博碩士論文 108881606 詳細資訊




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姓名 艾提曼(A T M BADRUZZAMAN)  查詢紙本館藏   畢業系所 生命科學系
論文名稱 Development of Seasonal Influenza Virus-like Particle (VLP) Vaccines Using Insect Cell-based Baculovirus Expressing System
(用昆蟲細胞衍生類病毒顆粒生產平台開發季節性流感疫苗)
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摘要(中) 季節性流感病毒對全球健康構成重大威脅,迫切需要有效的預防策略。疫苗接種仍然是預
防的基石,但當前的方法主要依賴於使用胚胎雞蛋(ECE)生產的滅活裂解病毒疫苗,此
方法存在各種缺點,包括過敏反應、血凝素(HA)基因的適應性突變、蛋供應中斷以及
生產放大問題。為了克服對 ECE的依賴,極需利用高效和穩定生產平台來開發流感疫苗。
已經有幾個疫苗生產系統顯示出作為替代品的潛力,包括類病毒顆粒(VLP)平台。在這
項研究中,我們使用桿狀病毒表達系統(BES),選殖流感 A/H1N1、A/H3N2、
B/Yamagata-like 和 B/Victoria-like 病 毒 株 ( A/Hawaii/70/2019, A/Minnesota/41/2019,
B/Brisbane/09/2014 & B/Brisbane/63/2014)的 HA、NA 和 M1 基因,以生產 VLP 疫苗抗原
H1N1-VLP、H3N2-VLP、Yamagata-VLP 和 Victoria-VLP,因此四種 homologus VLP 的 HA
抗原產量差距四倍以上。然後,我們開發了嵌合 VLP,以提高 HA 蛋白的產量。我們評估
了它們的功能和抗原特性,包括凝血試驗、蛋白組成、形態學、穩定性和免疫原性。我們
發現,同源和嵌合 VLP 的功能活性`形態和大小上類似於流感病毒顆粒,同時保持結構完
整性。小鼠的免疫原性比較評估顯示,我們的四價 VLP在誘導凝血抑制抗體、中和抗體與
上市的雞胚蛋及重組蛋白疫苗相比具有優越性,並對同源病毒提供 100%的保護。這些發
現表明,昆蟲細胞產出的 VLP疫苗作為四價季節性流感疫苗的候選者具有良好的商業潛力
,值得進一步開發。
摘要(英) Seasonal influenza viruses pose a significant threat to global health, necessitating effective
prevention strategies. While vaccination remains the cornerstone, current methods primarily rely
on inactivated split virus vaccines generated using embryonated chicken eggs (ECE), present
various drawbacks including allergic reactions, adaptive mutation in hemagglutinin (HA) gene,
disruptions in egg supply, and scalability issues. To overcome the dependency on ECE,
developments of influenza vaccines based on efficient and robust production platforms are urgently
needed. Several potential vaccine production systems have shown potential as replacers, including
a virus-like particle (VLP) platform. In this study, using a Baculovirus Expression System (BES),
we engineered HA, NA, and M1 genes of influenza A/H1N1, A/H3N2, B/Yamagata-like, and
B/Victoria-like virus strains (A/Hawaii/70/2019, A/Minnesota/41/2019, B/Brisbane/09/2014 &
B/Brisbane/63/2014) to produce VLP vaccine antigens H1N1-VLP, H3N2-VLP, Yamagata-VLP,
Victoria-VLP, respectively. We then assessed their functional and antigenic characteristics,
including hemagglutination assay, protein composition, HA protein productivity, VLPs
morphology, stability and immunogenicity. We found that recombinant VLPs displayed functional
activity, resembling influenza virions in morphology and size, while maintaining structural
integrity. Comparative immunogenicity assessments in mice showed that our quadrivalent VLPs
were consistent in inducing hemagglutination inhibition (HAI) and neutralizing (NT) antibody
titers against homologous viruses compared to both commercial recombinant HA (Flublok) and
egg-based vaccines (Vaxigrip). Since the HA antigen yields of the homologous VLPs varied more
than four folds, we further developed chimeric VLPs to improve HA protein production and
address the limitations of the homologous VLPs. We assessed their antigenic characteristics,
comparative HA protein productivity, immunogenicity and vaccine efficacy. We found that similar
to homologous VLPs, chimeric VLPs displayed functional activity, resembling influenza virions
in morphology and size. Comparative immunogenicity assessments in mice showed that the VLP
vaccine consistent in inducing higher hemagglutination inhibition and neutralizing antibody titers
and provided 100% protection against homologous viruses compared to the commercial vaccine.
The findings highlight insect cell-based VLP vaccines as promising candidates for quadrivalent
seasonal influenza vaccines.
論文目次 Table of Contents
中文摘要 …………………………………………………………………………………………... ⅴ
Abstract …………………………………………………………………………………………….. ⅴⅰ
Acknowledgement …………………………………………….…………………………………… ⅶ
Publication arising during PhD candidature …………………….…………………………………. ⅶⅰ
Abstracts arising from the thesis …………………………………...………………………………. ⅸ
Table of contents ………………………………………………….………………………………... ⅹ-xiii
List of figures ……………………………………………………...……………………………….. xiv-xv
List of tables ……………………………………………………….……………………………...... ⅹⅴi
List of abbreviations.……………………………………………….……………………………….
