[Kl-Hup] Tổng Quan Về Công Nghệ Vắc Xin Mrna Và Các Công Nghệ Sản Xuất Vắc Xin Khác Tại Việt Nam.pdf

BỘ YTẾ TRƯỜNG ĐẠI HỌC DƯỢC HÀ NỘI NGUYỄN THỊ THÚY THE CURRENT STATUS OF IÌ1RNA AND OTHER VACCINES MANUFACTURING TECHNOLOGIES IN VIETNAM KHÓA LUẬN TỐT NGHIỆP DƯỢC sĩ HÀ NỘI 2022 BỘ YTẾ TRƯỜNG ĐẠI HỌC D[.]

BỘ YTẾ TRƯỜNG ĐẠI HỌC DƯỢC HÀ NỘI NGUYỄN THỊ THÚY THE CURRENT STATUS OF IÌ1RNA AND OTHER VACCINES MANUFACTURING TECHNOLOGIES IN VIETNAM KHÓA LUẬN TỐT NGHIỆP DƯỢC sĩ HÀ NỘI - 2022 BỘ YTẾ TRƯỜNG ĐẠI HỌC DƯỢC HÀ NỘI NGUYỄN THỊ THÚY MẢ SINH VIÊN: 1501484 THE CURRENT STATUS OF IÌ1RNA AND OTHER VACCINES MANUFACTURING TECHNOLOGIES IN VIETNAM KHÓA LUẬN TỐT NGHIỆP DƯỢC sĩ Người hướng dẫn: PGS.TS Đàm Thanh Xuân TS Nguyễn Khắc Tiệp Nơi thực hiện: Bộ môn Công nghiệp dược HÀ NỘI - 2022 ACKNOWLEDGEMENT Foremost, I would like to express my sincere gratitude and give my warmest thanks to my supervisors and Associate Professor Dr Dam Thanh Xuan and Dr Nguyen Khac Tiep who made this work possible Their guidance, support and advice carried me through all the stages of writing my project I could not have undertaken this journey without their help and patience I would also like to thank school committee and professors for teaching, helping and especially inspiring me to see the values that pharmacists can create and contribute to the society Thanks to all professors and lecturers with their dedication and support, my 5-year program at Hanoi University of Pharmacy cannot be more amazing and precious Finally, I would like to give special thanks to my family and friends as a whole for their continuous support and understanding Due to the limited time and shortage of my knowledge, the thesis may have shortages I sincerely hope to have your feedback on my thesis to make it better Best regards, Hanoi, June 2022 Student Nguyen Thi Thuy TABLE OF CONTENTS ACKNOWLEDGEMENT TABLE OF CONTENTS LIST OF ABBREVIATIONS LIST OF TABLES LIST OF FIGURES ABSTRACT CHAPTER VACCINE DEFINITION AND CLASSIFICATION 1.1 Definition 1.2 Classification CHAPTER VACCINE MANUFACTURING TECHNOLOGY OVERVIEW IN VIETNAM 2.1 Live attenuated vaccine (LAV) technology 2.1.1 Overview 2.1.2 POLYVAC’s technology 2.1.2.1 Rotavirus vaccine (vaccine trade name: Rotavin-M 1) .6 2.1.2.2 Measles vaccine vaccine trade name: MVVAC) 2.1.2.3 Measles-rubella vaccine (vaccine trade name: MRVAC) 2.1.2.4 Polio vaccine (vaccine trade name: bOPV) 2.1.3 IVAC’s technology 2.2 Inactivated vaccine technology 2.2.1 Overview 2.2.2 VABIOTECH’s technology 2.2.2.1 Cholera vaccine (vaccine trade name: mORCVAX) 2.2.2.2 Japanese encephalitis vaccine (vaccine trade name: Jevax®) 2.2.2.3 Hepatitis A vaccine (vaccine trade name: Havax®) 10 2.2.3 IVAC’s technology 2.3 Toxoid vaccine technology 10 2.3.1 Overview 10 2.3.2 IVAC’s technology 11 2.4 Subunit vaccine technology 11 2.4.1 Overview 11 2.4.2 VABIOTECH’s technology 12 2.4.3 DAVAC’S technology T 12 2.4.4 Nanogen’s technology 12 CHAPTER mRNA TECHNOLOGY AND CURRENT STATUS OF mRNA TECHNOLOGY IN VACCINE MANUFACTURING IN VIETNAM 14 3.1 Overview 14 3.1.1 History of mRNA vaccine 14 3.1.2 Applications of mRNA vaccine 17 3.1.3 Advantages and disadvantages of mRNA vaccine 18 3.1.4 mRNA vaccine classification 18 3.1.5 Mechanism of immune response induced by mRNA vaccines 20 3.1.6 mRNA vaccine technology 21 3.1.6.1 Engineered mRNA 21 3.6.1.2 The manufacturing process 23 3.1.6.3 Purification 25 3.1.6.4 Conventional and self-amplifying mRNA design 25 3.1.6.5 Lipid nanoparticles (LNP) technology 26 3.1.7 COVID-19 and mRNA COVID-19 vaccine 29 3.2 mRNA technology in COVID-19 vaccine manufacturing in Vietnam 31 3.2.1 Technology 31 3.2.1.1 STARRTM mRNA technology 31 3.2.1.2 LUNAR® delivery system 32 3.2.2 Advantages and Disadvantages of ARCT-154 34 3.2.3 Clinical Trials 34 3.2.3.1 Phase I (2 trials in total and one of them was executed in Vietnam) 35 3.2.3.2 Phase II (2 trials in total and one of them was executed in Vietnam) 35 3.2.3.3 Phase III (1 trial in total and it is being executed in Vietnam) 35 