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研究生:楊季融
研究生(外文):Ji-Rong Yang
論文名稱:應用類病毒顆粒技術發展廣效性流感疫苗的機制研究
論文名稱(外文):Mechanistic study for broadly protective influenza vaccine based on virus-like particle platform
指導教授:蕭培文
口試委員:劉嚞睿楊淑美李明學劉銘燦
口試日期:2017-04-18
學位類別:博士
校院名稱:國立臺灣大學
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:2017
畢業學年度:105
語文別:英文
論文頁數:167
中文關鍵詞:H6N1流感病毒H3N2流感病毒抗原飄移類病毒顆粒疫苗廣效性保護抗體蛋白酶切割
外文關鍵詞:influenza A (H6N1) virusinfluenza A(H3N2) virusantigenic driftvirus-like particle vaccinecross-protective antibodyproteolytic cleavage
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流感病毒藉由其基因體的多變性持續影響人類公共衛生。疫苗是有效控制流感的重要利器,而以新技術產製新式疫苗已成為未來研發趨勢的主流。本研究利用哺乳類細胞,針對H6N1禽流感與H3N2人類季節性流感病毒,開發可提供廣效性保護力的類病毒顆粒(virus like particle, VLP)疫苗,突破病毒抗原飄移(antigenic drift)對於當前疫苗策略所造成的瓶頸;並以小鼠作為動物模式,比較此種新式疫苗與由去活化病毒(whole inactivated virus, WIV)組成的傳統疫苗,在病毒控制功效上的差異,進而探討造成保護力差異的可能機制。研究結果顯示,利用人類H6N1或H3N2流感病毒所衍生的兩種VLP疫苗,經以肌肉注射方式對小鼠進行初次與加強免疫(prime-boost immunization)之後,在不需佐劑的情形下,均可在其體內產生高力價且持久的抗體反應。這些抗體針對同源(homologous)的流感病毒具優異的中和效力。值得注意的是,與傳統去活化疫苗相比,H6N1-VLP與H3N2-VLP疫苗皆可進一步抑制異源性(heterologous)流感病毒在哺乳類細胞複製的能力,並誘發小鼠產生較強且針對病毒紅血球凝集素(hemagglutinin, HA)蛋白根部(stalk)區域的抗體反應(anti-HA stalk response)。此種抗體經後續證實與疫苗的廣效保護力有關,顯示由VLP疫苗所誘發的功能性抗體對於流感病毒的抗原飄移較不敏感,可延長保護效果。此外,進一步分析發現,誘導產生HA柄部抗體反應的機制與VLP所特有未經切割的HA0原態蛋白(uncleaved HA0 precursor)有關。因蛋白酶將HA0原態蛋白切割成HA1與HA2結構域(protein domain)為流感病毒複製所必需,這也是以去活化病毒組成的傳統疫苗無法有效誘發此類廣效性中和抗體的原因之一。這些發現除了首度找出VLP疫苗較易誘發可抵抗流感病毒變異之廣效性中和抗體的相關機制外,亦顯示使用類病毒顆粒疫苗可有效免除世衛組織每年皆須更新季節性流感疫苗抗原的不便。綜合以上結果,本研究所開發的新疫苗策略,因其結合以哺乳類細胞產製、採用類病毒顆粒抗原型式以及特有未經蛋白酶切割的HA0原態蛋白等特性,可做為未來研發廣效性通用疫苗(universal vaccine)的立論基礎,有效提高疫苗對於各類流感病毒的保護力。
Influenza viruses impact public health due to their continual evolution. Vaccination is an effective countermeasure for influenza intervention. To prepare for possible threats caused by avian and human influenza viruses, we investigated the drift-tolerance of virus-like particles (VLPs) as an improved vaccine candidate. Prime-boost intramuscular immunization in mice with unadjuvanted H6N1-VLPs or H3N2-VLPs engineered using mammalian cells induced long-lasting neutralizing antibody responses against the homologous viruses. Both vaccines were able to confer superior cross-clade humoral immunity against the heterologous viruses belonging to distinct representative antigenic clusters in comparison with the cognate conventional whole-inactivated virus (WIV) vaccines, indicating the antibody repertoire induced by VLP vaccine formulations was insensitive to viral antigenic drift. Furthermore, the H6N1-VLPs and H3N2-VLPs also elicited significantly higher levels of anti-stalk antibodies contributing to a broadened neutralization effect. This advantageous effect was attributed to the uncleaved precursor of their HA proteins. These results uncover a mechanism for induction of wide-range immunity that better tolerates the evolutionary dynamics of influenza viruses and point to the possible use of a VLP as a next-generation vaccine candidate. Collectively, our strategy that combines favorable features of mammalian cell culture-based manufacture, VLP structure and the full-recombinant precursor HA trimer thus builds proof of concept of a new vaccine and may fit into the larger picture of universal/broadly cross-reactive vaccination approach to enhance cross-protection against the dynamically evolving influenza viruses.