ⅹⅴiixviii
Chapter 1. Introduction ………………………………………………………………………. 1-24
1.1 Influenza virus ………………………………………………………….... 1
1.2 Structure of influenza virus.………………………………………………. 1
1.2.1 Hemagglutinin …………………………………………………... 2
1.2.2 Neuraminidase …………………………………………………... 3
1.2.3 Matrix proteins …………………………………………………... 3
1.2.4 Others internal virus proteins ……………………………………. 4
1.3 Prevention of seasonal influenza …………………………………………. 5
1.3.1 Introduction of inactivated influenza vaccine.…............................ 5
1.3.2 Antigenic drift and antigenic shift………………………………... 6
1.3.3 Development of trivalent vaccines ………………………………. 6
1.3.4 Expansion to quadrivalent vaccines ……………………………... 7
1.4 Different types of influenza vaccines …………………………………….. 8
1.4.1 Traditional inactivated vaccines ………………………………… 8
1.4.1.1 Whole-virus inactivated vaccines ………………........ 8
1.4.1.2 Split-virus inactivated vaccines.……………………... 9
1.4.1.3 Subunit inactivated vaccines ………………………… 9
1.4.2 Live attenuated influenza vaccine .………………………………. 10
1.4.3 Recombinant HA vaccine ……………………………………….. 10
xi
1.5 Influenza vaccine manufacturing process ………………………………… 11
1.5.1 Egg-based vaccine ………………………………………………. 11
1.5.2 Cell-based vaccine ………………………………………………. 12
1.5.3 New vaccine technologies ……………………………………….. 13
1.5.3.1 Rise of VLPs in vaccine development ………………. 13
1.5.3.2 Expression platforms for VLP production …………... 14
ⅰ. Insect cells-based expression systems …………. 15
ⅰⅰ. Mammalian cells-based expression systems …... 16
ⅰⅰⅰ. Plant-based expression systems ……………….. 16
ⅰⅴ Yeast-based expression systems ………………. 17
ⅴ. Bacterial expression systems ………………….. 17
1.5.3.3 Key attractive characteristics VLPs candidates ……… 18
1.5.3.4 Immunological mechanisms of VLP vaccine ………. 19
ⅰ. Humoral immune responses …………………… 19
ⅰⅰ. Cell-mediated immune responses ……………... 20
1.5.3.5 Transformative success stories of VLP vaccines ……. 21
1.5.3.6 Challenges and Solutions in VLP Vaccine
Development …………………………………………

22
1.6 Research objectives ………………………………………………………. 24
Chapter 2. Materials and methods …………………………………………………………… 25-38
2.1. Viruses, cell lines and media ……………………………………………… 25
2.2. Construction of plasmid ………………………………………………….. 26
2.2.1 Construction of plasmid for homologous VLPs ………………… 26
2.2.2 Construction of plasmid for chimeric VLPs ……….……………. 26
2.3 Production of recombinant baculovirus ……...…………………………… 27
2.4 Plaque assay ……………………………………………………………… 27
2.5 Production of virus-like particles …………………………………………. 28
2.4 Purification of the virus-like particles ……………………………………. 29
2.5 Hemagglutination assay ………………………………………………….. 29
2.6 Western blot and SDS-PAGE analysis …………………………………… 29
2.6.1 Western blot and SDS-PAGE analysis for homologous VLPs ….. 29
xii
2.6.2 Western blot and SDS-PAGE analysis for chimeric VLPs ……… 30
2.7 Single radial immunodiffusion assay ……………………………………... 31
2.8 Total protein and HA protein quantification ……………………………… 31
2.9 Dynamic light scattering ………………………………………………….. 31
2.10 Size exclusion chromatography …………………………………………... 32
2.11 Transmission electron microscopy ……………………………………….. 32
2.12 Mice study ………………………………………………………………... 32
2.12.1 Immunization of mice with monovalent and bivalent VLPs ……. 32
2.12.2 Immunization of mice with homologous VLPs …………………. 33
2.12.3 Immunization of mice with chimeric VLPs and influenza virus
challenges ……………………………………………………….. 34
2.12.2.1 Mice lethal dose determination ……………………… 34
2.12.2.2 Immunization ………………………………………... 35
2.12.2.3 Virus challenges ……………………………………... 35
2.13 Hemagglutination inhibition assay……………...………………………… 36
2.14 Virus neutralization assay ……………………...………………………..... 37
2.15 Tissue-culture infectious dose …………………….……………………… 37
2.16 RT-qPCR …………………………………………………………………. 37
2.17 Immunohistochemistry ……...……………………………………………. 38
2.18 Statistical analysis …………………………………………………........... 38
Chapter 3. Results ……………………………………………………………………………. 39-62
3.1 Development of homologous seasonal influenza VLP vaccines …………. 39
3.1.1 Expression and characterization of homologous type A and type
B VLPs …………………………………………………………... 39
3.1.2 Pilot evaluation of VLPs stability ………………………………... 42
3.1.3 Immunogenicity of monovalent and bivalent VLPs in mice …… 43
3.1.4 Immunogenicity of quadrivalent VLPs in mice ………………… 46
3.2 Development of chimeric seasonal influenza VLP vaccines ……………… 49
3.2.1 Expression and characterization of chimeric VLPs ……………… 49
3.2.2 Immunogenicity of chimeric quadrivalent VLPs in mice………… 54
3.2.2.1 HAI and NT antibody responses of chimeric VLPs …. 54
xiii
3.2.2.2 Mice body weight loss and survivability against
lethal influenza challenges ………………………….. 57
3.2.2.3 Viral clearance from the respiratory tracts after lethal
influenza challenges …………………………………. 60
3.2.2.4 Lungs histopathology after lethal influenza
challenges……………………………………………. 61
Chapter 4. Discussion ...……………………………………………………………………… 63-71
4.1 Evaluation of homologous VLP…………………………………………... 63
4.2 Evaluation of chimeric VLP………………………………………………. 67
Chapter 5. Conclusions and future directions…………………………………………............ 72
Bibliography ………………………………………………………………………………….… 73-82
參考文獻 Bibliography
1. Arbeitskreis Blut, U., Influenza Virus. Transfus Med Hemother, 2009. 36(1): p. 32-39.
2. Kaaijk, P., et al., Contribution of Influenza Viruses, Other Respiratory Viruses and Viral CoInfections to Influenza-like Illness in Older Adults. Viruses, 2022. 14(4).
3. Wang, X., et al., Global burden of respiratory infections associated with seasonal influenza in
children under 5 years in 2018: a systematic review and modelling study. Lancet Glob
Health, 2020. 8(4): p. e497-e510.
4. Wong, P.L., et al., The effects of age on clinical characteristics, hospitalization and mortality
of patients with influenza-related illness at a tertiary care centre in Malaysia. Influenza Other
Respir Viruses, 2020. 14(3): p. 286-293.
5. WHO, Influenza (Seasonal). 2018: Geneva, Switzerland.
6. CDC, 2021-2022 U.S. Flu Season: Preliminary In-Season Burden Estimates. 2022.
7. Long, J.S., et al., Host and viral determinants of influenza A virus species specificity. Nat Rev
Microbiol, 2019. 17(2): p. 67-81.
8. Zhai, S.L., et al., Influenza D Virus in Animal Species in Guangdong Province, Southern
China. Emerg Infect Dis, 2017. 23(8): p. 1392-1396.
9. Tong, S., et al., New world bats harbor diverse influenza A viruses. PLoS Pathog, 2013. 9(10):
p. e1003657.
10. Reina, J., [The Victoria and Yamagata Lineages of Influenza B Viruses, unknown and
undervalued]. Rev Esp Quimioter, 2022.
11. Caini, S., et al., Epidemiological and virological characteristics of influenza B: results of the
Global Influenza B Study. Influenza Other Respir Viruses, 2015. 9 Suppl 1: p. 3-12.