3.2.3.4 Outcome measures 36 CHAPTER mRNA VACCINE IN THE FUTURE 38 CONCLUSION AND RECOMMENDATION 40 REFERENCES LIST OF ABBREVIATIONS Abbreviation Meaning APC Antigen-presenting cell ATX BCG Arcturus Bacille Calmette-Guérin CCID50 Cell culture infectious dose 50 CD4, Cluster of differentiation 4, CDC Centers for Disease Control and Prevention CDS Coding sequence CHO Chinese hamster ovary CIGB Center for Genetic Engineering and Biotechnology COVID-19 Coronavirus disease of 2019 CQA Critical quality attribute CTL Cytoxic T lymphocyte DAVAC Vaccine Company Limited of Dalat Pasteur DC Dendritic cell DMEM Dulbecco’s Modified Eagle’s DNA Deoxyribonucleic Acid DOPE Dioleoylphosphatidylethanolamine DOTAP 1,2-dioleoyloxy-3 -trimethylammoniumpropane DPT Diptheria, tetanus toxoids and pertussis dsRNA Double-stranded RNA EPO Erythropoetin E.Ư.LPS Endotoxin Units lipopolysaccharide FDA Food and Drug Administration FFU Fluorecent Focus-Forming Unit FPLC Fast protein liquid chromatography HbsAg Hepatitis B surface antigen HIV Human immunodeficiency virus HPLC High-performance liquid chromatography HPV Human papillomavirus GAVI Global Alliance for Vaccines and Immunization GFP Green fluorescent protein GMP Good Manufacturing Practice IFN Interferon IFIT1 IFN-induced proteins with tetratricopeptide repeats IPV Inactivated polio vaccine IVAC Institute of Vaccines and Medical Biologicals IVT In vitro transcribed LAV Live attenuated vaccine LNP Lipid nanoparticle MDA5 Melanoma differentiation-associated gene MERS-CoV Middle East Respiratory Syndrome MMR Measles, mumps and rubella mRNA Messenger RNA MSV Master seed virus MS Master seed NOD2 Nucleotide Binding Oligomerization Domain Containing NRM Non-replicating Mma ORF Open-reading frame pDNA Plasmid DNA PEG Polyethylene glycol PEI Polyethylenimine PFU Plaque-forming unit pKa The acid dissociation constant PKR Protein kinase R Pmkc Primary monkey kidney cells POLYVAC Center for Research and Production of Vaccines and Biologicals RIG-I Retinoic acid-inducible gene I RNA Ribonucleic acid RT-PCR Real time - polymerase chain reaction SAM Self-amplifying Mrna SARS-CoV-2 Severe Acute Respiratory Syndrome SARS-CoV Severe Acute Respiratory Syndrome siRNA Small interfering RNA SPF Specific Pathogen Free ssRNA Single-stranded RNA TAA Tumor-associated antigen TFH T follicular helper TLR Toll-like receptor TNF Tumor Necrosis Facto TSA Tumor-specific antigen USA United States of America ƯTR Untranslated region ưv Ultra-Violet VABIOTECH Vaccine and Biological Production Company No WSV Working seed virus ws Working seed LIST OF TABLES Table 2.1 Six Vietnam Vaccine Manufacturers Table 2.2 Six Vietnam Vaccine Manufacturers and their Products Table 3.1 Primary outcome measures 36 LIST OF FIGURES Figure 3.1 Development timeline of mRNA vaccine [38], [44], [45] 16 Figure 3.2 Two categories of mRNA constructs from designing stage to antigen expressing stage [54] 19 Figure 3.3 How mRNA vaccines elicit immunity [59] 21 Figure 3.4 Five critical quality attributes (CQAs) dictating the performance of mRNA construct to express the gene of interest efficiently [54] 22 Figure 3.5 In vitro transcription reaction component [80] 23 Figure 3.6 mRNA caps [81] .24 Figure 3.7 Conventional (A) and self-amplifying mRNA (B) vaccine designs [115].26 Figure 3.8 Major LNP and polymer delivery methods for mRNA vaccines 27 Figure 3.9 COVID-19 mRNA vaccine manufacturing process [133] 30 Figure 3.10 Arcturus’s COVID-19 vaccine technology 31 against cholera,” Clin Infect Dis., vol 52, no 11, pp 1343-1349, 2011, doi: 10.1093/cid/cirl41 [22] “JEVAX,” 2019 https://www.vabiotech.com.vn/jevax/?lang=en [23] “Inactivated Japanese Encephalitis Virus Vaccine Recommendations of the Advisory Committee on Immunization Practices (ACIP),” 1993 https://www.cdc gov/mmwr/preview/mmwrhtml/00020599.htm#:~:text=The Biken vaccine is prepared,filtration%2C and ammonium sulfate precipitation [24] “Havax,” 2022 https://www.vabiotech.com.vn/havax/?lang=en [25] “Toxoid,” 2022 