口試委員會審定書 i
謝辭.......... ii
中文摘要.. iii
Abstract.… iv
List of Figures xi
List of Tables xv
Chapter 1 General introduction 1
1.1 General introduction of influenza viruses 2
1.2 Past human influenza pandemics in the world 3
1.3 Human infections with avian influenza viruses 5
1.4 Avian and human influenza A(H6N1) viruses circulating in Taiwan 6
1.5 Genetic diversity of influenza viruses 8
1.6 Global migration and evolution of human influenza A(H3N2) viruses 10
1.7 Global vaccine strategy for seasonal influenza viruses 12
1.8 Achievement of novel influenza vaccine technology 15
1.9 Influenza virus surveillance and epidemic trends in Taiwan 17
1.10 Motivation and specific aims 20
1.10.1 Specific aim 1: To develop an influenza H6N1 virus-like particle vaccine and evaluate the protective spectrum of the humoral immune responses against human and avian H6N1 viruses 25
1.10.2 Specific aim 2: To develop an influenza H3N2 virus-like particle vaccine and evaluate the protective spectrum of the humoral immune responses against long-term virus antigenic drift 26
1.10.3 Specific aim 3: To investigate the underlying mechanisms contributing to broadly protective humoral immunity induced by the recombinant VLP vaccines 28
Chapter 2 Materials and Methods 30
2.1 Collection of clinical specimens and virus isolates 31
2.2 Production of ferret antisera raised against influenza viruses 32
2.3 Hemagglutination inhibition assay 33
2.4 Genetic analysis of influenza viruses 34
2.5 Phylogenetic analysis of influenza viruses 35
2.6 Proteotyping analysis 35
2.7 Microneutralization assay 35
2.8 Immunogold electron microscopy of purified mammalian virus-like particles 36
2.9 Generation of 6:2 reassortant influenza viruses 36
2.10 Whole inactivated virus (WIV) preparation 38
2.11 Generation of H3N2 virus-like particle (VLP) 38
2.12 Generation of H6N1 virus-like particle (VLP) 39
2.13 Western blot analysis 41
2.14 Enzyme-linked immunosorbent assay 41
2.15 Influenza H6N1 viruses used in the study 42
2.16 Influenza H3N2 viruses used in the study 42
2.17 Production of recombinant HA2 protein derived from the human H3N2 and H6N1 viruses 43
2.18 Production of recombinant full-length HA protein derived from the human H6N1 virus 44
2.19 Production of polyclonal antibodies against influenza A(H6N1) virus 45
2.20 Depletion of anti-HA2 antibodies induced by the H3N2-VLP or H3N2-WIV vaccines 45
2.21 Proteolytic cleavage of H3N2-VLPs 46
2.22 Immunization and virus challenge in mice 46
2.23 Passive serum transfer in mice 47
2.24 Neuraminidase enzymatic activity assay 47
2.25 Neuraminidase inhibition assay 47
2.26 Quantification of HA content in H3N2-VLP and H3N2-WIV 48
2.27 Ethics Statement 49
2.28 Sequence information 49
2.29 Statistical analysis 50
Chapter 3 Results 51
Part 1. A novel H6N1 virus-like particle vaccine induces long-lasting cross-clade antibody immunity against human and avian H6N1 viruses 52
3.1 Production of influenza H6N1-VLP and H6N1-WIV vaccines 52
3.1.1 Construction and characterization of the influenza H6N1-VLPs and H6N1-WIVs derived from the human H6N1 virus 52
3.2 Humoral immunity and in vivo protection conferred by the newly-developed H6N1-VLP and conventional H6N1-WIV vaccines in mouse model 53
3.2.1 Influenza H6N1-VLP vaccine elicits robust humoral immune responses 53
3.2.2 H6N1-VLP vaccine induced a long-lasting response of functional antibodies 53
