için Preklinik Sonrası Proses Geliştirilmesi” başlıklı proje kapsamında hazırlanan derlemede kuruma destekleri için teşekkür ederiz.

Kaynakça

• Adler, R., Kelsey, N., Maik, M., & Song, J. H. (2021). Production of a SARS-CoV-2 Spike Protein Vaccine Using the Baculovirus Expression Vector System. Senior Design Reports (CBE). Erişim adresi: https://repository.upenn.edu/cbe_sdr/131
• Al-Barwani, F., Donaldson, B., Pelham, S. J. Young, S.L., & Ward, V.K. (2014) Antigen delivery by virus-like particles for immunotherapeutic vaccination. Ther Deliv 5:1223–1240. https://doi.org/10.4155/tde.14.74
• Baden, L. R., El Sahly, H. M., Essink, B., Kotloff, K., Frey, S., Novak, R., ve diğerleri. (2021). Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. New England Journal of Medicine, 384(5), 403–416. https://doi.org/10.1056/nejmoa2035389
• Bancel, S., Issa, W. J., Aunins, J. G., & Chakraborty, T. (2014). Manufacturing Methods for Production of Rna Transcripts.
• Bangari, Dinesh S., & Suresh K. Mittal. (2006). “Development of Nonhuman Adenoviruses as Vaccine Vectors.” Vaccine 24(7):849–62. doi: 10.1016/j.vaccine.2005.08.101.
• Calina, D., Docea, A. O., Petrakis, D., Egorov, A. M., Ishmukhametov, A. A., Gabibov, A. G., ve diğerleri. (2020). Towards effective COVID-19 vaccines: Updates, perspectives and challenges (Review). International Journal of Molecular Medicine, 46(1), 3. https://doi.org/10.3892/IJMM.2020.4596
• Carlson, R., & Lutmer, H. (2021). EpiVacCorona Vaccine — Precision Vaccinations. Erişim adresi: https://www.precisionvaccinations.com/vaccines/epivaccorona-vaccine
• Centers for Disease Control and Prevention. (2020), Erişim adresi: https://www.cdc.gov/coronavirus/2019-ncov/hcp/therapeutic-options.html
• Chen, Q., Lai, H., Hurtado, J., ve diğerleri. (2013) Agroinfiltration as an Effective and Scalable Strategy of Gene Delivery for Production of Pharmaceutical Proteins. Adv Tech Biol Med 01:1–21. https://doi.org/10.4172/atbm.1000103
• Chen, W. H., Chag, S. M., Poongavanam, M. V., Biter, A. B., Ewere, E. A., Rezende, W., ve diğerleri. (2017). Optimization of the Production Process and Characterization of the Yeast-Expressed SARS-CoV Recombinant Receptor-Binding Domain (RBD219-N1), a SARS Vaccine Candidate. Journal of Pharmaceutical Sciences, 106(8), 1961–1970. https://doi.org/10.1016/J.XPHS.2017.04.037
• ClinicalTrials.gov. (2021). Study of a Recombinant Coronavirus-Like Particle COVID-19 Vaccine in Adults. Erişim adresi: https://clinicaltrials.gov/ct2/show/NCT04636697
• ClinicalTrials.gov. (2021). Study of the Tolerability, Safety, Immunogenicity and Preventive Efficacy of the EpiVacCorona Vaccine for the Prevention of COVID-19. Erişim adresi: https://clinicaltrials.gov/ct2/show/NCT04780035
• Coronavirus disease (COVID-19): Vaccines.WHO., What types of COVID-19 vaccines are being developed? How would they work? (2021). Erişim adresi: https://www.who.int/news-room/q-a-detail/coronavirus-disease-(covid-19)-vaccines?adgroupsurvey=%7Badgroupsurvey%7Dvegclid=CjwKCAjwjJmIBhA4EiwAQdCbxgEpRqmN1zv1xwgjNghhEg9zGLvZdlf-wQX6AMrz87oGoZKl0jdTuBoCUUwQAvD_BwE
• Dai, L., & Gao, G. F. (2020). Viral targets for vaccines against COVID-19. Nature Reviews Immunology 2020 21:2, 21(2), 73–82. https://doi.org/10.1038/s41577-020-00480-0
• Dai, S., Wang, H., & Deng, F. (2018). Advances and challenges in enveloped virus-like particle (VLP)-based vaccines. Journal of Immunological Sciences, 2(2), 36–41. https://doi.org/10.29245/2578-3009/2018/2.1118
• Delrue, I., Verzele, D., Madder, A., & Nauwyck, H. J. (2012). Inactivated virus vaccines from chemistry to prophylaxis: Merits, risks and challenges. Expert Review of Vaccines, 11(6), 695–719. https://doi.org/10.1586/erv.12.38
• Edelstein, M., Scott, P. E., Sherlund, M., Hansen, A. L., & Hughes, J. L. (1986). Design Considerations for Pilot Scale Solid Phase Peptide Synthesis Reactors. Chemical Engineering Science, 41(4), 617–624.