https://www.sciencedirect.com/topics/medicine-anddentistry/toxoid [26] WHO, “Tetanus.” https://www.who.int/teams/health-product-policy-andstandards/standards-and-specifications/vaccinestandardization/tetanus#:~:text=Tetanus vaccines&text=tetani are grown in liquid,and administered by intramuscular injection [27] “Method for the preparation of diphtheria toxoid vaccine.” https://patents.google.com/patent/KR20060121507A/en [28] WHO, “Subunit vaccines.” https://web.archive.org/web/20210808211206/https://vaccine-safetytraining.org/subunit-vaccines.html [29] “Subunit vaccines,” 2022 https://www.sciencedirect.com/topics/medicine-anddentistry/subunit-vaccine [30] “Gene-HBvax,” 2019 https://www.vabiotech.com.vn/r-hbvax/?lang=en [31 ] “Process for producing hepatitis b vaccine.” https://patents.google.com/patent/WO 1981000050A 1/en [32] “Vắc xin từ Đà Lạt,” 2021 http://baolamdong.vn/xahoi/202102/vac-xin-tu-da- lat-3043766/ [33] T T Ư Thi Nhu Mai Tran, Bruce Pearson May, “Preclinical Immune Response and Safety Evaluation of the Protein Subunit Vaccine Nanocovax for COVID- 19,” Front Immunol., 2021, [Online] Available: https://www.frontiersin.org/articles/10.3389/fimmu.2021.766112/full [34] Nanogen, “NanoCovax.” https://nanogenpharma.com/products/nanocovax141.html [35] “FDA Approves First COVID-19 Vaccine,” https://www.fda.gov, 2021 https://www.fda.gov/news-events/press-announcements/fda-approves-firstcovid-19-vaccmc#:~:text=Thc first EUA%2C issued Dec,trial of thousands of individuals [36] c Beyrer, “The Long History of mRNA Vaccines,”publichealth.jhu.edu, 2021 https://publichealth.jhu.edu/2021/the-long-history-of-mrna-vaccines [37] M Cobb, “Who discovered messenger RNA?,” Curr Biol., vol 25, no 13, pp R526-R532, 2015, doi: 10.1016/j.cub.2015.05.032 [38] E Dolgin, “The tangled history of mRNA vaccines,” Nature, vol 597, no 7876, pp 318-324, 2021, doi: 10.1038/d41586-021-02483-w [39] V J Dwarki, R w Malone, and I M Verma, “Cationic Liposome-Mediated RNA Transfection,” Methods Enzymol., vol 217, no c, pp 644-654, 1993, doi: 10.1016/0076-6879(93)17093-K [40] D A Krieg, p A & Melton, “Functional messenger RNAs are produced by SP6 in vitro transcription of cloned cDNAs,” Methods, vol 12, no 21, pp 8235- 8251, 1980 [41] D A et al Melton, “Efficient in vitro synthesis of biologically active RNA and RNA hybridization probes from plasmids containing a bacteriophage SP6 promoter,” Methods, vol 12, no 21, pp 8235-8251, 1980 [42] J o N A Wolff et al., “DNA (pRSVL) constructs containing the firefly luciferase reporter gene (Fig 3A) The injection often times more DNA result,” Science (80-.)., vol 247, no 4949, pp 1465-1468, 1990 [43] F Martinon et al., “Induction of virus-specific cytotoxic T lymphocytes in vivo by liposome-entrapped mRNA,” Eur J Immunol., vol 23, no 7, pp 1719-1722, 1993, doi: 10.1002/eji 1830230749 [44] Ư Sahin, K Karikó, and Ồ Tureci, “MRNA-based therapeutics-developing a new class of drugs,” Nat Rev Drug Discov., vol 13, no 10, pp 759-780, 2014, doi: 10.1038/nrd4278 [45] X Hou, T Zaks, R Langer, and Y Dong, “Lipid nanoparticles for mRNA delivery,” Nat Rev Mater., vol 6, no 12, pp 1078-1094, 2021, doi: 10.1038/S41578-021-00358-0 [46] p G Coulie, B J Van Den Eynde, p Van Der Bruggen, and T Boon, “Tumour antigens recognized by T lymphocytes: At the core of cancer immunotherapy,” Ato Rev Cancer, vol 14, no 2, pp 135-146, 2014, doi: 10.1038/nrc3670 [47] L Miao, Y Zhang, and L Huang, “mRNA vaccine for cancer immunotherapy,” Mol Cancer, vol 20, no l,pp 1-23, 2021, doi: 10.1186/sl2943-021-01335-5 [48] K Fiedler, s Lazzaro, J Lutz, s Rauch, and R Heidenreich, “mRNA cancer vaccines,” Recent Results Cancer Res., vol 209, pp 61-85, 2016, doi: 10.1007/978-3-319-42934-2-5 [49] E Faghfuri, F Pourfarzi, A H Faghfouri, M Abdoli Shadbad, K Hajiasgharzadeh, and B Baradaran, “Recent developments of RNA-based vaccines in cancer immunotherapy,” Expert Opin Biol Ther., vol 21, no 2, pp 201-218, 2021, doi: 10.1080/14712598.2020.1815704 [50] N Pardi et al., “Administration