The Application Progress of Serum-free Suspension Culture Technology of MDCK Cells in Influenza Vaccine Study and Production

doi:10.13560/j.cnki.biotech.bull.1985.2023-0787

Abstract

Abstract:

Influenza is a common respiratory disease caused by influenza viruses. MDCK（Madin-Darby Canine Kidney）cells have the characteristics of easy culture and high production, which can support the replication and proliferation of influenza viruses, and are widely used in the research and production of influenza viruses. With the deepening of research on influenza virus, and in order to further optimize the ability of MDCK cells to be used for influenza virus research and industrial application, researchers began to develop the domestication technology of MDCK cells. Through long-term cultivation and selection, the domesticated MDCK cells strain can better adapt to the growth environment of influenza virus, and improve the production and infectivity of influenza virus. In conclusion, the domestication technology of MDCK cells plays an important role in influenza virus research and industrial application, which may improve the production and infectivity of influenza viruses and provide better tools for influenza vaccine production and anti influenza drug development. Concurrently we have to also pay attention to the safety of MDCK cells and take appropriate measures to ensure the safety and reliability of its application.

Key words: MDCK cells, cell suspension demestication, serum-free medium, influenza vaccine, safety

JIN Li-wu, ZHANG Zhen-yu, JIN Dong-wu, MA Hua, MA Yu-mei, QIAO Zi-lin, WANG Jia-min. The Application Progress of Serum-free Suspension Culture Technology of MDCK Cells in Influenza Vaccine Study and Production[J]. Biotechnology Bulletin, 2024, 40(2): 38-47.