12. Vajda, J., et al., Size distribution analysis of influenza virus particles using size exclusion
chromatography. J Chromatogr A, 2016. 1465: p. 117-25.
13. Li, X., et al., Packaging signal of influenza A virus. Virol J, 2021. 18(1): p. 36.
14. Krammer, F., et al., Influenza. Nat Rev Dis Primers, 2018. 4(1): p. 3.
15. Sriwilaijaroen, N. and Y. Suzuki, Molecular basis of the structure and function of H1
hemagglutinin of influenza virus. Proc Jpn Acad Ser B Phys Biol Sci, 2012. 88(6): p. 226-49.
16. Bouvier, N.M. and P. Palese, The biology of influenza viruses. Vaccine, 2008. 26 Suppl
4(Suppl 4): p. D49-53.
17. Hamilton, B.S., G.R. Whittaker, and S. Daniel, Influenza virus-mediated membrane fusion:
determinants of hemagglutinin fusogenic activity and experimental approaches for
assessing virus fusion. Viruses, 2012. 4(7): p. 1144-68.
18. Bertram, S., et al., Novel insights into proteolytic cleavage of influenza virus hemagglutinin.
Rev Med Virol, 2010. 20(5): p. 298-310.
19. Kim, J.I. and M.S. Park, N-linked glycosylation in the hemagglutinin of influenza A viruses.
Yonsei Med J, 2012. 53(5): p. 886-93.
20. Trombetta, C.M., et al., Influenza Viruses and Vaccines: The Role of Vaccine Effectiveness
Studies for Evaluation of the Benefits of Influenza Vaccines. Vaccines (Basel), 2022. 10(5).
21. Yang, J., et al., A new role of neuraminidase (NA) in the influenza virus life cycle: implication
for developing NA inhibitors with novel mechanism of action. Rev Med Virol, 2016. 26(4): p.
242-50.
22. McAuley, J.L., et al., Influenza Virus Neuraminidase Structure and Functions. Front
Microbiol, 2019. 10: p. 39.
23. Shtyrya, Y.A., L.V. Mochalova, and N.V. Bovin, Influenza virus neuraminidase: structure and
function. Acta Naturae, 2009. 1(2): p. 26-32.
74
24. Liu, L., et al., Receptor Binding Properties of Neuraminidase for influenza A virus: An
Overview of Recent Research Advances. Virulence, 2023. 14(1): p. 2235459.
25. Park, S., et al., Adaptive mutations of neuraminidase stalk truncation and deglycosylation
confer enhanced pathogenicity of influenza A viruses. Sci Rep, 2017. 7(1): p. 10928.
26. Goto, H. and Y. Kawaoka, A novel mechanism for the acquisition of virulence by a human
influenza A virus. Proc Natl Acad Sci U S A, 1998. 95(17): p. 10224-8.
27. Rossman, J.S. and R.A. Lamb, Influenza virus assembly and budding. Virology, 2011. 411(2):
p. 229-36.
28. Liu, L., et al., Phosphorylation of Influenza A Virus Matrix Protein 1 at Threonine 108 Controls
Its Multimerization State and Functional Association with the STRIPAK Complex. mBio, 2023.
14(1): p. e0323122.
29. Moreira, E.A., Y. Yamauchi, and P. Matthias, How Influenza Virus Uses Host Cell Pathways
during Uncoating. Cells, 2021. 10(7).
30. Roberts, K.L., et al., The amphipathic helix of influenza A virus M2 protein is required for
filamentous bud formation and scission of filamentous and spherical particles. J Virol, 2013.
87(18): p. 9973-82.
31. Sridhar, S., K.A. Brokstad, and R.J. Cox, Influenza Vaccination Strategies: Comparing
Inactivated and Live Attenuated Influenza Vaccines. Vaccines (Basel), 2015. 3(2): p. 373-89.
32. Mtambo, S.E., et al., Influenza Viruses: Harnessing the Crucial Role of the M2 Ion-Channel
and Neuraminidase toward Inhibitor Design. Molecules, 2021. 26(4).
33. Tisoncik, J.R., et al., The NS1 protein of influenza A virus suppresses interferon-regulated
activation of antigen-presentation and immune-proteasome pathways. J Gen Virol, 2011.
92(Pt 9): p. 2093-2104.
34. O′Neill, R.E., J. Talon, and P. Palese, The influenza virus NEP (NS2 protein) mediates the
nuclear export of viral ribonucleoproteins. EMBO J, 1998. 17(1): p. 288-96.
35. Turrell, L., et al., The role and assembly mechanism of nucleoprotein in influenza A virus
ribonucleoprotein complexes. Nat Commun, 2013. 4: p. 1591.
36. Te Velthuis, A.J. and E. Fodor, Influenza virus RNA polymerase: insights into the mechanisms
of viral RNA synthesis. Nat Rev Microbiol, 2016. 14(8): p. 479-93.
37. Dias, A., et al., The cap-snatching endonuclease of influenza virus polymerase resides in the
PA subunit. Nature, 2009. 458(7240): p. 914-8.
38. Czudai-Matwich, V., et al., PB2 mutations D701N and S714R promote adaptation of an
influenza H5N1 virus to a mammalian host. J Virol, 2014. 88(16): p. 8735-42.
39. Kawaguchi, A., T. Naito, and K. Nagata, Involvement of influenza virus PA subunit in
assembly of functional RNA polymerase complexes. J Virol, 2005. 79(2): p. 732-44.
40. Lutz Iv, M.M., et al., Key Role of the Influenza A Virus PA Gene Segment in the Emergence of
Pandemic Viruses. Viruses, 2020. 12(4).
41. Stevaert, A. and L. Naesens, The Influenza Virus Polymerase Complex: An Update on Its
Structure, Functions, and Significance for Antiviral Drug Design. Med Res Rev, 2016. 36(6): p.
1127-1173.
42. Nuwarda, R.F., A.A. Alharbi, and V. Kayser, An Overview of Influenza Viruses and Vaccines.
Vaccines (Basel), 2021. 9(9).
43. Puzelli, S., et al., Co-circulation of the two influenza B lineages during 13 consecutive
influenza surveillance seasons in Italy, 2004-2017. BMC Infect Dis, 2019. 19(1): p. 990.
44. Paul Glezen, W., et al., The burden of influenza B: a structured literature review. Am J Public
Health, 2013. 103(3): p. e43-51.
45. Chen, J., et al., Advances in Development and Application of Influenza Vaccines. Front
Immunol, 2021. 12: p. 711997.
75
46. Francis, T., et al., Protective Effect of Vaccination against Induced Influenza A. J Clin Invest,
1945. 24(4): p. 536-46.
