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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 翁啟惠(Chi-Huey Wong) | |
| dc.contributor.author | Kuang-Cheng Lee | en |
| dc.contributor.author | 李光正 | zh_TW |
| dc.date.accessioned | 2023-03-19T23:26:15Z | - |
| dc.date.copyright | 2022-09-29 | |
| dc.date.issued | 2022 | |
| dc.date.submitted | 2022-09-26 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/85846 | - |
| dc.description.abstract | 季節性流感是一種急性呼吸道症候群由數種在全世界傳播的流行性感冒病毒(Influenza virus)所引起的疾病。大部分的人得到只會有輕微的症狀和發燒並且可以康復。然而，流感病毒對某些族群會引起嚴重的症狀甚至死亡，特別是新生兒、老年人、慢性病患者及缺乏醫療資源的地區。如今，科學家尚未解決對抗未來新型流感病毒疫苗及藥物的需求。世界衛生組織每年都會預測下一年流行哪些流感病毒株，以便準時製作出下一個年度的流感疫苗。這樣設計的季節性流感疫苗可以預防特定的流感病毒株，但這樣限制了疫苗的保護效果，而且必須每年重新製造以針對即將出現的流感病毒株。因此，去研發一個可以保護多種流感病株的廣效型流感疫苗對社會大眾是非常重要的。我的研究目的就是去研發同時具有B型流感病毒血凝集素(Hemagglutinin)和A型流感病毒血凝集素組成的嵌合型血凝集素(Chimeric Hemagglutinin)疫苗作為對抗季節性流感以及尚未出現的新型流感的有效工具。在此研究中，我設計出了特別的嵌合型血凝集素蛋白並將其產出。接續研究了此重組蛋白的構型和評估它的免疫反應。結果顯示了嵌合型血凝集素蛋白可以使免疫系統產生抗體對抗四種主要的流感病毒血凝集素(H1, H3, Victoria, Yamagata)並且可以引起CD4+ and CD8+ T 細胞免疫反應。所以，此種嵌合型血凝集素是具有潛力開發成對付流感病毒感染的廣效型疫苗。 | zh_TW |
| dc.description.abstract | Seasonal influenza is an acute respiratory disease caused by different types of influenza virus which are circulated in all parts of the world. Most people who get influenza can recover from fever and slight symptoms. However, influenza can cause severe illness or even death particularly in newborns, the elderly, and those with underlined disease or without medical treatments. Nowadays, combating the ongoing epidemic influenza is an unmet medical need. Every year the World Health Organization makes predictions on which influenza strains will circulate in the following year so that a vaccine can be designed, manufactured and administered to the public on time. Seasonal influenza vaccines thus designed can protect against specific viral strains but have to be renewed annually to target the upcoming strains, which limits their protective breadth and efficacy. Therefore, developing a universal influenza vaccine which is broadly protective against diverse influenza virus strains would have a great benefit to public health. My research goal is to design a chimeric hemagglutinin (cHA) that contains the head domain from influenza virus B and the stem domain from influenza A to induce broadly protective activity against seasonal influenza and unexpected pandemic influenza. cHA was designed and expressed. The properties of the recombinant protein were further characterized and used for evaluation of the immune response. Moreover, the effects of N-glycosylation on immunogenicity induced by HA nucleoside vaccine were also evaluated. The result showed that cHA protein can elicit significant IgG titer against variants of HA among H1, H3, Vic and Yam and CD8+ and CD4+ T cell response, suggesting that the cHA has the potential to be a universal vaccine. | en |
| dc.description.provenance | Made available in DSpace on 2023-03-19T23:26:15Z (GMT). No. of bitstreams: 1 U0001-2209202211573000.pdf: 7189646 bytes, checksum: 9e4582fd4f8ec95d1a286d42d676a11e (MD5) Previous issue date: 2022 | en |
| dc.description.tableofcontents | Table of contents Acknowledgement……………………………………………………………...……. i Chinese abstract….………………………………………………………………...... ii English abstract……………………………………………………………………. iii Table of contents….………………………………………………………………... iv Figures……………………………………………………………………….……. vii Tables………………………………………………………………...……………. ix List of abbreviations………………………………………………………………… x 1. INTRODUCTION……………………………………………………………. 1 2. MATERIALS AND METHODS……………………………………………. 6 2.1 Materials…………………………………………………………………… 6 2.2 Chimeric and consensus hemagglutinin protein design……………………. 6 2.3 Construction of cHA protein expression plasmid…………………………. 7 2.4 Plasmid construction for HA mRNA production…………………….……. 7 2.5 In vitro transcription……………………………………………………… 8 2.6 cHA protein expression and purification…………………………………… 8 2.7 Expression of mRNA in HEK293 cells………………………………… 9 2.8 Size exclusion chromatography…………………………………………… 10 2.9 Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting…………………………………………………………. 10 2.10 Protein identification and Glycan profiling by LC-MS/MS analysis……. 11 2.11 Lipid nanoparticle encapsulation of the mRNA…………………. 12 2.12 Formulation mRNA-nanocarrier complex………………………………. 13 2.13 Size measurement of lipid nanoparticles……………………………...