• El Hajjami, N., Brantner, M. M., Boumlic, A., Mantri, S., & Cebi, B. (2021). Manufacturing Strategies for mRNA Vaccines and Therapeutics | Sigma-Aldrich. In Merck Technical Documents. Erişim adresi: https://www.sigmaaldrich.com/technical-documents/articles/white-papers/manufacturing-strategies-for-mrna-vaccines.html
• Ellis, R. W. (2001). MIU 26 MEDICAL INTELLIGENCE UNIT 26 New Vaccine Technologies (R. W. Ellis, Ed.). Eurekah.com / Landes Bioscience, 810 South Church Street. Erişim adresi: www.Eurekah.com
• Giese, M. (2016). Types of Recombinant Vaccines. Introduction to Molecular Vaccinology, 199–232. https://doi.org/10.1007/978-3-319-25832-4_9
• Giroux, D.D., Ramachandra, M., & Shabram, P. Viral production process. US5994134; (1999).
• Gopal, R. & Schneemann, A. (2018) Production and application of insect virus-based VLPs. Methods Mol Biol 1776:125–141. https://doi.org/10.1007/978-1-4939-7808-3_8
• Hartman, A. L., Cole, K. S., & Homer, L. C. (2012). Verification of Inactivation Methods for Removal of Biological Materials from a Biosafety Level 3 Select Agent Facility. Applied Biosafety, 17(2), 70–75. https://doi.org/10.1177/153567601201700204
• Heartlein, M., Derosa, F., Dıas, A., & Karve, S. (2014). Patent No. WO 2014/152966 Al. WIPO (PCT). Erişim adresi: https://patents.google.com/patent/WO2014152966A1/en#citedBy
• Hsieh, C., Goldsmith, J.A., Schaub, J.M., ve diğerleri. (2020) Structure-based design of prefusion-stabilized SARS-CoV-2 spikes. 0826:1–9
• Huang, Y., Yang, C., Xu, X., Xu, W., & Liu, S. (2020). Structural and functional properties of SARS-CoV-2 spike protein: potential antivirus drug development for COVID-19. Acta Pharmacologica Sinica 2020 41:9, 41(9), 1141–1149. https://doi.org/10.1038/s41401-020-0485-4
• Icosavax Initiates Phase 1/2 Trial of COVID-19 VLP Vaccine Candidate, 2021. Erişim adresi: https://investors.icosavax.com/news-releases/news-release-details/icosavax-initiates-phase-12-trial-covid-19-vlp-vaccine-candidate/
• Iversen, P. L., & Bavari, S. (2021). Inactivated COVID-19 vaccines to make a global impact. The Lancet Infectious Diseases, 21(6), 746–748. https://doi.org/10.1016/S1473-3099(21)00020-7
• Iyer, P., Ostrove, J. & Vacante, D. (1999). “Comparison of Manufacturing Techniques for Adenovirus Production.” Cytotechnology 30(1–3):169–72. doi: 10.1023/a:1008040221630.
