NGUYỄN THỊ THÚY THE CURRENT STATUS OF mRNA AND OTHER VACCINES MANUFACTURING TECHNOLOGIES IN VIETNAM KHÓA LUẬN tốt NGHIỆP dược sĩ

BỘ Y TẾ TRƯỜNG ĐẠI HỌC DƯỢC HÀ NỘI NGUYỄN THỊ THÚY THE CURRENT STATUS OF mRNA AND OTHER VACCINES MANUFACTURING TECHNOLOGIES IN VIETNAM KHÓA LUẬN TỐT NGHIỆP DƯỢC SĨ HÀ NỘI – 2022 BỘ Y TẾ TRƯỜNG ĐẠI HỌC DƯỢC HÀ NỘI NGUYỄN THỊ THÚY MÃ SINH VIÊN: 1501484 THE CURRENT STATUS OF mRNA 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 .1 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-M1) 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 .10 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 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 Arcturus BCG 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.U.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 Mrna 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 UTR Untranslated region UV 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…………………………………….3 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/cir141 [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.” 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TRƯỜNG ĐẠI HỌC DƯỢC HÀ NỘI NGUYỄN THỊ THÚY MÃ SINH VIÊN: 1501484 THE CURRENT STATUS OF mRNA AND OTHER VACCINES MANUFACTURING TECHNOLOGIES IN VIETNAM KHÓA LUẬN TỐT NGHIỆP DƯỢC SĨ Người hướng dẫn:... facilitate the entry of candidate vaccines into early-phase clinical trials and the market [51] Other applications of mRNA is targeted immunotherapy in oncology Therapeutic mRNA vaccines rely... development of the vaccine manufacturing field, especially with the birth of mRNA vaccines and other modern vaccines, this definition appears to be not appropriate and updated According to the USA