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研究生:林冠丞
研究生(外文):Lin, Guan-Cheng
論文名稱:利用腺病毒載體及第三區域套膜蛋白融合重組鞭毛蛋白進行prime-boost免疫法研發四價登革熱疫苗
論文名稱(外文):Prime-boost immunization using adenovirus vector and envelope domain III protein fused with flagellin for tetravalent dengue vaccine development
指導教授:吳夙欽
指導教授(外文):Wu, Suh-Chin
學位類別:碩士
校院名稱:國立清華大學
系所名稱:生物科技研究所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2013
畢業學年度:101
語文別:英文
論文頁數:65
中文關鍵詞:腺病毒鞭毛蛋白登革熱第三區域套膜蛋白
外文關鍵詞:prime-boost immunizationdengue virusflagellinEDIIIadenovirus
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每年感染登革熱的病人有顯著增加的現象,顯示登革熱已經成為全球密切注意的健康問題。套膜蛋白中的第三區域是病毒與細胞受器結合的位置,此外第三區域蛋白也被證實是一段具有血清型特異性的片段。在此篇研究中,我們利用大腸桿菌製造出一個融合蛋白,此蛋白除了帶有膜蛋白的第三區域之外還具有TLR5的配體(鞭毛重組蛋白flagellin),實驗證實在小鼠體內,這一種特殊的蛋白可以誘發顯著的中和性抗體。除此之外,我們結合這一種融合蛋白與帶有前膜蛋白和套膜蛋白序列的腺病毒載體來引誘更高的免疫反應,這一種方式稱為heterologous prime-boost strategy。我們發現在小鼠的血清中,第三區域特異性的抗體是主要提供中和能力的亞群,同時我們也偵測到heterologous prime-boost strategy可誘發顯著的第三區域特異性total IgG力價。最重要的是,heterologous prime-boost strategy可以引誘出針對四種血清型的中和性抗體。這些結果顯示以腺病毒載體與套膜第三區域片段組合而成的heterologous prime-boost strategy具有發展登革熱疫苗的可行性。
A dramatic increase in incidents has been documented indicating that DENV has become a major international health concern. E protein domain III (EDIII) is the receptor binding domain, and was demonstrated that EDIII contains serotype-specific epitopes. In this study, the E.coli-based fusion protein, containing a TLR5 agonist, flagellin (FliC), and EDIII epitopes in a single polypeptide, which could elicit significantly higher neutralizing antibodies than EDIII mixed with FliC. We further evaluated the heterologous prime-boost strategy using adenovirus vector encoding prME and FliC-EDIII fusion protein in BALB/c mice. We found anti-EDIII specific antibodies were the dominant neutralizing ability, while heterologous prime-boost strategy elicited significantly higher anti-EDIII total IgG titer compared with homologous prime-boost immunization. Moreover, the neutralizing ability against all serotypes of DENV was observed in tetravalent Ad-prME prime/FliC-EDIII boost regimen. These result demonstrated the feasibility of developing DENV vaccine using heterologous prime-boost strategy.
中文摘要 I
ABSTRACT II
致謝 III
CONTENT IV
1. INTRODUCTION 1
1.1 Overview of dengue virus 1
1.2 Live-attenuated vaccine development 2
1.3 DNA vaccine development 5
1.4 Adenovirus-vectored vaccine development 6
1.5 Subunit vaccine development and Toll like receptor adjuvants 7
1.6 Study goals 9
2. MATERIALS AND METHODS 10
2.1 Recombinant proteins expression, purification and characterization 10
2.2 Functional assay of FliC-fused proteins 11
2.3 Cells and viruses 11
2.4 Determination of dengue virus titer 12
2.5 Preparation of recombinant adenoviral vectors 12
2.6 Titering Adenovirus stock 13
2.7 SDS-PAGE and Western blotting 13
2.8 Immunization of BALB/c mice 14
2.9 Enzyme-linked immunosorbent assay (ELISA) 15
2.10 Plaque reduction neutralization assay (PRNT) 16
2.11 Preparation of EDIII-specific depleted sera 17
2.12 Enzyme-linked immunosorbent spot (ELISPOT) 17
3. RESULTS 19
3.1 Recombinant proteins of EDIII, FliC, and FliC-EDIII 19
3.2 Comparison of neutralizing antibody responses elicited by FliC combined with D2EDIII and FliC-D2EDIII 20
3.3 Preparation of adenoviral vectors encoding the full-length prM-E of four dengue serotypes 20
3.4 Antibody responses elicited by monovalent vaccine 21
3.5 Neutralizing antibody responses elicited by monovalent vaccine 22
3.6 T cell responses in monovalent vaccine 23
3.7 EDIII-specific total IgG responses elicited by tetravalent vaccine 23
3.8 Neutralizing antibody responses elicited by tetravalent vaccine 24
3.9 EDIII-specific total IgG titer in tetravalent vaccine with adjusted formulation of FliC-EDIII booster protein 25
3.10 Neutralizing antibody responses elicited by tetravalent vaccine with adjusted formulation of FliC-EDIII booster protein 26
4. DISCUSSION 27
5. REFERENCES 32
6. FIGURES 42
Figure 1. Preparation of recombinant proteins 42
Figure 2. Functional assay of FliC and FliC-fused proteins 43
Figure 3. Immunization schedule 44
Figure 4. Neutralizing antibodies elicited by two-dose FliC-D2EDIII proteins or FliC mixed with EDIII proteins 45
Figure 5. Analysis of recombinant proteins produced by adenoviral vector encoding dengue prM-E sequence 46
Figure 6. Characterization of total IgG in monovalent model 47
Figure 7. Analysis of neutralizing antibodies in monovalent model 48
Figure 8. Determination of neutralizing abilities with EDIII-specific depleted sera 49
Figure 9. T cell responses in monovalent model 50
Figure 10. Characterization of anti-EDIII total IgG in tetravalent model 51
Figure 11. Analysis of neutralizing antibodies in tetravalent model 52
Figure 12. Characterization of anti-EDIII total IgG in tetravalent model with adjusted booster protein 53
7. TABLES 55
Table 1. Strains for construction 55
Table 2. Immunization regimens of different conformation between EDIII and FliC 56
Table 3. Immunization regimens of three strategies for monovalnet vaccine analysis 57
Table 4. Immunization regimens of two strategies for tetravalent vaccine analysis 58
Table 5. Immunization regimens of tetravalent vaccine with adjusted booster proteins 59

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