• Jackson, N. A. C., Kester, K. E., Casimiro, D., Gurunathan, S., & Derosa, F. (2020). The promise of mRNA vaccines: a biotech and industrial perspective. Nature Partner Journals. https://doi.org/10.1038/s41541-020-0159-8
• Jeyanathan, M., Afkhami, S., Smaill, F., Miller, M. S., Lichty, B. D., & Xing, Z. (2020). Immunological considerations for COVID-19 vaccine strategies. Nature Reviews Immunology, 20(10), 615–632. https://doi.org/10.1038/S41577-020-00434-6
• Karandikar, S., Mirani, A., Waybhase, V., Patravale, V. B., & Patankar, S. (2017). Nanovaccines for oral delivery-formulation strategies and challenges. In Nanostructures for Oral Medicine (pp. 263–293). Elsevier. https://doi.org/10.1016/B978-0-323-47720-8.00011-0
• Kocagöz, S. (2017). Aşı Teknolojisi ve Aşı Tipleri.
• Kon, T. C., Onu, A., Berbecila, L., Lupulescu, E., Ghiorgisor, A., Kersten, G. F., ve diğerleri. (2016). Influenza vaccine manufacturing: Effect of inactivation, splitting and site of manufacturing. Comparison of influenza vaccine production processes. PLoS ONE, 11(3), 1–19. https://doi.org/10.1371/journal.pone.0150700
• Kowalzik, F., Schreiner, D., Jensen, C., Teschner, D., Gehring, S., & Zepp, F. (2021). mRNA-Based Vaccines. Vaccines, 9(390), 1–15.
• Kwon, H., Kim, M., Seo, Y., Moon, Y. S., Lee, H. J., Lee, K., & Lee, H. (2018). Emergence of synthetic mRNA: In vitro synthesis of mRNA and its applications in regenerative medicine. Biomaterials, 156, 172–193. https://doi.org/10.1016/j.biomaterials.2017.11.034
• Kyriakidis, N. C., López-Cortés, A., González, E. V., Grimaldos, A. B., & Prado, E. O. (2021). SARS-CoV-2 vaccines strategies: a comprehensive review of phase 3 candidates. Npj Vaccines 2021 6:1, 6(1), 1–17. https://doi.org/10.1038/s41541-021-00292-w
• Li, W., Joshi, M. D., Singhania, S., Ramsey, K. H., & Murthy, A. K. (2014). Peptide vaccine: Progress and challenges. Vaccines, Vol. 2, pp. 515–536. MDPI AG. https://doi.org/10.3390/vaccines2030515
• Liang, Z., Zhu, H., Wang, X., Jing, B., Li, Z., Xia, X., ve diğerleri. (2020). Adjuvants for Coronavirus Vaccines. Frontiers in Immunology, 11(November). https://doi.org/10.3389/fimmu.2020.589833
• Lusky, M. (2005). “Good Manufacturing Practices Production of Adenoviral Vectors for Clinical Trials.” Human Gene Therapy 291(March):281–91.
• Lodish, H., Berk, A., Zipursky, S.L., Matsudaira, P., Baltimore, D. & Darnell, J. (2010). Molecular Cell Biology. In Fourth Edition, W. H. Freeman.
• MacLachlan, J. N., & Dubovi, E. J. (2011). Fenner’s Veterinary Virology. In Fourth Edition, Elsevier.