of nucleoside-modified mRNA encoding broadly neutralizing antibody protects humanized mice from HIV-1 challenge,” Nat Commun., vol 8, pp 6-13, 2017, doi: 10.1038/ncomms 14630 [51] c Zhang, G Maruggi, H Shan, and J Li, “Advances in mRNA vaccines for infectious diseases,” Front Immunol., vol 10, no MAR, pp 1-13, 2019, doi: 10.3389/fimmu.2019.00594 [52] M z Salleh, M N Norazmi, and z z Deris, “Immunogenicity mechanism of mRNA vaccines and their limitations in promoting adaptive protection against SARS-CoV-2.,” PeerJ, vol 10, p el3083, 2022, doi: 10.7717/peerj 13083 [53] A B Vogel et al., “Self-Amplifying RNA Vaccines Give Equivalent Protection against Influenza to mRNA Vaccines but at Much Lower Doses,” Mol Ther., vol 26, no 2, pp 446-455, 2018, doi: 10.1016/j.ymthe.2017.11.017 [54] N A c Jackson, K E Kester, D Casimiro, s Gurunathan, and F DeRosa, “The promise of mRNA vaccines: a biotech and industrial perspective,” npj Vaccines, vol 5, no 1, pp 3-8, 2020, doi: 10.1038/s41541-020-0159-8 [55] D Goubau et al., “Antiviral immunity via RIG-I-mediated recognition of RNA bearing 59-diphosphates,” Nature, vol 514, no 7522, pp 372-375, 2014, doi: 10.103 8/nature 13590 [56] L Alexopoulou, A c Holt, R Medzhitov, and R A Flavell, “Recognition of double-stranded RNA and activation of NF-kB by Toll-like receptor 3,” Nature, vol 413, no 6857, pp 732-738, 2001, doi: 10.1038/35099560 [57] T Kawai and s Akira, “Signaling to NF-kB by Toll-like receptors,” Trends Mol Med., vol 13, no 11, pp 460-469, 2007, doi: 10.1016/j.molmed.2007.09.002 [58] N Pardi, M J Hogan, F w Porter, and D Weissman, “mRNA vaccines-a new era in vaccinology,” Nat Rev Drug Discov., vol 17, no 4, pp 261-279, 2018, doi: 10.1038/nrd.2017.243 [59] J R Teijaro and D L Farber, “COVID-19 vaccines: modes of immune activation and future challenges,” Nat Rev Immunol., vol 21, no 4, pp 195- 197, 2021, doi: 10.1038/s41577-021-00526-x [60] “VinFuture foundation officially launches the call for 2022,” bloomberg.com, 2022 https://www.bloomberg.com/press-releases/2022-02-17/vinfuturefoundation-officially-launches-the-call-for-2022 [61] w F Cheng et al., “Enhancement of sindbis virus self-replicating RNA vaccine potency by targeting antigen to endosomal/lysosomal compartments,” Hum Gene Ther., vol 12, no 3, pp 235-252, 2001, doi: 10.1089/10430340150218387 [62] K Ljungberg and p Liljestrom, “Self-replicating alphavirus RNA vaccines,” Expert Rev Vaccines, vol 14, no 2, pp 177-194, 2014, doi: 10.1586/14760584.2015.965690 [63] J F Milligan, D R Groebe, G w Whherell, and o c Uhlenbeck, “Nucleic Acids Research © IR L Pnss Limited , Oxford , England Nucleic Acids Research,” Nucleic Acids Res., vol 15, no 21, pp 8783-8798, 1987 [64] K H N F J Triana-Alonso 1, M Dabrowski, J Wadzack, “Self-coded 3’extension of run-off transcripts produces aberrant products during in vitro transcription with T7 RNA polymerase,” Nucleic Acids Res., vol 15, no 11, pp 6298-6307, 1995, doi: 10.1074/jbc.270.11.6298 [65] K Karikó, H Muramatsu, J Ludwig, and D Weissman, “Generating the optimal mRNA for therapy: HPLC purification eliminates immune activation and improves translation of nucleoside-modified, protein-encoding mRNA,” Nucleic Acids Res., vol 39, no 21, pp 1-10, 2011, doi: 10.1093/nar/gkr695 [66] R L Tanguay and D R Gallie, “Translational efficiency is regulated by the length of the 3’ untranslated region,” Mol Cell Biol., vol 16, no 1, pp 146— 156, 1996, doi: 10.1128/mcb 16.1.146 [67] K Leppek, R Das, and M Barna, “Functional 5' UTR mRNA structures in eukaryotic translation regulation and how to find them,” Nat Rev Mol Cell Biol., vol 19, no 3, pp 158-174, 2018, doi: 10.1038/nrm.2017.103 [68] c Lăssig and K p Hopfner, “Discrimination of cytosolic self and non-self RNA by RIG-I-like receptors,” J Biol Chem., vol 292, no 22, pp 9000-9009, 2017, doi: 10.1074/jbc.Rl 17.788398 [69] X xiao Xu, H Wan, L Nie, T Shao, L xin Xiang, and J zhong Shao, “RIG-I: a multifunctional protein beyond a pattern recognition receptor,” Protein