47. Kurth, R., Obituary: Maurice R. Hilleman (1919-2005). Nature, 2005. 434(7037): p. 1083.
48. Shao, W., et al., Evolution of Influenza A Virus by Mutation and Re-Assortment. Int J Mol Sci,
2017. 18(8).
49. Kim, H., R.G. Webster, and R.J. Webby, Influenza Virus: Dealing with a Drifting and Shifting
Pathogen. Viral Immunol, 2018. 31(2): p. 174-183.
50. Liang, Y., Pathogenicity and virulence of influenza. Virulence, 2023. 14(1): p. 2223057.
51. Barberis, I., et al., History and evolution of influenza control through vaccination: from the
first monovalent vaccine to universal vaccines. J Prev Med Hyg, 2016. 57(3): p. E115-E120.
52. Li, J., et al., Influenza and Universal Vaccine Research in China. Viruses, 2022. 15(1).
53. Tisa, V., et al., Quadrivalent influenza vaccine: a new opportunity to reduce the influenza
burden. J Prev Med Hyg, 2016. 57(1): p. E28-33.
54. Kalarikkal SM, S.H., Jaishankar GB, Influenza Vaccine. StatPearls [Internet], 2024.
55. CDC, Influenza Vaccination: A Summary for Clinicians. March 21, 2024.
56. Hoft, D.F., et al., Comparisons of the Humoral and Cellular Immune Responses Induced by
Live Attenuated Influenza Vaccine and Inactivated Influenza Vaccine in Adults. Clin Vaccine
Immunol, 2017. 24(1).
57. al-Mazrou, A., et al., Comparison of adverse reactions to whole-virion and split-virion
influenza vaccines in hospital personnel. CMAJ, 1991. 145(3): p. 213-8.
58. Soema, P.C., et al., Current and next generation influenza vaccines: Formulation and
production strategies. Eur J Pharm Biopharm, 2015. 94: p. 251-63.
59. Kon, T.C., et al., Influenza Vaccine Manufacturing: Effect of Inactivation, Splitting and Site of
Manufacturing. Comparison of Influenza Vaccine Production Processes. PLoS One, 2016.
11(3): p. e0150700.
60. Sabbaghi, A., et al., Inactivation methods for whole influenza vaccine production. Rev Med
Virol, 2019. 29(6): p. e2074.
61. Lee, K.K., et al., Quantitative determination of the surfactant-induced split ratio of influenza
virus by fluorescence spectroscopy. Hum Vaccin Immunother, 2016. 12(7): p. 1757-65.
62. Squarcione, S., et al., Comparison of the reactogenicity and immunogenicity of a split and a
subunit-adjuvanted influenza vaccine in elderly subjects. Vaccine, 2003. 21(11-12): p. 1268-
74.
63. TGA, 2024 Seasonal influenza vaccines, D.o.H.a.A. Care, Editor. 2024, Therapeutic Goods
Administration (TGA): Australia.
64. Khalaj-Hedayati, A., et al., Nanoparticles in influenza subunit vaccine development:
Immunogenicity enhancement. Influenza Other Respir Viruses, 2020. 14(1): p. 92-101.
65. Maassab, H.F., Adaptation and growth characteristics of influenza virus at 25 degrees c.
Nature, 1967. 213(5076): p. 612-4.
66. Beyer, W.E., et al., Cold-adapted live influenza vaccine versus inactivated vaccine: systemic
vaccine reactions, local and systemic antibody response, and vaccine efficacy. A metaanalysis. Vaccine, 2002. 20(9-10): p. 1340-53.
67. FDA, FluMist Quadrivalent. 2023.
68. EMA, Fluenz Tetra. 2023, European Medicines Agency.
69. Geisler, C. and D.L. Jarvis, Adventitious viruses in insect cell lines used for recombinant
protein expression. Protein Expr Purif, 2018. 144: p. 25-32.
70. Grohskopf, L.A., et al., Prevention and Control of Seasonal Influenza with Vaccines:
Recommendations of the Advisory Committee on Immunization Practices-United States,
2018-19 Influenza Season. MMWR Recomm Rep, 2018. 67(3): p. 1-20.
76
71. Cox, M.M., P.A. Patriarca, and J. Treanor, FluBlok, a recombinant hemagglutinin influenza
vaccine. Influenza Other Respir Viruses, 2008. 2(6): p. 211-9.
72. Treanor, J.J., et al., Safety and immunogenicity of a recombinant hemagglutinin vaccine for
H5 influenza in humans. Vaccine, 2001. 19(13-14): p. 1732-7.
73. Sahly, A.F.G.H.E., Recombinant hemagglutinin protein vaccine: a new option in
immunization against influenza. FUTURE VIROLOGY 2015. VOL. 10(NO. 9 ).
74. Dunkle, L., et al., Introducing Modern Recombinant Technology to the Realm of Seasonal
Influenza Vaccine: Flublok® For Prevention of Influenza in Adults. 2015. 2: p. 224-234.
75. Milian, E. and A.A. Kamen, Current and emerging cell culture manufacturing technologies for
influenza vaccines. Biomed Res Int, 2015. 2015: p. 504831.
76. Rajaram, S., et al., Influenza vaccines: the potential benefits of cell-culture isolation and
manufacturing. Ther Adv Vaccines Immunother, 2020. 8: p. 2515135520908121.
77. Wong, S.S. and R.J. Webby, Traditional and new influenza vaccines. Clin Microbiol Rev, 2013.
26(3): p. 476-92.
78. Couch, R.B., Seasonal inactivated influenza virus vaccines. Vaccine, 2008. 26 Suppl 4(Suppl
4): p. D5-9.
79. Krause, J.C. and J.E. Crowe, Jr., Committing the Oldest Sins in the Newest Kind of WaysAntibodies Targeting the Influenza Virus Type A Hemagglutinin Globular Head. Microbiol
Spectr, 2014. 2(5).
80. Stohr, K., et al., Influenza virus surveillance, vaccine strain selection, and manufacture.
Methods Mol Biol, 2012. 865: p. 147-62.
81. Peck, H., et al., Enhanced isolation of influenza viruses in qualified cells improves the
probability of well-matched vaccines. NPJ Vaccines, 2021. 6(1): p. 149.
82. Skowronski, D.M., et al., Low 2012-13 influenza vaccine effectiveness associated with
mutation in the egg-adapted H3N2 vaccine strain not antigenic drift in circulating viruses.
PLoS One, 2014. 9(3): p. e92153.
83. Hegde, N.R., Cell culture-based influenza vaccines: A necessary and indispensable
investment for the future. Hum Vaccin Immunother, 2015. 11(5): p. 1223-34.