• Marcelino, I., Vachiéry, N., Amaral, A. I., Roldão, A., Lefrançois, T., Carrondo, M. J. T. ve diğerleri. (2007). Effect of the purification process and the storage conditions on the efficacy of an inactivated vaccine against heartwater. Vaccine, 25(26), 4903–4913. https://doi.org/10.1016/j.vaccine.2007.04.055
• Moisa, A. A., & Kolesanova, E. F. (2010). Synthetic peptide vaccines. Biochemistry (Moscow) Supplement Series B: Biomedical Chemistry, 4(4), 321–332. https://doi.org/10.1134/S1990750810040025
• Montagnon, B. J., Fanget, B., & Vincent-Falquet, J. C. (1984). Industrial-scale production of inactivated poliovirus vaccine prepared by culture of Vero cells on microcarrier. Reviews of Infectious Diseases, 6 Suppl 2(June), 0–3. https://doi.org/10.1093/clinids/6.supplement_2.s341
• Nascimento, I. P., & Leite, L. C. C. (2012). Recombinant vaccines and the development of new vaccine strategies. Brazilian Journal of Medical and Biological Research, 45(12), 1102. https://doi.org/10.1590/S0100-879X2012007500142
• Ndwandwe, D., & Wiysonge, C. S. (2021). COVID-19 vaccines. Current Opinion in Immunology, 71(Figure 1), 111–116. https://doi.org/10.1016/j.coi.2021.07.003
• Nooraei, S., Bahrulolum, H., Hoseini, Z.S., ve diğerleri. (2021) Virus-like particles: preparation, immunogenicity and their roles as nanovaccines and drug nanocarriers. J Nanobiotechnology 19:59. https://doi.org/10.1186/s12951-021-00806-7
• Novavax Publishes Results of United Kingdom Phase 3 Clinical Trial in New England Journal of Medicine, Demonstrating High Levels of Efficacy of COVID-19 Vaccine - Jun 30, 2021. (2021). Erişim tarihi ve adresi: 9 Ağustos 2021, https://ir.novavax.com/2021-06-30-Novavax-Publishes-Results-of-United-Kingdom-Phase-3-Clinical-Trial-in-New-England-Journal-of-Medicine,-Demonstrating-High-Levels-of-Efficacy-of-COVID-19-Vaccine
• Okyay, P. (2020). “Covid-19 Aşı Çalışmaları.” Türk Tabi̇pleri Bi̇rli̇ği̇ Covi̇d-19 Pandemi̇si̇ Altıncı Ay Değerlendi̇rme Raporu, 228–52.
• Özcan, Ö. Ö., Karahan, M., Vijayaraj Kumar, P., Leng Tan, S., & Na Tee, Y. (2020). New Generation Peptide-Based Vaccine Prototype. In Prototyping Technology (pp. 1–20). https://doi.org/10.5772/intechopen.89115
• Pardi, N., Hogan, M. J., Porter, F. W., & Weissman, D. (2018). mRNA vaccines-a new era in vaccinology. Nature Reviews Drug Discovery, 17(4), 261–279. https://doi.org/10.1038/nrd.2017.243
• Pelit Arayıcı, P., Acar, T., Karahan, M., & Mustafaeva, Z. (2016). Review Paper / Derleme Makalesi A New Approach For Development Of Synthetıc Peptide Vaccınes For Vıral Infectıons. Sigma J Eng ve Nat Sci, 7(2), 193–204.
• Peters, J. (2020). What are the advantages of an mRNA vaccine for COVID-19? Massive Science. Erişim adresi: https://massivesci.com/articles/mrna-vaccine-covid19-coronavirus-moderna/
• Philippidis, A. (2020). The Cold Truth about COVID-19 Vaccines. Erişim adresi: https://www.genengnews.com/news/the-cold-truth-about-covid-19-vaccines/
• Pino, P., Kint, J., Kiseljak, D., Agnolon, V., Corradin, G., Kajava, A. V., ve diğerleri (2020). Trimeric SARS-CoV-2 Spike Proteins Produced from CHO Cells in Bioreactors Are High-Quality Antigens. Processes 2020, Vol. 8, Page 1539, 8(12), 1539. https://doi.org/10.3390/PR8121539
• Polack, F. P., Thomas, S. J., Kitchin, N., Absalon, J., Gurtman, A., Lockhart, S., ve diğerleri. (2020). Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. New England Journal of Medicine, 383(27), 2603–2615. https://doi.org/10.1056/nejmoa2034577
• Pollet, J., Chen, W. H., & Strych, U. (2021a). Recombinant protein vaccines, a proven approach against coronavirus pandemics. Advanced Drug Delivery Reviews, 170, 71. https://doi.org/10.1016/J.ADDR.2021.01.001