Cell, vol 9, no 3, pp 246-253, 2018, doi: 10.1007/s 13238-017-0431 -5 [70] s c Devarkar et al., “Structural basis for m7G recognition and 2'-O-methyl discrimination in capped RNAs by the innate immune receptor RIG-I,” Proc Natl Acad Sci Ư s A., vol 113, no 3, pp 596-601, 2016, doi: 10.1073/pnas.1515152113 [71] M Habjan et al., “Sequestration by IFIT1 Impairs Translation of 2'0unmethylated Capped RNA,” PLoSPathog., vol 9, no 10, 2013, doi: 10.1371/journal.ppat 1003663 [72] R Ziist et al., “Ribose 2’-O-methylation provides a molecular signature for the distinction of self and non-self mRNA dependent on the RNA sensor Mda5,” Nat Immunol., vol 12, no 2, pp 137-143, 2011, doi: 10.1038/ni 1979 [73] s A Lima et al., “Short poly(A) tails are a conserved feature of highly expressed genes,” Nat Struct Mol Biol., vol 24, no 12, pp 1057-1063, 2017, doi: 10.1038/nsmb.3499 [74] A c Goldstrohm and M Wickens, “Multifunctional deadenylase complexes diversify mRNA control,” Nat Rev Mol Cell Biol., vol 9, no 4, pp 337-344, 2008, doi: 10.1038/nrm2370 [75] G Kudla, L Lipinski, F Caffin, A Helwak, and M Zylicz, “High guanine and cytosine content increases mRNA levels in mammalian cells,” PLoS Biol., vol 4, no 6, pp 0933-0942, 2006, doi: 10.1371/joumal.pbio.0040180 [76] N Pardi et al., “Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses,” J Exp Med., vol 215, no 6, pp 1571-1588, 2018, doi: 10.1084/jem.20171450 [77] o Andries, s Me Cafferty, s c De Smedt, R Weiss, N N Sanders, and T Kitada, “Nl-methylpseudouridine-incorporated mRNA outperforms pseudouridine-incorporated mRNA by providing enhanced protein expression and reduced immunogenicity in mammalian cell lines and mice,” J Control Release, vol 217, pp 337-344, 2015, doi: 10.1016/j.jconrel.2015.08.051 [78] B R Anderson et al., “Incorporation of pseudouridine into mRNA enhances translation by diminishing PKR activation,” Nucleic Acids Res., vol 38, no 17, pp 5884-5892, 2010, doi: 10.1093/nar/gkq347 [79] M Rong, H Biao, w T Mcallister, and R K Durbin, “Promoter specificity determinants of T7 RNA polymerase,” Proc Natl Acad Sci u s A., vol 95, no 2, pp 515-519, 1998, doi: 10.1073/pnas.95.2.515 [80] K D Nance and J L Meier, “Modifications in an Emergency: The Role ofNlMethylpseudouridine in COVID-19 Vaccines,” ACS Cent Sci., vol 7, no 5, pp 748-756, 2021, doi: 10.1021/acscentsci.lc00197 [81] A Ramanathan, G B Robb, and s H Chan, “mRNA capping: Biological functions and applications,” Nucleic Acids Res., vol 44, no 16, pp 7511-7526, 2016, doi: 10.1093/nar/gkw551 [82] s Daffis et al., “2'-0 methylation of the viral mRNA cap evades host restriction by IFIT family members,” Nature, vol 468, no 7322, pp 452-456, 2010, doi: 10.1038/nature09489 [83] and J w Aimee L Jalkanen, Stephen J Coleman, “Determinants and Implications of mRNA Poly(A) Tail Size - Does this,” Semin Cell Dev Biol., vol 0, no 1, pp 24-32, 2014, doi: 10.1016/j.semcdb.2014.05.018.Determinants [84] A o Subtelny, s w Eichhorn, G R Chen, H Sive, and D p Bartel, “Poly(A)-tail profiling reveals an embryonic switch in translational control,” Nature, vol 508, no l,pp 66-71,2014, doi: 10.1038/nature 13007 [85] s M Bresson and N K Conrad, “The Human Nuclear Poly(A)-Binding Protein Promotes RNA Hyperadenylation and Decay,” PLoS Genet., vol 9, no 10, 2013, doi: 10.1371/journal.pgen 1003893 [86] c Y A Chen and A Bin Shyu, “Mechanisms of deadenylation-dependent decay,” Wiley Interdiscip Rev RNA, vol 2, no 2, pp 167-183, 2011, doi: 10.1002/wrna.40 [87] N B Y Tsui, E K o Ng, and Y M D Lo, “Stability of endogenous and added RNA in blood specimens, serum, and plasma,” c/ờỉ Chem., vol 48, no 10, pp 1647-1653,2002, doi: 10.1093/clinchem/48.10.1647 [88] J Houseley and D Tollervey, “The Many Pathways of RNA Degradation,” Cell, vol 136, no 4, pp 763-776, 2009, doi: 10.1016/j.cell.2009.01.019 [89] p s Kowalski, A Rudra, L Miao, and D G Anderson, “Delivering the Messenger: Advances in Technologies for Therapeutic mRNA Delivery,” Mol Then., vol 27, no 4, pp 710-728, 2019, doi: 