84. An, Y., et al., Comparative glycomics analysis of influenza Hemagglutinin (H5N1) produced
in vaccine relevant cell platforms. J Proteome Res, 2013. 12(8): p. 3707-20.
85. Hutter, J., et al., Toward animal cell culture-based influenza vaccine design: viral
hemagglutinin N-glycosylation markedly impacts immunogenicity. J Immunol, 2013. 190(1):
p. 220-30.
86. Paules, C.I., et al., Chasing Seasonal Influenza - The Need for a Universal Influenza Vaccine.
N Engl J Med, 2018. 378(1): p. 7-9.
87. Lin, Y., et al., The characteristics and antigenic properties of recently emerged subclade
3C.3a and 3C.2a human influenza A(H3N2) viruses passaged in MDCK cells. Influenza Other
Respir Viruses, 2017. 11(3): p. 263-274.
88. Ward, B.J., et al., Efficacy, immunogenicity, and safety of a plant-derived, quadrivalent, viruslike particle influenza vaccine in adults (18-64 years) and older adults (>/=65 years): two
multicentre, randomised phase 3 trials. Lancet, 2020. 396(10261): p. 1491-1503.
89. Tariq, H., et al., Virus-Like Particles: Revolutionary Platforms for Developing Vaccines
Against Emerging Infectious Diseases. Front Microbiol, 2021. 12: p. 790121.
90. Yan, D., et al., The application of virus-like particles as vaccines and biological vehicles. Appl
Microbiol Biotechnol, 2015. 99(24): p. 10415-32.
91. Chen, Q. and H. Lai, Plant-derived virus-like particles as vaccines. Hum Vaccin Immunother,
2013. 9(1): p. 26-49.
77
92. McAleer, W.J., et al., Human hepatitis B vaccine from recombinant yeast. Nature, 1984.
307(5947): p. 178-80.
93. Zeltins, A., Construction and characterization of virus-like particles: a review. Mol
Biotechnol, 2013. 53(1): p. 92-107.
94. Wang, J.W. and R.B. Roden, Virus-like particles for the prevention of human papillomavirusassociated malignancies. Expert Rev Vaccines, 2013. 12(2): p. 129-41.
95. Pillet, S., et al., Immunogenicity and safety of a quadrivalent plant-derived virus like particle
influenza vaccine candidate-Two randomized Phase II clinical trials in 18 to 49 and >/=50
years old adults. PLoS One, 2019. 14(6): p. e0216533.
96. Mohsen, M.O. and M.F. Bachmann, Virus-like particle vaccinology, from bench to bedside.
Cell Mol Immunol, 2022. 19(9): p. 993-1011.
97. Ong, H.K., W.S. Tan, and K.L. Ho, Virus like particles as a platform for cancer vaccine
development. PeerJ, 2017. 5: p. e4053.
98. Fuenmayor, J., F. Godia, and L. Cervera, Production of virus-like particles for vaccines. N
Biotechnol, 2017. 39(Pt B): p. 174-180.
99. Hong, M., et al., Genetic engineering of baculovirus-insect cell system to improve protein
production. Front Bioeng Biotechnol, 2022. 10: p. 994743.
100. Scholz, J. and S. Suppmann, A new single-step protocol for rapid baculovirus-driven protein
production in insect cells. BMC Biotechnol, 2017. 17(1): p. 83.
101. Roldão, A., et al., Viruses and virus-like particles in biotechnology: fundamentals and
applications. 2011: p. 625.
102. Strobl, F., et al., Evaluation of screening platforms for virus-like particle production with the
baculovirus expression vector system in insect cells. Sci Rep, 2020. 10(1): p. 1065.
103. Gupta, R., et al., Platforms, advances, and technical challenges in virus-like particles-based
vaccines. Front Immunol, 2023. 14: p. 1123805.
104. Kang, H.J., et al., Influenza M2 virus-like particle vaccination enhances protection in
combination with avian influenza HA VLPs. PLoS One, 2019. 14(6): p. e0216871.
105. Shi, L., et al., VLPs containing stalk domain and ectodomain of matrix protein 2 of influenza
induce protection in mice. Virol J, 2023. 20(1): p. 38.
106. Dumont, J., et al., Human cell lines for biopharmaceutical manufacturing: history, status,
and future perspectives. Crit Rev Biotechnol, 2016. 36(6): p. 1110-1122.
107. Gray, D., Overview of protein expression by mammalian cells. Curr Protoc Protein Sci, 2001.
Chapter 5(1): p. Unit5 9.
108. Qian, C., et al., Recent Progress on the Versatility of Virus-Like Particles. Vaccines (Basel),
2020. 8(1).
109. Eidenberger, L., B. Kogelmann, and H. Steinkellner, Plant-based biopharmaceutical
engineering. Nat Rev Bioeng, 2023. 1(6): p. 426-439.
110. Hemmati, F., et al., Plant-derived VLP: a worthy platform to produce vaccine against SARSCoV-2. Biotechnol Lett, 2022. 44(1): p. 45-57.
111. Ward, B.J., et al., Phase III: Randomized observer-blind trial to evaluate lot-to-lot
consistency of a new plant-derived quadrivalent virus like particle influenza vaccine in
adults 18-49 years of age. Vaccine, 2021. 39(10): p. 1528-1533.
112. Srivastava, V., et al., Yeast-Based Virus-like Particles as an Emerging Platform for Vaccine
Development and Delivery. Vaccines (Basel), 2023. 11(2).
113. Shirbaghaee, Z. and A. Bolhassani, Different applications of virus-like particles in biology
and medicine: Vaccination and delivery systems. Biopolymers, 2016. 105(3): p. 113-32.
114. Vieira Gomes, A.M., et al., Comparison of Yeasts as Hosts for Recombinant Protein
Production. Microorganisms, 2018. 6(2).
78
115. Huang, X., et al., Escherichia coli-derived virus-like particles in vaccine development. NPJ
Vaccines, 2017. 2: p. 3.
116. Yang, J., et al., Exploration on the expression and assembly of virus-like particles. 2021. 2: p.
51-58.
117. Martins, S.A., et al., How promising are HIV-1-based virus-like particles for medical
applications. Front Cell Infect Microbiol, 2022. 12: p. 997875.
118. Donaldson, B., et al., Virus-like particle vaccines: immunology and formulation for clinical
translation. Expert Rev Vaccines, 2018. 17(9): p. 833-849.
119. Nooraei, S., et al., Virus-like particles: preparation, immunogenicity and their roles as
nanovaccines and drug nanocarriers. J Nanobiotechnology, 2021. 19(1): p. 59.