• Roldão, A., Mellado, M. C. M., Castilho, L. R., Carrondo, M. J., & Alves, P. M. (2010). Virus-like particles in vaccine development. Expert Review of Vaccines, 9(10), 1149–1176. https://doi.org/10.1586/erv.10.115
• Rowe, P.W., Ruebner, H. J., Gilmore, L. K., Parrott R.H., & Ward T. K. (1953). Isolation of a Cytopathogenic Agent from Human Adenoids Undergoing Spontaneous Degeneration in Tissue Culture. Proceedings of the Society for Experimental Biology and Medicine, 84(3):570-573. doi:10.3181/00379727-84-20714
• Sabbaghi, A., Miri, S. M., Keshavarz, M., Zargar, M., & Ghaemi, A. (2019). Inactivation methods for whole influenza vaccine production. Reviews in Medical Virology, 29(6), 1–11. https://doi.org/10.1002/rmv.2074
• Sapsford, K.E., Algar, W.R., Berti, L., ve diğerleri. (2013) Functionalizing Nanoparticles with Biological Molecules: Developing Chemistries that Facilitate Nanotechnology. Chem Rev 113:1904–2074. https://doi.org/10.1021/cr300143v SCB-2019 as COVID-19 Vaccine (NCT number): NCT04405908. (2021). 11 Ağustos 2021 tarihinde ClinicalTrials.gov’dan erişilmiştir. Erişim adresi: https://clinicaltrials.gov/ct2/show/NCT04405908
• Schoenmaker, L., Witzigmann, D., Kulkarni, J. A., Verbeke, R., Kersten, G., Jiskoot, W., & Crommelin, D. J. A. (2021). mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability. International Journal of Pharmaceutics, 601, 120586. https://doi.org/10.1016/j.ijpharm.2021.120586
• Sesardic, D. (1993). Synthetic peptide vaccines. Medical Microbiology, 39, 241–242.
• Singh, S., Kumar, R., & Agrawal, B. (2019). Chapter 4 Adenoviral Vector-Based Vaccines and Gene Therapies : Current Status and Future Prospects.
• Skwarczynski, M., & Toth, I. (2016). Peptide-based synthetic vaccines. Chemical Science, 7(2), 842–854. https://doi.org/10.1039/c5sc03892h
• Smith, M.T., Hawes, A.K., & Bundy, B.C. (2013) Reengineering viruses and virus-like particles through chemical functionalization strategies. Curr Opin Biotechnol 24:620–626. https://doi.org/10.1016/j.copbio.2013.01.011
• Soler, E., & Houdebine, L. M. (2007). Preparation of recombinant vaccines. Biotechnology Annual Review, 13, 65–94. https://doi.org/10.1016/S1387-2656(07)13004-0 SpyBiotech and Serum Institute of India announce that the first subjects have been dosed in a Phase I/II trial of a novel virus-like particle vaccine targeting COVID-19. (2020, September 8). Erişim adresi: https://www.spybiotech.com/news/-/ Status of COVID-19 Vaccines within WHO EUL/PQ. (2021).
• Stuible, M., Gervais, C., Lord-Dufour, S., Perret, S., L’Abbé, D., Schrag, J., ve diğerleri. (2021). Rapid, high-yield production of full-length SARS-CoV-2 spike ectodomain by transient gene expression in CHO cells. Journal of Biotechnology, 326, 21. https://doi.org/10.1016/J.JBIOTEC.2020.12.005
• Tagliamonte, M., Tornesello, M.L., Buonaguro, F. M., & Buonaguro, L. (2017) Virus-Like Particles. In: Micro and Nanotechnology in Vaccine Development. Elsevier, pp 205–219
• Tan, T.K., Rijal, P., Rahikainen, R., ve diğerleri. (2021) A COVID-19 vaccine candidate using SpyCatcher multimerization of the SARS-CoV-2 spike protein receptor-binding domain induces potent neutralising antibody responses. Nat Commun 12:542. https://doi.org/10.1038/s41467-020-20654-7
• Tanriover, M. D., Doğanay, H. L., Akova, M., Güner, H. R., Azap, A., Akhan, S., ve diğerleri (2021). Efficacy and safety of an inactivated whole-virion SARS-CoV-2 vaccine (CoronaVac): interim results of a double-blind, randomised, placebo-controlled, phase 3 trial in Turkey. The Lancet, 398(10296), 213–222. https://doi.org/10.1016/S0140-6736(21)01429-X
• Tatsis, N., & Ertl, H.C.J. (2004). “Adenoviruses as Vaccine Vectors.” Molecular Therapy 10(4):616–29. doi: 10.1016/j.ymthe.2004.07.013.
