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| ???org.dspace.app.webui.jsptag.ItemTag.dcfield??? | Value | Language |
|---|---|---|
| dc.contributor.advisor | 陳慧文 | zh_TW |
| dc.contributor.advisor | Hui-Wen Chen | en |
| dc.contributor.author | 邱軍達 | zh_TW |
| dc.contributor.author | Chun-Ta Chiu | en |
| dc.date.accessioned | 2023-08-09T16:16:46Z | - |
| dc.date.available | 2023-11-09 | - |
| dc.date.copyright | 2023-08-09 | - |
| dc.date.issued | 2023 | - |
| dc.date.submitted | 2023-07-24 | - |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/88265 | - |
| dc.description.abstract | 目前的SARS-CoV-2疫苗若單獨使用棘蛋白受體結合區作為疫苗抗原，便無法誘發良好的免疫反應，過去的研究指出，使用免疫細胞標靶策略即可提升疫苗的免疫原性與產出強大的免疫反應，但如何選擇合適的標靶配體至今仍是未解之謎，因此，我們使用了mRNA的技術來探索多種不同配體的效能，以促進疫苗之發展。在此研究中，我們進行了三種配體的比較，包含補體成分C3b（mC3）、分化群40配體（mCD40L）以及免疫球蛋白G1之結晶區域片段（mFc），並將它們分別結合上SARS-CoV-2 Omicron變異株（B.1.1.529）的棘蛋白受體結合區，接著生產可以轉譯出這些抗原蛋白的mRNA，優化它們並將其包進脂質奈米顆粒中製成疫苗，我們將mRNA轉染至HEK293T細胞株之後，具有完整抗原性的抗原能夠有效地被表達，在免疫染色實驗中也呈現了三種配體（mC3、mCD40L、mFc）能夠分別標定並結合各自的受體（CR1、CD40、Fc𝛄R），展現出強而有力的免疫細胞標靶特性。在小鼠（C57BL/6）實驗中測試了不同的疫苗劑量，由每劑1 微克至每劑40 微克，每隻小鼠共接種三劑，使用肌肉注射方式施打疫苗，我們所生產的疫苗可保存至少三個月且不會在小鼠體內引起不良副作用，尤其，我們的三種標靶樹突細胞mRNA疫苗能夠有效誘發強力的抗體反應，並且這三種疫苗皆達到相當的抗體效價，此外，三種疫苗也展現了各自的獨特性，有利於我們更了解不同標靶配體所引起的免疫反應，並作為未來疫苗發展的應用依據。此篇研究作為第一個探討不同標靶配體的差異的先驅，首先嘗試使用了mRNA技術作為免疫細胞標靶疫苗的疫苗型式，研究中三種標靶配體皆展現了高效的標靶能力，期待在未來，此研究能夠被廣泛應用，並有效地改善抗原傳遞效率、增進疫苗免疫原性與促進體液免疫反應。 | zh_TW |
| dc.description.abstract | Current SARS-CoV-2 vaccines using receptor binding domain (RBD) alone induce weak immune responses. Studies have shown that immune cell-targeting strategies can improve vaccine immunogenicity and generate potent immunity. However, what to select as an appropriate targeting ligand is still a secret. Hence, we applied mRNA technology to explore targeting ligands, including mC3, mCD40L, and mFc, shedding light on the enhancement of vaccines. Ligands were fused to the RBD of SARS-CoV-2 Omicron variant (B.1.1.529). The mRNAs were optimized for promoting expression, produced with high quality, and encapsulated in lipid nanoparticles (LNPs) for effective delivery. HEK293T cell line, transfected by each mRNA, efficiently expressed the vaccine antigens with correct antigenicity. Immunofluorescence staining revealed that the three targeting ligands, mC3, mCD40L, and mFc, were successfully co-expressed with the RBD and were able to target their receptors, CR1, CD40, and Fc𝛄 receptors, respectively, presenting highly correlated interaction and showing convincing targeting properties. In animal studies, C57BL/6 mice were vaccinated intramuscularly with different doses, from 1 µg to 40 µg, and each mouse underwent three doses of vaccination. The mRNA-LNP vaccines displayed great stability for lasting over three months and presented safety without causing adverse effects in mice. Notably, targeting mRNA vaccines elicited a promising elevation of antigen-specific antibody responses compared to the non-targeting vaccine. Furthermore, they achieved a similar antibody level, demonstrating their analogously robust targeting capabilities. Each vaccine has exhibited its own unique characterization and potential future application. This is the first study that uses mRNA vaccine to explore various targeting ligands and proves their promising targeting ability. These innovative vaccine candidates hold tremendous potential for improving antigen delivery, increasing vaccine immunogenicity, and enhancing humoral immunity. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2023-08-09T16:16:46Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2023-08-09T16:16:46Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 序言 i