120. Taghizadeh, M.S., A. Niazi, and A. Afsharifar, Virus-like particles (VLPs): A promising platform
for combating against Newcastle disease virus. Vaccine X, 2024. 16: p. 100440.
121. Braun, M., et al., Virus-like particles induce robust human T-helper cell responses. Eur J
Immunol, 2012. 42(2): p. 330-40.
122. Bachmann, M.F. and R.M. Zinkernagel, The influence of virus structure on antibody
responses and virus serotype formation. Immunol Today, 1996. 17(12): p. 553-8.
123. Fehr, T., et al., T cell-independent type I antibody response against B cell epitopes expressed
repetitively on recombinant virus particles. Proc Natl Acad Sci U S A, 1998. 95(16): p. 9477-
81.
124. Chackerian, B., M.R. Durfee, and J.T. Schiller, Virus-like display of a neo-self antigen reverses
B cell anergy in a B cell receptor transgenic mouse model. J Immunol, 2008. 180(9): p. 5816-
25.
125. Bessa, J., et al., Low-affinity B cells transport viral particles from the lung to the spleen to
initiate antibody responses. Proc Natl Acad Sci U S A, 2012. 109(50): p. 20566-71.
126. Bachmann, M.F., et al., The influence of antigen organization on B cell responsiveness.
Science, 1993. 262(5138): p. 1448-51.
127. MacLennan, I.C., et al., Extrafollicular antibody responses. Immunol Rev, 2003. 194: p. 8-18.
128. Nutt, S.L. and D.M. Tarlinton, Germinal center B and follicular helper T cells: siblings,
cousins or just good friends? Nat Immunol, 2011. 12(6): p. 472-7.
129. Fairfax, K.A., et al., Plasma cell development: from B-cell subsets to long-term survival
niches. Semin Immunol, 2008. 20(1): p. 49-58.
130. Yang, R., et al., B lymphocyte activation by human papillomavirus-like particles directly
induces Ig class switch recombination via TLR4-MyD88. J Immunol, 2005. 174(12): p. 7912-
9.
131. Bessa, J., et al., Alveolar macrophages and lung dendritic cells sense RNA and drive
mucosal IgA responses. J Immunol, 2009. 183(6): p. 3788-99.
132. Brandtzaeg, P., Mucosal immunity in the female genital tract. J Reprod Immunol, 1997. 36(1-
2): p. 23-50.
133. Hillaire, M.L., A.D. Osterhaus, and G.F. Rimmelzwaan, Induction of virus-specific cytotoxic T
lymphocytes as a basis for the development of broadly protective influenza vaccines. J
Biomed Biotechnol, 2011. 2011: p. 939860.
134. Sommerfelt, M.A., T-cell-mediated and humoral approaches to universal influenza vaccines.
Expert Rev Vaccines, 2011. 10(10): p. 1359-61.
135. Roldao, A., et al., Virus-like particles in vaccine development. Expert Rev Vaccines, 2010.
9(10): p. 1149-76.
136. Chackerian, B., Virus-like particles: flexible platforms for vaccine development. Expert Rev
Vaccines, 2007. 6(3): p. 381-90.
79
137. Townsend, A. and H. Bodmer, Antigen recognition by class I-restricted T lymphocytes. Annu
Rev Immunol, 1989. 7: p. 601-24.
138. Kovacsovics-Bankowski, M., et al., Efficient major histocompatibility complex class I
presentation of exogenous antigen upon phagocytosis by macrophages. Proc Natl Acad Sci
U S A, 1993. 90(11): p. 4942-6.
139. Bachmann, M.F., et al., Dendritic cells process exogenous viral proteins and virus-like
particles for class I presentation to CD8+ cytotoxic T lymphocytes. Eur J Immunol, 1996.
26(11): p. 2595-600.
140. Fifis, T., et al., Size-dependent immunogenicity: therapeutic and protective properties of
nano-vaccines against tumors. J Immunol, 2004. 173(5): p. 3148-54.
141. Roozendaal, R., R.E. Mebius, and G. Kraal, The conduit system of the lymph node. Int
Immunol, 2008. 20(12): p. 1483-7.
142. Lenz, P., et al., Papillomavirus-like particles induce acute activation of dendritic cells. J
Immunol, 2001. 166(9): p. 5346-55.
143. Bosio, C.M., et al., Ebola and Marburg virus-like particles activate human myeloid dendritic
cells. Virology, 2004. 326(2): p. 280-7.
144. Chroboczek, J., I. Szurgot, and E. Szolajska, Virus-like particles as vaccine. Acta Biochim Pol,
2014. 61(3): p. 531-9.
145. Zhu, F.C., et al., Efficacy and safety of a recombinant hepatitis E vaccine in healthy adults: a
large-scale, randomised, double-blind placebo-controlled, phase 3 trial. Lancet, 2010.
376(9744): p. 895-902.
146. Weber, J., et al., Immunogenicity of the yeast recombinant p17/p24:Ty virus-like particles
(p24-VLP) in healthy volunteers. Vaccine, 1995. 13(9): p. 831-4.
147. Gao, S., S. Song, and L. Zhang, Recent Progress in Vaccine Development Against
Chikungunya Virus. Front Microbiol, 2019. 10: p. 2881.
148. Moon, K.B., et al., Construction of SARS-CoV-2 virus-like particles in plant. Sci Rep, 2022.
12(1): p. 1005.
149. Mo, Y., et al., Prophylactic and Therapeutic HPV Vaccines: Current Scenario and
Perspectives. Front Cell Infect Microbiol, 2022. 12: p. 909223.
150. Mohsen, M.O., et al., Major findings and recent advances in virus-like particle (VLP)-based
vaccines. Semin Immunol, 2017. 34: p. 123-132.
151. Aguado-Garcia, D., et al., Evaluation of the Thermal Stability of a Vaccine Prototype Based
on Virus-like Particle Formulated HIV-1 Envelope. Vaccines (Basel), 2022. 10(4).
152. Servin-Blanco, R., et al., Antigenic variability: Obstacles on the road to vaccines against
traditionally difficult targets. Hum Vaccin Immunother, 2016. 12(10): p. 2640-2648.
153. REED, L.J. and H. MUENCH, A SIMPLE METHOD OF ESTIMATING FIFTY PER CENT
ENDPOINTS. American Journal of Epidemiology, 1938. 27(3): p. 493-497.
154. Lai, C.C., et al., Process development for pandemic influenza VLP vaccine production using
a baculovirus expression system. J Biol Eng, 2019. 13: p. 78.