3.2.3 Immunization with H6N1-VLP vaccine confers in vivo protection from lethal infection by homologous virus 54
3.2.4 H6N1-VLP vaccine induced serum antibodies that reduced viral loads in infected mice 55
3.2.5 H6N1-VLP but not egg-propagated whole inactivated virus induces cross-reactive antibodies against distantly related avian H6N1 strains 56
3.2.6 H6N1-VLP induces greater antibody responses against the HA2 subunit of H6 HA proteins than H6N1-WIV 58
Part 2. A virus-like particle vaccination strategy expands its tolerance to H3N2 antigenic drift by enhancing neutralizing antibodies against hemagglutinin stalk 59
3.3 Evolutionary analyses of the human influenza A(H3N2) viruses in Taiwan 59
3.3.1 Influenza virus surveillance and monitoring 59
3.3.2 Genetic characterization of the influenza A(H3N2) virus 59
3.3.3 Antigenic characterization of the influenza A(H3N2) virus 62
3.3.4 Comparison of evolutionary trends of the A(H3N2) viruses in Taiwan and other regions (continents) in the Northern Hemisphere 63
3.4 Production of influenza H3N2-VLP and H3N2-WIV vaccines 63
3.4.1 Selection of the candidate H3N2 vaccine virus based on the virus characterization results in Taiwan 63
3.4.2 Construction and characterization of the H3N2-VLPs 64
3.4.3 Construction and Characterization of the H3N2-WIVs 65
3.5 Humoral immunity conferred by the newly-developed H3N2-VLP and conventional H3N2-WIV vaccines in mouse model 66
3.5.1 Influenza H3N2-VLP vaccine elicits protective and long-lasting humoral immune responses 66
3.5.2 H3N2-VLPs but not H3N2-WIVs induce cross-neutralization antibody activity against drifted human influenza A(H3N2) strains 67
3.5.3 H3N2-VLPs confer greater anti-stalk responses contributing to a broadened neutralization effect 69
3.6 The mechanism through which VLP can induce humoral immunity better tolerating the evolutionary dynamics of influenza viruses 70
3.6.1 Proteolytic processing of HA protein in H3N2-VLPs abolished the induction of anti-stalk antibodies and the cross-neutralizing responses 70
Chapter 4 Discussion 73
4.1 Conclusion and importance of the current H6N1-VLP and H3N2 VLP studies 74
4.2 The H6N1 virus continues to impose non-negligible threats to public health 76
4.3 The antigenic site B of the recent H3N2 viruses is important for generation of new antigenic variants 77
4.4 The global circulation trend of the recent H3N2 viruses may be different from that observed previously 78
4.5 Advancement of our H6N1 and H3N2 VLP studies compared to previously reported ones 79
4.5.1 Conserved epitopes shared by various H6N1 strains which located at viral HA1 and HA2 subunits may be better presented in the H6N1-VLPs and concomitantly induced broad-spectrum protective immunity 80
4.5.2 The cross-neutralization activity conferred by the H3N2-VLP vaccine was mediated by the drift-tolerant antibodies exhibiting an essential anti-stalk effect 82
4.5.3 The broad-spectrum neutralizing responses of H3N2-VLP vaccines are due to the enhanced anti-stalk antibodies attributed to the HA pre-fusion structure in the mammalian-expressed VLPs 83
4.6 Application of adjuvants for influenza virus-like particle vaccines 85
4.7 Limitations of the current study 87
4.8 Prospective of the influenza VLP technology in universal influenza vaccination approach 88
Chapter 5 Figures and Tables 90
Chapter 6 References 148
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