中文摘要 ii Abstract iii Contents v List of Figures viii List of Tables x Chapter 1. Introduction 1 1.1. Introduction of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 1 1.2. Introduction of mRNA vaccines against infectious diseases 2 1.3. Design and delivery of mRNA vaccine 3 1.4. SARS-CoV-2 mRNA vaccine 5 1.4.1. Full-length spike mRNA vaccines 6 1.4.2. Spike receptor binding domain (RBD) mRNA vaccines 8 1.4.3. Challenges and future potential of SARS-CoV-2 mRNA vaccine development 9 1.5. Importance of dendritic cells (DCs) in immunity 10 1.6. DC receptors for the vaccine targeting 11 1.6.1. Fc𝛄 receptor (Fc𝛄R) and Fc𝛄R-targeting vaccines 12 1.6.2. CD40 receptor and CD40-targeting vaccines 13 1.7. Follicular dendritic cell (FDC) and complement receptor 1 (CR1) 15 1.8. The objective of this research 17 Chapter 2. Materials and methods 19 2.1. Ethics statement 19 2.2. Cell culture 19 2.3. Construction of plasmids 19 2.4. In vitro transcription (IVT) and mRNA purification 22 2.5. Denaturing single-stranded RNA (ssRNA) electrophoresis 23 2.6. Lipid nanoparticle (LNP) formulations 24 2.7. LNP observation via cryo-electron microscope (Cryo-EM) 24 2.8. Validation of mRNA-LNP quality 24 2.9. Cell transfection 25 2.10. SDS-PAGE and Western blot 26 2.11. Immunofluorescence assay (IFA) 27 2.11.1. Expression of RBD antigens 27 2.11.2. Binding test of immune cell receptors and targeting ligands 28 2.12. Mouse immunization studies 29 2.13. Enzyme-linked immunosorbent assay (ELISA) 30 2.14. Statistical analysis 31 Chapter 3. Results 32 3.1 Design of immune cell-targeting RBD antigens 32 3.2 Optimization of mRNA design 32 3.3 Production of mRNA antigens 34 3.4 Optimization of antigen expression 35 3.5 Characterization of mRNA-LNP 36 3.6 Detection for the expression of vaccine antigens 37 3.7 Assessment of interaction between immune cell receptors and targeting ligands 38 3.8 Analysis of RBD-specific humoral immune responses in mice 40 Chapter 4. Discussion 45 Chapter 5. Figures and tables 53 References 85 | - |
| dc.language.iso | en | - |
| dc.subject | mRNA疫苗 | zh_TW |
| dc.subject | Omicron變異株 | zh_TW |
| dc.subject | 棘蛋白受體結合區 | zh_TW |
| dc.subject | 新冠病毒 | zh_TW |
| dc.subject | 免疫細胞受體標靶策略 | zh_TW |
| dc.subject | spike RBD | en |
| dc.subject | SARS-CoV-2 | en |
| dc.subject | mRNA vaccine | en |
| dc.subject | Omicron variant | en |
| dc.subject | immune cell receptor-targeting strategies | en |
| dc.title | 以免疫細胞受體為標靶提升 SARS-CoV-2 RBD mRNA 疫苗免疫原性之探討 | zh_TW |
| dc.title | Exploration of Immune Cell Receptor-Targeting Strategies for Enhancing SARS-CoV-2 RBD mRNA Vaccine Immunogenicity | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 111-2 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 胡哲銘;黃立民 | zh_TW |
| dc.contributor.oralexamcommittee | Che-Ming Hu;Li-Min Huang | en |
| dc.subject.keyword | mRNA疫苗,免疫細胞受體標靶策略,新冠病毒,Omicron變異株,棘蛋白受體結合區, | zh_TW |
| dc.subject.keyword | mRNA vaccine,immune cell receptor-targeting strategies,SARS-CoV-2,Omicron variant,spike RBD, | en |
| dc.relation.page | 110 | - |
| dc.identifier.doi | 10.6342/NTU202301874 | - |
| dc.rights.note | 同意授權(限校園內公開) | - |
| dc.date.accepted | 2023-07-25 | - |
| dc.contributor.author-college | 生物資源暨農學院 | - |
| dc.contributor.author-dept | 獸醫學系 | - |
| Appears in Collections: | 獸醫學系 | |
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| ntu-111-2.pdf Access limited in NTU ip range | 15.06 MB | Adobe PDF |
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