• Terkis, S., Pavel, I., Yetiskin, H., Aydin, G., Id, C. H., Uygut, M. A., ve diğerleri. (2020). Isolation and characterization of severe acute respiratory syndrome coronavirus 2 in Turkey. 1–17. https://doi.org/10.1371/journal.pone.0238614
• Thomassen, Y. E., van ’t Oever, A. G., Vinke, M., Spiekstra, A., Wijffels, R. H., van der Pol, L. A., & Bakker, W. A. M. (2013). Scale-down of the inactivated polio vaccine production process. Biotechnology and Bioengineering, 110(5), 1354–1365. https://doi.org/10.1002/bit.24798
• Thrane, S., Janitzek, C.M., Matondo, S., ve diğerleri. (2016). Bacterial superglue enables easy development of efficient virus-like particle based vaccines. J Nanobiotechnology 14:30. https://doi.org/10.1186/s12951-016-0181-1
• Tian, J.H., Patel, N., Haupt, R., ve diğerleri. (2021). SARS-CoV-2 spike glycoprotein vaccine candidate NVX-CoV2373 immunogenicity in baboons and protection in mice. Nat Commun 12: https://doi.org/10.1038/s41467-020-20653-8
• Topuzoğulları, M., Acar, T., Pelit Arayici, P., Uçar, B., Uğurel, E., Abamor, E. Ş., Arasoğlu, T., Turgut-Balik, D., & Derman, S. (2020). An insight into the epitope-based peptide vaccine design strategy and studies against COVID-19. Turkish journal of biology = Turk biyoloji dergisi, 44(3), 215–227. https://doi.org/10.3906/biy-2006-1
• Toriniwa, H., & Komiya, T. 2007. Japanese encephalitis virus production in Vero cells with serum-free medium using a novel oscillating bioreactor. 1–6. https://doi.org/10.1016/j.biologicals.2007.02.002
• Tsao, Y.S., Condon, R., Schaefer, E., Lio, P., & Liu, Z. (2001). “Development and Improvement of a Serum-Free Suspension Process for the Production of Recombinant Adenoviral Vectors Using HEK293 Cells.” Cytotechnology 37(3):189–98. doi: 10.1023/A:1020555310558.
• Turner, G. S., Squires, E. J., & Murray, H. G. S. 1970. Inactivated smallpox vaccine. A comparison of inactivation methods. Journal of Hygiene, 68(2), 197–210. https://doi.org/10.1017/S0022172400028679 van Riel, D., & de Wit, E. 2020. Next-generation vaccine platforms for COVID-19. Nature Materials (2020) 19:8, 19(8), 810–812. https://doi.org/10.1038/s41563-020-0746-0
• Vannucci, L., Lai, M., Chiuppesi, F., Ceccherini-Nelli, L., ve Pistello, M. (2013). Viral vectors: A look back and ahead on gene transfer technology. New Microbiologica, 36(1), 1–22.
• Vemula, S.V., & Mittal, S.K. 2010. “Production of Adenovirus Vectors and Their Use as a Delivery System for Influenza Vaccines.” Expert Opinion on Biological Therapy 10(10):1469–87. doi: 10.1517/14712598.2010.519332.