155. ThermoFisher, User guide: Bac-to-Bac® Baculovirus Expression System. 2018: United
States.
156. WHO, Who Manual on Animal Influenza Virus Diagnosis and Surveilance. 2002.
157. Wood, J.M., et al., An improved single-radial-immunodiffusion technique for the assay of
influenza haemagglutinin antigen: application for potency determinations of inactivated
whole virus and subunit vaccines. J Biol Stand, 1977. 5(3): p. 237-47.
158. Chia, M.Y., et al., Evaluation of MDCK cell-derived influenza H7N9 vaccine candidates in
ferrets. PLoS One, 2015. 10(3): p. e0120793.
80
159. Lin, C.Y., et al., Assessment of pathogenicity and antigenicity of American lineage influenza
H5N2 viruses in Taiwan. Virology, 2017. 508: p. 159-163.
160. REED, L.J. and H. MUENCH, A SIMPLE METHOD OF ESTIMATING FIFTY PER CENT
ENDPOINTS12. American Journal of Epidemiology, 1938. 27(3): p. 493-497.
161. Wei, J., et al., A newly developed real-time PCR assay for discriminating influenza B virus
Yamagata and Victoria lineages. J Med Virol, 2020. 92(12): p. 3067-3072.
162. WHO, Who Expert Comittee on Biological Standartisation Recommendations for the
Production and Control of Influenza Vaccine (Inactivated). 2005.
163. van Baalen, C.A., et al., Detection of nonhemagglutinating influenza A(H3) viruses by
enzyme-linked immunosorbent assay in quantitative influenza virus culture. J Clin Microbiol,
2014. 52(5): p. 1672-7.
164. Correia, R., et al., Improving Influenza HA-Vlps Production in Insect High Five Cells via
Adaptive Laboratory Evolution. Vaccines (Basel), 2020. 8(4).
165. Kong, D., et al., Supplementation of H7N9 Virus-Like Particle Vaccine With Recombinant
Epitope Antigen Confers Full Protection Against Antigenically Divergent H7N9 Virus in
Chickens. Front Immunol, 2022. 13: p. 785975.
166. Athmaram, T.N., et al., Yeast expressed recombinant Hemagglutinin protein of novel H1N1
elicits neutralising antibodies in rabbits and mice. Virol J, 2011. 8: p. 524.
167. Marchal, I., et al., Glycoproteins from insect cells: sialylated or not? Biol Chem, 2001.
382(2): p. 151-9.
168. Bao, D., et al., N-Linked Glycosylation Plays an Important Role in Budding of Neuraminidase
Protein and Virulence of Influenza Viruses. J Virol, 2021. 95(3).
169. Khan, A.H., et al., Humanizing glycosylation pathways in eukaryotic expression systems.
World J Microbiol Biotechnol, 2017. 33(1): p. 4.
170. Pushko, P., et al., Recombinant H1N1 virus-like particle vaccine elicits protective immunity
in ferrets against the 2009 pandemic H1N1 influenza virus. Vaccine, 2010. 28(30): p. 4771-6.
171. Krammer, F., et al., Trichoplusia ni cells (High Five) are highly efficient for the production of
influenza A virus-like particles: a comparison of two insect cell lines as production platforms
for influenza vaccines. Mol Biotechnol, 2010. 45(3): p. 226-34.
172. Matsuda, T., et al., Production of influenza virus-like particles using recombinant insect
cells. Biochem Eng J, 2020. 163: p. 107757.
173. Buffin, S., et al., Influenza A and B virus-like particles produced in mammalian cells are
highly immunogenic and induce functional antibodies. Vaccine, 2019. 37(46): p. 6857-6867.
174. Shin, J.I., Y.C. Park, and J.M. Song, Influence of temperature on the antigenic changes of
virus-like particles. Clin Exp Vaccine Res, 2020. 9(2): p. 126-132.
175. Health, A.G.D.o., National Vaccine Storage Guidelines-Strive for 5, A.G.D.o. Health, Editor.
2019: Canberra, Australia.
176. Kim, S.H., Y.C. Park, and J.M. Song, Evaluation of the antigenic stability of influenza virus like
particles after exposure to acidic or basic pH. Clin Exp Vaccine Res, 2021. 10(3): p. 252-258.
177. Lynch, A., et al., Stability studies of HIV-1 Pr55gag virus-like particles made in insect cells
after storage in various formulation media. Virol J, 2012. 9: p. 210.
178. Correia, R., et al., Improved storage of influenza HA-VLPs using a trehalose-glycerol natural
deep eutectic solvent system. Vaccine, 2021. 39(24): p. 3279-3286.
179. Kim, Y.C., et al., Influenza immunization with trehalose-stabilized virus-like particle vaccine
using microneedles. Procedia Vaccinol, 2010. 2(1): p. 15-19.
180. Kissmann, J., et al., H1N1 influenza virus-like particles: physical degradation pathways and
identification of stabilizers. J Pharm Sci, 2011. 100(2): p. 634-45.
81
181. Quan, F.S., et al., Long-term protective immunity from an influenza virus-like particle vaccine
administered with a microneedle patch. Clin Vaccine Immunol, 2013. 20(9): p. 1433-9.
182. Jang, Y.H., et al., Protective efficacy in mice of monovalent and trivalent live attenuated
influenza vaccines in the background of cold-adapted A/X-31 and B/Lee/40 donor strains.
Vaccine, 2014. 32(5): p. 535-43.
183. Hu, J., et al., Baculovirus-derived influenza virus-like particle confers complete protection
against lethal H7N9 avian influenza virus challenge in chickens and mice. Vet Microbiol,
2022. 264: p. 109306.
184. Liu, Y.V., et al., Recombinant virus-like particles elicit protective immunity against avian
influenza A(H7N9) virus infection in ferrets. Vaccine, 2015. 33(18): p. 2152-8.
185. Mai, Z., et al., Protection efficacy of the H1 and H3 bivalent virus-like particle vaccine against
swine influenza virus infection. Vet Microbiol, 2023. 280: p. 109719.
186. Cox, M.M. and J.R. Hollister, FluBlok, a next generation influenza vaccine manufactured in
insect cells. Biologicals, 2009. 37(3): p. 182-9.
187. Cox, M.M., et al., Safety, efficacy, and immunogenicity of Flublok in the prevention of
seasonal influenza in adults. Ther Adv Vaccines, 2015. 3(4): p. 97-108.
188. Keitel, W.A., et al., Comparative immunogenicity of recombinant influenza hemagglutinin
(rHA) and trivalent inactivated vaccine (TIV) among persons > or =65 years old. Vaccine,
2009. 28(2): p. 379-85.