10.1016/j.ymthe.2019.02.012 [90] M G Stanton, “Current Status of Messenger RNA Delivery Systems,” Nucleic Acid Then, vol 28, no 3, pp 158-165, 2018, doi: 10.1089/nat.2018.0726 [91] p Midoux and c Pichon, “Lipid-based mRNA vaccine delivery systems,” Expert Rev Vaccines, vol 14, no 2, pp 221-234, 2014, doi: 10.1586/14760584.2015.986104 [92] F DeRosa et al., “Improved Efficacy in a Fabry Disease Model Using a Systemic mRNA Liver Depot System as Compared to Enzyme Replacement Therapy,” Mol Then., vol 27, no 4, pp 878-889, 2019, doi: 10.1016/j.ymthe.2019.03.001 [93] F DeRosa et al., “Therapeutic efficacy in a hemophilia B model using a biosynthetic mRNA liver depot system,” Gene Ther., vol 23, no 10, pp 699707, 2016, doi: 10.1038/gt.2016.46 [94] D An et al., “Systemic Messenger RNA Therapy as a Treatment for Methylmalonic Acidemia,” Cell Rep., vol 21, no 12, pp 3548-3558, 2017, doi: 10.1016/j.celrep.2017.11.081 [95] K H Asrani, L Cheng, c J Cheng, and R R Subramanian, “Arginase I mRNA therapy-a novel approach to rescue arginase enzyme deficiency,” RNA Biol., vol 15, no 7, pp 914-922, 2018, doi: 10.1080/15476286.2018.1475178 [96] K J Kallen et al., “A novel, disruptive vaccination technology: Self-adjuvanted RNActive ® vaccines,” Hum Vaccines Immunother., vol 9, no 10, pp 2263- 2276, 2013, doi: 10.4161 /hv.25181 [97] B Weide et al., “Results of the first phase I/II clinical vaccination trial with direct injection of mRNA,” J Immunother., vol 31, no 2, pp 180-188, 2008, doi: 10.1097/CJI.0b013e31815ce501 [98] B Petsch et al., “Protective efficacy of in vitro synthesized, specific mRNA vaccines against influenza A virus infection,” Nat Biotechnol., vol 30, no 12, pp 1210-1216, 2012, doi: 10.1038/nbt.2436 [99] s Sabnis et al., “A Novel Amino Lipid Series for mRNA Delivery: Improved Endosomal Escape and Sustained Pharmacology and Safety in Non-human Primates,” Mol Ther., vol 26, no 6, pp 1509-1519, 2018, doi: 10.1016/j.ymthe.2018.03.010 [100] N Pardi et al., “Zika virus protection by a single low-dose nucleoside-modified mRNA vaccination,” Nature, vol 543, no 7644, pp 248-251, 2017, doi: 10.1038/nature21428 [101] A G Orlandini von Niessen et al., “Improving mRNA-Based Therapeutic Gene Delivery by Expression-Augmenting 3' UTRs Identified by Cellular Library Screening,” Mol Ther., vol 27, no 4, pp 824-836, 2019, doi: 10.1016/j.ymthe.2018.12.011 [102] L Wasungu and D Hoekstra, “Cationic lipids, lipoplexes and intracellular delivery of genes,” J Control Release, vol 116, no SPEC ISS., pp 255-264, 2006, doi: 10.1016/j.jconrel.2006.06.024 [103] K w c Mok and p R Cullis, “Structural and fusogenic properties of cationic liposomes in the presence of plasmid DNA,” Biophys J., vol 73, no 5, pp 2534-2545, 1997, doi: 10.1016/S0006-3495(97)78282-l [104] K J Kauffman et al., “Optimization of Lipid Nanoparticle Formulations for mRNA Delivery in Vivo with Fractional Factorial and Definitive Screening Designs,” Nano Lett., vol 15, no 11, pp 7300-7306, 2015, doi: 10.1021 /acs.nanolett.5b02497 [105] o s Fenton et al., “Bioinspired Alkenyl Amino Alcohol Ionizable Lipid Materials for Highly Potent in Vivo mRNA Delivery,” Adv Mater., vol 28, no 15, pp 2939-2943, 2016, doi: 10.1002/adma.201505822 [106] A M Rydzik et al., “MRNA cap analogues substituted in the tetraphosphate chain with CX2: Identification of O-to-CC12 as the first bridging modification that confers resistance to decapping without impairing translation,” Nucleic Acids Res., vol 45, no 15, pp 8661-8675, 2017, doi: 10.1093/nar/gkx569 [107] E Grudzien, J Stepinski, M Jankowska-Anyszka, R Stolarski, E Darzynkiewicz, and R E Rhoads, “Novel cap analogs for in vitro synthesis of mRNAs with high translational efficiency,” Rna, vol 10, no 9, pp 1479-1487, 2004, doi: 10.1261/rna.7380904 [108] E Grudzien-Nogalska, J Jemielity, J Kowalska, E Darzynkiewicz, and R E Rhoads, “Phosphorothioate cap analogs stabilize mRNA and increase translational efficiency in mammalian cells,” Rna, vol 13, no 10, pp 17451755, 2007, doi: 