…. 13 2.14 Quantification of mRNA loading in lipid nanoparticles…………………. 13 2.15 Animal immunization……………………………………………………. 14 2.16 ELISA analysis………………………………………………………… 14 2.17 Enzyme linked immunospot (ELISpot) assay……………………… 15 3. RESULTS…………………………………………………………………. 17 Part I. Design of Chimeric HA as a universal vaccine…………………… 17 I.1 Design of a universal vaccine…………………………………… 17 I.2 In vitro expression of designed chimeric HA…………………….... 18 I.3 Purification of cHA protein………………………………………. 18 I.4 Characterization of cHA protein…………………………………. 19 I.5 The immunogenicity of cHA vaccine…………………………… 20 Part II. Effects of glycosylation on HA mRNA vaccine…………………… 22 II.1 Production of HA and HAdG mRNA……………………………. 22 II.2 Production and characterization of HA and HAdG from mRNA-transfected cells………………………………………………………. 23 II.3 Characterization of HA and HAdG from mRNA-transfected cells. 23 II.4 Encapsulation of mRNA with lipid nanoparticle…………………. 24 II.5 Protein expression in mRNA-LNP transfected cells……………… 25 II.6 Immunogenicity of mRNA-LNP………………………………… 26 4. DISCUSSION……………………………………………………………….... 28 5. REFFERENCES…………………………………...………………………… 30 Figures Figure 1. The workflow of chimeric HA design………………………………………………. 37 Figure 2. The phylogenetic tree of HA subtypes that were constructed with HA sequences extracted from GISAID database by MEGA 11 software……………………………. 38 Figure 3. Sequence comparison of HA sequences obtained from GISAID database and used for cHA design…………………………………………………………………………. 39 Figure 4. The proteins sequences of chimeric HA……………………………………………… 40 Figure 5. The design and expression of recombinant cHA proteins…………………………… 41 Figure 6. The final sequence of chimeric HA used in this study. The cHA352 was aligned with conTypeA and conTypeB…………………………………………………………… 42 Figure 7. Purification of cHA with Ni++ Sepharose chromatography and DEAE Sepharose chromatography……………………………………………………………………… 43 Figure 8. Protein identification of cHA by LC-MS/MS analysis……………………………… 44 Figure 9. Glycan-profiling of cHA by LC-MS/MS……………………………………………. 45 Figure 10. cHA protein characterization by size exclusion chromatography………………… 47 Figure 11. Animal experiment time-line and immunogenicity of cHA………………………. 48 Figure 12. ELISpot analysis of splenocytes from cHA immunized mice……………………. 49 Figure 13. mRNA synthesis constructions…………………………………………………… 50 Figure 14. Agarose gel of in vitro transcript mRNA and western blotting of mRNA transfected cell…………………………………………………………………………………. 51 Figure 15. LC-MS/MS of mRNA translated HA and HAdG protein identification………… 52 Figure 16. HA And HAdg protein size determined by size exclusion chromatography…… 53 Figure 17. Size distribution of prepared mRNA-Lipid nanoparticle…………………………. 54 Figure 18. mRNA-Lipid nanoparticle encapsulation efficiency……………………………… 55 Figure 19. Western blotting of mRNA-LNP transfected cell………………………………. 56 Figure 20. Animal experiment time line and immunogenicity of HA and HAdG nucleotides vaccine………………………………………………………………………………. 57 Figure 21. ELISpot analysis of splenocytes from HA and HAdG mRNA immunized mice… 58 Tables Table 1. The primers used for mutation of N-glycosylation sites………………………………. 59 | |
| dc.language.iso | en | |
| dc.subject | 廣效型疫苗 | zh_TW |
| dc.subject | 免疫 | zh_TW |
| dc.subject | 信使RNA疫苗 | zh_TW |
| dc.subject | 嵌合型血凝集素 | zh_TW |
| dc.subject | 流行性感冒病毒 | zh_TW |
| dc.subject | mRNA vaccine | en |
| dc.subject | Immunity | en |
| dc.subject | Chimeric hemagglutinin | en |
| dc.subject | Universal vaccine | en |
| dc.subject | Influenza virus | en |
| dc.title | 廣效A/B型流感疫苗的開發 | zh_TW |
| dc.title | Development of a Broad-Spectrum Influenza A/B vaccine | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 110-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 馬徹(Che Ma),林國儀(Kuo-I Lin) | |
| dc.subject.keyword | 流行性感冒病毒,廣效型疫苗,嵌合型血凝集素,信使RNA疫苗,免疫, | zh_TW |
| dc.subject.keyword | Influenza virus,Universal vaccine,Chimeric hemagglutinin,mRNA vaccine,Immunity, | en |
| dc.relation.page | 59 | |
| dc.identifier.doi | 10.6342/NTU202203801 | |
| dc.rights.note | 同意授權(全球公開) | |
| dc.date.accepted | 2022-09-26 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 生化科學研究所 | zh_TW |
| dc.date.embargo-lift | 2022-09-29 | - |
| 顯示於系所單位： | 生化科學研究所 | |
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