189. Ruiz-Palacios, G.M., et al., Immunogenicity of AS03-adjuvanted and non-adjuvanted
trivalent inactivated influenza vaccines in elderly adults: A Phase 3, randomized trial and
post-hoc correlate of protection analysis. Hum Vaccin Immunother, 2016. 12(12): p. 3043-
3055.
190. Treanor, J.J., et al., Safety and immunogenicity of a baculovirus-expressed hemagglutinin
influenza vaccine: a randomized controlled trial. JAMA, 2007. 297(14): p. 1577-82.
191. Heinimaki, S., et al., Live baculovirus acts as a strong B and T cell adjuvant for monomeric
and oligomeric protein antigens. Virology, 2017. 511: p. 114-122.
192. Rockman, S., et al., Cell-Based Manufacturing Technology Increases Antigenic Match of
Influenza Vaccine and Results in Improved Effectiveness. Vaccines (Basel), 2022. 11(1).
193. Rajaram, S., et al., Retrospective Assessment of the Antigenic Similarity of Egg-Propagated
and Cell Culture-Propagated Reference Influenza Viruses as Compared with Circulating
Viruses across Influenza Seasons 2002-2003 to 2017-2018. Int J Environ Res Public Health,
2020. 17(15).
194. Rajaram, S., et al., The impact of candidate influenza virus and egg-based manufacture on
vaccine effectiveness: Literature review and expert consensus. Vaccine, 2020. 38(38): p.
6047-6056.
195. Ross, T.M., et al., A trivalent virus-like particle vaccine elicits protective immune responses
against seasonal influenza strains in mice and ferrets. PLoS One, 2009. 4(6): p. e6032.
196. Allen, J.D., et al., Elicitation of Protective Antibodies against 20 Years of Future H3N2
Cocirculating Influenza Virus Variants in Ferrets Preimmune to Historical H3N2 Influenza
Viruses. J Virol, 2019. 93(3).
197. Bright, R.A., et al., Influenza virus-like particles elicit broader immune responses than whole
virion inactivated influenza virus or recombinant hemagglutinin. Vaccine, 2007. 25(19): p.
3871-8.
198. Novavax, I., Novavax Announces Positive Data From Phase 2 Trial of Quadrivalent Seasonal
Influenza VLP. 2015: Gaithersburg, Maryland, United States.
199. Novavax, I., Novavax’ Preclinical Influenza Nanoparticle Study Published in Vaccine. 2017:
Gaithersburg, Maryland, United States.
82
200. Liu, X., et al., A mosaic influenza virus-like particles vaccine provides broad humoral and
cellular immune responses against influenza A viruses. NPJ Vaccines, 2023. 8(1): p. 132.
201. Chen, B.J., et al., Influenza virus hemagglutinin and neuraminidase, but not the matrix
protein, are required for assembly and budding of plasmid-derived virus-like particles. J
Virol, 2007. 81(13): p. 7111-23.
202. Zanin, M., et al., An Amino Acid in the Stalk Domain of N1 Neuraminidase Is Critical for
Enzymatic Activity. J Virol, 2017. 91(2).
203. Manolova, V., et al., Nanoparticles target distinct dendritic cell populations according to
their size. Eur J Immunol, 2008. 38(5): p. 1404-13.
204. Steppert, P., et al., Quantification and characterization of virus-like particles by sizeexclusion chromatography and nanoparticle tracking analysis. J Chromatogr A, 2017. 1487:
p. 89-99.
205. Carvalho, S.B., et al., Bioanalytics for Influenza Virus-Like Particle Characterization and
Process Monitoring. Front Bioeng Biotechnol, 2022. 10: p. 805176.
206. Wu, C.Y., et al., Mammalian expression of virus-like particles for advanced mimicry of
authentic influenza virus. PLoS One, 2010. 5(3): p. e9784.
207. Latham, T. and J.M. Galarza, Formation of wild-type and chimeric influenza virus-like
particles following simultaneous expression of only four structural proteins. J Virol, 2001.
75(13): p. 6154-65.
208. Organization, W.H., WHO Expert Comittee on Biological Standartisation Recommendations
for the Production and Control of Influenza Vaccine (Inactivated). 2005. WHO Technical
Report Series No. 927 (Annex 3).
209. OECD, Guidance document on Baculoviruses as plant protection products 2023,
Organisation for Economic Co-operation and Development
210. Tabarsi, P., et al., Evaluating the efficacy and safety of SpikoGen(R), an Advax-CpG55.2-
adjuvanted severe acute respiratory syndrome coronavirus 2 spike protein vaccine: a phase
3 randomized placebo-controlled trial. Clin Microbiol Infect, 2023. 29(2): p. 215-220.
211. Shinde, V., et al., Comparison of the safety and immunogenicity of a novel Matrix-Madjuvanted nanoparticle influenza vaccine with a quadrivalent seasonal influenza vaccine in
older adults: a phase 3 randomised controlled trial. Lancet Infect Dis, 2022. 22(1): p. 73-84.
212. Padilla-Quirarte, H.O., et al., Protective Antibodies Against Influenza Proteins. Front
Immunol, 2019. 10: p. 1677.
213. Nath Neerukonda, S., R. Vassell, and C.D. Weiss, Neutralizing Antibodies Targeting the
Conserved Stem Region of Influenza Hemagglutinin. Vaccines (Basel), 2020. 8(3).
214. Zost, S.J., et al., Contemporary H3N2 influenza viruses have a glycosylation site that alters
binding of antibodies elicited by egg-adapted vaccine strains. Proc Natl Acad Sci U S A,
2017. 114(47): p. 12578-12583.
215. Melidou, A., et al., Iotanfluenza A(H3N2) genetic variants in vaccinated patients in northern
Greece. J Clin Virol, 2017. 94: p. 29-32.
216. Belongia, E.A., et al., Variable influenza vaccine effectiveness by subtype: a systematic
review and meta-analysis of test-negative design studies. Lancet Infect Dis, 2016. 16(8): p.
942-51.
217. Dunkle, L.M., et al., Randomized Comparison of Immunogenicity and Safety of Quadrivalent
Recombinant Versus Inactivated Influenza Vaccine in Healthy Adults 18-49 Years of Age. J
Infect Dis, 2017. 216(10): p. 1219-1226.
218. Galarza, J.M., T. Latham, and A. Cupo, Virus-like particle vaccine conferred complete
protection against a lethal influenza virus challenge. Viral Immunol, 2005. 18(2): p. 365-72
指導教授 李敏西 黃佳瑜(Min-Shi Lee Chia-Yu Huang) 審核日期 2024-7-30
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