• Verdecia, M., Kokai-Kun, J. F., Kibbey, M., Acharya, S., Venema, J., ve Atouf, F. (2021). COVID-19 vaccine platforms: Delivering on a promise? Human Vaccines and Immunotherapeutics, 00(00), 1–21. https://doi.org/10.1080/21645515.2021.1911204
• Walls, A.C., Fiala, B., Schäfer, A. ve diğerleri. (2020) Elicitation of Potent Neutralizing Antibody Responses by Designed Protein Nanoparticle Vaccines for SARS-CoV-2. Cell 183:1367-1382.e17. https://doi.org/10.1016/j.cell.2020.10.043
• Wang, F., Kream, R. M., & Stefano, G. B. (2020). An evidence based perspective on mRNA-SARScov-2 vaccine development. Medical Science Monitor, 26, 1–8. https://doi.org/10.12659/MSM.924700
• Wang, J., Peng, Y., Xu, H., Cui, Z., & Williams, R. O. (2020). The COVID-19 Vaccine Race: Challenges and Opportunities in Vaccine Formulation. AAPS PharmSciTech, 21(6), 1–12. https://doi.org/10.1208/s12249-020-01744-7
• Wikipedia, (2021). EpiVacCorona Definition Wikipedia. Erişim adresi: https://en.wikipedia.org/wiki/EpiVacCorona
• Wolff, J. A., Malone, R. W., Williams, P., Chong, W., Acsadi, G., Jani, A., & Felgner, P. L. (1990). Direct Gene Transfer into Mouse Muscle in Vivo. Science, 247(4949), 1465–1468.
• World Health Organization. (1999). Guidelines for the production and quality control of synthetic peptide vaccines.
• Xıaojuan, C., Chen Yan, Hou Ye, Lan Qın, Sı Huanhuan ve Song Chunyu. (2020). Patent No. CN112552413A. Taizhou Baike Biological Tech Co Ltd. Erişim adresi: https://worldwide.espacenet.com/patent/search/family/075031652/publication/CN112552413A?q=ti all %22recombinant%22 AND ta all %22protein%22 AND ta all %22vaccine%22 AND ta all %22cov%22
• Yadav, T., Srivastava, N., Mishra, G., Dhama, K., Kumar, S., Puri, B., & Saxena, S. K. (2020). Recombinant vaccines for COVID-19. Human Vaccines ve Immunotherapeutics, 16(12), 1. https://doi.org/10.1080/21645515.2020.1820808
• Yang, S., Li, Y., Dai, L., Wang, J., He, P., Li, C.,ve diğerleri. (2021). Safety and immunogenicity of a recombinant tandem-repeat dimeric RBD-based protein subunit vaccine (ZF2001) against COVID-19 in adults: two randomised, double-blind, placebo-controlled, phase 1 and 2 trials. The Lancet. Infectious Diseases, 21(8), 1107. https://doi.org/10.1016/S1473-3099(21)00127-4
• Yilmaz, I. C., Ipekoglu, E., Bulbul, A., ve diğerleri. (2021). Development and Preclinical Evaluation of Virus Like Particle Vaccine Against COVID-19 Infection. Authorea. https://doi.org/10.22541/au.162615692.26217047/v2
• Zeng, C., Zhang, C., Walker, P. G., & Dong, Y. (2020). Formulation and Delivery Technologies for mRNA Vaccines. In Current Topics in Microbiology and Immunology (pp. 1–40). https://doi.org/10.1007/82_2020_217
• Zhang, C., Maruggi, G., Shan, H., & Li, J., (2019). Advances in mRNA Vaccines for Infectious Diseases. Frontiers in Immunology, 10(MAR), 1–13. https://doi.org/10.3389/fimmu.2019.00594
• Zhao, M., Vandersluis, M., Stout, J., Haupts, U., Sanders, M., & Jacquemart, R. (2019). Affinity chromatography for vaccines manufacturing: Finally ready for prime time? Vaccine, 37(36), 5491–5503. https://doi.org/10.1016/j.vaccine.2018.02.090
• Zhao, Q., Gao, Y., Xiao, M., Huang, X., & Wu, X. (2021). Synthesis and immunological evaluation of synthetic peptide based anti-SARS-CoV-2 vaccine candidates. Chem Commun (Camb),15;57 (12): 1474-1477. doi: 10.1039/d0cc08265a.
• Борисович, Р. А., Александрович, Р. Е., Поликарповна, Б. М., Васильевна, Г. Е., Дмитриевна, Д. Е., Рамисович, И. И., ve diğerleri (2021). Peptide immunogens and a vaccine composition against coronavirus infection covid-19 using peptide immunogens, RU2738081C1.