10.1261/ma.701307 [109] A R Kore, M Shanmugasundaram, I Charles, A V Vlassov, and T J Barta, “Locked nucleic acid (LNA)-Modified dinucleotide mRNA cap analogue: Synthesis, enzymatic incorporation, and utilization,” J Am Chem Soc., vol 131, no 18, pp 6364-6365, 2009, doi: 10.1021/ja901655p [110] V Presnyak et al., “Codon optimality is a major determinant of mRNA stability,” Cell,vol 160, no 6, pp 1111-1124, 2015, doi: 10.1016/j.cell.2O15.02.029 [111] J Lutz et al., “Unmodified mRNA in LNPs constitutes a competitive technology for prophylactic vaccines,” npj Vaccines, vol 2, no 1, pp 1-9, 2017, doi: 10.1038/s41541-017-0032-6 [112] A Thess et al., “Sequence-engineered mRNA Without Chemical Nucleoside Modifications Enables an Effective Protein Therapy in Large Animals,” Mol Then, vol 23, no 9, pp 1456-1464, 2015, doi: 10.1038/mt.2015.103 [113] K J Kauffman et al., “Efficacy and immunogenicity of unmodified and pseudouridine-modified mRNA delivered systemically with lipid nanoparticles in vivo,” Biomaterials, vol 109, pp 78-87, 2016, doi: 10.1016/j biomaterials.2016.09.006 [114] V Potapov, X Fu, N Dai, I R Corrêa, N A Tanner, and J L Ong, “Base modifications affecting RNA polymerase and reverse transcriptase fidelity,” Nucleic Acids Res., vol 46, no 11, pp 5753-5763, 2018, doi: 10.1093/nar/gky341 [115] K Bloom, F van den Berg, and p Arbuthnot, “Self-amplifying RNA vaccines for infectious diseases,” Gene Ther., vol 28, no 3-4, pp 117-129, 2021, doi: 10.103 8/s41434-020-00204-y [116] A M Reichmuth, M A Oberli, A Jeklenec, R Langer, and D Blankschtein, “mRNA vaccine delivery using lipid nanoparticles,” Ther Deliv., vol 7, no 5, pp 319-334, 2016, doi: 10.4155/tde-2016-0006 [117] s Guan and J Rosenecker, “Nanotechnologies in delivery of mRNA therapeutics using nonviral vector-based delivery systems,” Gene Then, vol 24, no 3, pp 133-143, 2017, doi: 10.1038/gt.2017.5 [118] K J Kauffman, M J Webber, and D G Anderson, “Materials for non-viral intracellular delivery of messenger RNA therapeutics,” J Control Release, vol 240, pp 227-234, 2016, doi: 10.1016/j.jconrel.2015.12.032 [119] w M Bogers et al., “Potent immune responses in rhesus macaques induced by nonviral delivery of a self-amplifying RNA vaccine expressing HIV type envelope with a cationic nanoemulsion,” J Infect Dis., vol 211, no 6, pp 947955, 2015, doi: 10.1093/infdis/jiu522 [120] L A Brito et al., “A cationic nanoemulsion for the delivery of next-generation RNA vaccines,” Mol Ther., vol 22, no 12, pp 2118-2129, 2014, doi: 10.1038/mt.2014.133 [121] H Lv, s Zhang, B Wang, s Cui, and J Yan, “Toxicity of cationic lipids and cationic polymers in gene delivery,” J Control Release, vol 114, no 1, pp 100-109, 2006, doi: 10.1016/j.jconrel.2006.04.014 [122] c Pollard et al., “Type i IFN counteracts the induction of antigen-specific immune responses by lipid-based delivery of mRNA vaccines,” Mol Ther., vol 21, no 1, pp 251-259, 2013, doi: 10.1038/mt.2012.202 [123] M Zhao, M Li, z Zhang, T Gong, and X Sun, “Induction of HIV-1 gag specific immune responses by cationic micelles mediated delivery of gag mRNA,” Drug Deliv., vol 23, no 7, pp 2596-2607, 2016, doi: 10.3109/10717544.2015.1038856 [124] M Li et al., “Enhanced intranasal delivery of mRNA vaccine by overcoming the nasal epithelial barrier via intra- A nd paracellular pathways,” J Control Release, vol 228, pp 9-19, 2016, doi: 10.1016/j.jconrel.2016.02.043 [125] L M Kranz et al., “Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy,” Nature, vol 534, no 7607, pp 396-401, 2016, doi: 10.1038/nature 18300 [126] K Bahl et al., “Preclinical and Clinical Demonstration of Immunogenicity by mRNA Vaccines against H10N8 and H7N9 Influenza Viruses,” Mol Ther., vol 25, no 6, pp 1316-1327, 2017, doi: 10.1016/j.ymthe.2017.03.035 [127] J M Scott et al., “Cellular and Humoral Immunity Protect against Vaginal Zika Virus Infection in Mice,” J Virol., vol 92, no 7, pp 1-47, 2018, doi: 10.1128/jvi.00038-18 [128] J M Richner et al., “Modified mRNA Vaccines Protect against Zika Virus Infection,” Cell, vol 168, no 6, pp 1114-1125.el 0, 2017, doi: 10.1016/j.cell.2017.02.017 [129] M Meyer, E Huang, o Yuzhakov, p Ramanathan, G Ciaramella, and A Bukreyev, “Modified mRNA-Based Vaccines Elicit Robust Immune Responses and Protect Guinea Pigs from Ebola Virus Disease,” J Infect Dis., vol 217, no 3, pp 451-455, 2018, doi: 10.1093/infdis/jix592 [130] “Coronavirus disease (COVID-19) pandemic,” euro.who.int, 2022 https://www.euro.who.int/en/health-topics/health-emergencies/coronaviruscovid-19/novel-coronavirus-2019-ncov [131] K s Corbett et al., “SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness,” Nature, vol 586, no 7830, pp 567-571, 2020, doi: 10.1038/s41586-020-2622-0 [132] “COVID-19 vaccines approved,” covid19.trackvaccines.or, 2022 https://covidl9.trackvaccines.Org/vaccines/approved/#vaccine-list [133] N Chaudhary, D Weissman, and K A Whitehead, “mRNA vaccines for infectious diseases: principles, delivery and clinical translation,” Nat Rev Drug Discov., nq\ 20, no 11, pp 817-838, 2021, doi: 10.1038/s41573-021-00283-5 [134] “Viet Nam,” covidl9.trackvaccines.org, 2022 https ://covid 19 trackvaccines org/country/viet-nam/ [135] “Arcturus & VinBioCare,” sec.gov, 2021 https://www.sec.gov/Archives/edgar/data/! 768224/000156459021042750/arctexl033_46.htm [136] “Arcturus Therapeutics and Duke-NUS Medical School Partner to Develop a Coronavirus (COVID-19) Vaccine using STARR TechnologyTM,” sec.gov, 2020 https://www.sec.gov/Archives/edgar/data/1768224/000119380520000295/e6194 29_ex99-l.htm [137] “LUNAR® Delivery Technology,” arcturusrx.com, 2022 https://arcturusrx.com/ma-mrna-proprietary-technologies/lunar/ [138] “ARCTURUS THERAPEUTICS LTD & UNITED STATES SECURITIES AND EXCHANGE COMMISSION,” sec.gov, 2018 https://www.sec.gov/Archives/edgar/data/OOO 1566049/000156459019008092/ar ct-10k_20181231.htm [139] J Kim, Y Eygeris, M Gupta, and G Sahay, “Self-assembled mRNA vaccines Jeonghwan,” Adv Drug Deliv Rev., vol 170, no January, pp 83-112, 2020 [140] “The ARCT-154 Self-Amplifying RNA Vaccine Efficacy Study (ARCT-154-01) (ARCT-154-01),” clinicaltrials.gov, 2021 https://clinicaltrials.gov/ct2/show/NCT05012943 [141] M N Fleeton et al., “Self-replicative RNA vaccines elicit protection against influenza A virus, respiratory syncytial virus, and a tickborne encephalitis virus,” J Infect Dis., vol 183, no 9, pp 1395-1398, 2001, doi: 10.1086/319857 [142] D Magini et al., “Self-amplifying mRNA vaccines expressing multiple conserved influenza antigens confer protection against homologous and heterosubtypic viral challenge,” PLoS One, vol 11, no 8, pp 1-25, 2016, doi: 10.1371/joumal.pone.0161193 [143] o F Khan et al., “Erratum: Dendrimer-RNA nanoparticles generate protective immunity against lethal Ebola, H1N1 influenza, and Toxoplasma gondii challenges with a single dose (Proceedings of the National Academy of Sciences of the United States of America (2016) 113 (E4133-,” Proc Natl Acad Sci u s A., vol 113, no 35, p E5250, 2016, doi: 10.1073/pnas 1612792113 [144] M Brazzoli et al., “Induction of Broad-Based Immunity and Protective Efficacy by Self-amplifying mRNA Vaccines Encoding Influenza Virus Hemagglutinin,” J Virol., vol 90, no 1, pp 332-344, 2016, doi: 10.1128/jvi.01786-15 [145] F B Scorza and N Pardi, “New kids on the block: RNA-based influenza virus vaccines,” Vaccines, vol 6, no 2, pp 1-15, 2018, doi: 10.3390/vaccines6020020 [146] s J Zost et al., “Contemporary H3N2 influenza viruses have a glycosylation site that alters binding of antibodies elicited by egg-adapted vaccine strains,” Proc Natl Acad Sci Ư s A., vol 114, no 47, pp 12578-12583, 2017, doi: 10.1073/pnas.1712377114 [147] N c Wu et al., “A structural explanation for the low effectiveness of the seasonal influenza H3N2 vaccine,” PLoSPathog., vol 13, no 10, pp 1-17, 2017, doi: 10.1371/journal.ppat 1006682 [148] D V Parums, “Editorial: mRNA Vaccines and Immunotherapy in Oncology: A New Era for Personalized Medicine,” Med Sci Monit., 2021, doi: 10.12659/MSM.933088