Figures/Tables 4

References 65

[1]	Influenza(Seasonal). WHO fact sheet on influenza: includes key facts, definition, symptoms, transmission, seasonal epidemics, effects, prevention, WHO response[EB/OL].(2018-03-31)(2023-07-07). https://www.who.int/zh/news-room/fact-sheets/detail/influenza-(seasonal).
[2]	Grohskopf LA, Olsen SJ, Sokolow LZ, et al. Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices(ACIP)—United States, 2014-15 influenza season[J]. Morb Mortal Wkly Rep, 2014, 63(32): 691-697.
[3]	McLean KA, Goldin S, Nannei C, et al. The 2015 global production capacity of seasonal and pandemic influenza vaccine[J]. Vaccine, 2016, 34(45): 5410-5413. doi: S0264-410X(16)30676-4 pmid: 27531411
[4]	Ping JH, Lopes TJS, Neumann G, et al. Development of high-yield influenza B virus vaccine viruses[J]. Proc Natl Acad Sci USA, 2016, 113(51): E8296-E8305.
[5]	Becker T, Elbahesh H, Reperant LA, et al. Influenza vaccines: successes and continuing challenges[J]. J Infect Dis, 2021, 224(12 Suppl 2): S405-S419. doi: 10.1093/infdis/jiab269 URL
[6]	Skowronski DM, Janjua NZ, De Serres G, et al. Low 2012-13 influenza vaccine effectiveness associated with mutation in the egg-adapted H3N2 vaccine strain not antigenic drift in circulating viruses[J]. PLoS One, 2014, 9(3): e92153. doi: 10.1371/journal.pone.0092153 URL
[7]	Govorkova EA, Murti G, Meignier B, et al. African green monkey kidney(Vero)cells provide an alternative host cell system for influenza A and B viruses[J]. J Virol, 1996, 70(8): 5519-5524. pmid: 8764064
[8]	Govorkova EA, Kaverin NV, Gubareva LV, et al. Replication of influenza A viruses in a green monkey kidney continuous cell line(Vero)[J]. J Infect Dis, 1995, 172(1): 250-253. pmid: 7797924
[9]	Pau MG, Ophorst C, Koldijk MH, et al. The human cell line PER.C6 provides a new manufacturing system for the production of influenza vaccines[J]. Vaccine, 2001, 19(17-19): 2716-2721. pmid: 11257414
[10]	Brown SW, Mehtali M. The avian EB66(R)cell line, application to vaccines, and therapeutic protein production[J]. PDA J Pharm Sci Technol, 2010, 64(5): 419-425.
[11]	Rajaram S, Boikos C, Gelone DK, et al. Influenza vaccines: the potential benefits of cell-culture isolation and manufacturing[J]. Ther Adv Vaccines Immunother, 2020, 8: 2515135520908121.
[12]	Gregersen JP, Schmitt HJ, Trusheim H, et al. Safety of MDCK cell culture-based influenza vaccines[J]. Future Microbiol, 2011, 6(2): 143-152. doi: 10.2217/fmb.10.161 URL
[13]	Hegde NR. Cell culture-based influenza vaccines: a necessary and indispensable investment for the future[J]. Hum Vaccin Immunother, 2015, 11(5): 1223-1234. doi: 10.1080/21645515.2015.1016666 URL
[14]	Madin SH, Jr DARBY NB. Established kidney cell lines of normal adult bovine and ovine origin[J]. Proc Soc Exp Biol Med, 1958, 98(3): 574-576. doi: 10.3181/00379727-98-24111 pmid: 13567776
[15]	Omeir RL, Teferedegne B, Foseh GS, et al. Heterogeneity of the tumorigenic phenotype expressed by Madin-Darby canine kidney cells[J]. Comp Med, 2011, 61(3): 243-250.
[16]	Leighton J, Brada Z, Estes LW, et al. Secretory activity and oncogenicity of a cell line(MDCK)derived from canine kidney[J]. Science, 1969, 163(3866): 472-473. pmid: 5762397
[17]	Gaush CR, Hard WL, Smith TF. Characterization of an established line of canine kidney cells(MDCK)[J]. Proc Soc Exp Biol Med, 1966, 122(3): 931-935. doi: 10.3181/00379727-122-31293 pmid: 5918973
[18]	Taub M, Jr Saier MH. An established but differentiated kidney epithelial cell line(MDCK)[J]. Methods Enzymol, 1979, 58: 552-560. pmid: 218080
[19]	Mochizuki M. Growth characteristics of canine pathogenic viruses in MDCK cells cultured in RPMI 1640 medium without animal protein[J]. Vaccine, 2006, 24(11): 1744-1748. doi: 10.1016/j.vaccine.2005.07.114 pmid: 16271422
[20]	Rodgers SE, Barton ES, Oberhaus SM, et al. Reovirus-induced apoptosis of MDCK cells is not linked to viral yield and is blocked by Bcl-2[J]. J Virol, 1997, 71(3): 2540-2546. pmid: 9032397
[21]	Mochizuki M, Hashimoto T. Growth of feline panleukopenia virus and canine parvovirus in vitro[J]. Nihon Juigaku Zasshi, 1986, 48(4): 841-844. doi: 10.1292/jvms1939.48.841 URL
[22]	Green IJ. Serial propagation of influenza B(Lee)virus in a transmissible line of canine kidney cells[J]. Science, 1962, 138(3536): 42-43. doi: 10.1126/science.138.3536.42 URL
[23]	Tree JA, Richardson C, Fooks AR, et al. Comparison of large-scale mammalian cell culture systems with egg culture for the production of influenza virus A vaccine strains[J]. Vaccine, 2001, 19(25-26): 3444-3450. pmid: 11348709
[24]	Cox N, Hannoun C, Hay A, et al. Cell culture as a substrate for the production of influenza vaccines: memorandum from a WHO meeting[J]. Bull World Health Organ, 1995, 73(4): 431-435.
[25]	Peschel B, Frentzel S, Laske T, et al. Comparison of influenza virus yields and apoptosis-induction in an adherent and a suspension MDCK cell line[J]. Vaccine, 2013, 31(48): 5693-5699. doi: 10.1016/j.vaccine.2013.09.051 pmid: 24113260
[26]	Huang D, Peng WJ, Ye Q, et al. Serum-free suspension culture of MDCK cells for production of influenza H1N1 vaccines[J]. PLoS One, 2015, 10(11): e0141686. doi: 10.1371/journal.pone.0141686 URL
[27]	Perdue ML, Arnold F, Li S, et al. The future of cell culture-based influenza vaccine production[J]. Expert Rev Vaccines, 2011, 10(8): 1183-1194. doi: 10.1586/erv.11.82 pmid: 21854311
[28]	Chu CA, Lugovtsev V, Golding H, et al. Conversion of MDCK cell line to suspension culture by transfecting with human siat7e gene and its application for influenza virus production[J]. Proc Natl Acad Sci USA, 2009, 106(35): 14802-14807. doi: 10.1073/pnas.0905912106 pmid: 19706449
[29]	Kluge S, Benndorf D, Genzel Y, et al. Monitoring changes in proteome during stepwise adaptation of a MDCK cell line from adherence to growth in suspension[J]. Vaccine, 2015, 33(35): 4269-4280. doi: 10.1016/j.vaccine.2015.02.077 pmid: 25891398
[30]	Jaluria P, Betenbaugh M, Konstantopoulos K, et al. Application of microarrays to identify and characterize genes involved in attachment dependence in HeLa cells[J]. Metab Eng, 2007, 9(3): 241-251. pmid: 17240181
[31]	黄锭, 赵亮, 谭文松. 犬肾细胞MDCK无血清贴壁及单细胞悬浮培养[J]. 生物工程学报, 2011, 27(4): 645-652.
	Huang D, Zhao L, Tan WS. Adherent and single-cell suspension culture of Madin-Darby canine kidney cells in serum-free medium[J]. Chin J Biotechnol, 2011, 27(4): 645-652.
[32]	Taub M, Chuman L, Saier Jr MH, et al. Growth of Madin-Darby canine kidney epithelial cell(MDCK)line in hormone-supplemented, serum-free medium[J]. Proc Natl Acad Sci USA, 1979, 76(7): 3338-3342. pmid: 291007
[33]	梅建国, 庄金秋, 沈志强. 动物细胞无血清培养技术研究进展[J]. 生物技术, 2010, 20(3): 87-89.
	Mei JG, Zhuang JQ, Shen ZQ. Advances in research on serum-free culture technology of animal cell[J]. Biotechnology, 2010, 20(3): 87-89.
[34]	van der Valk J, Mellor D, Brands R, et al. The humane collection of fetal bovine serum and possibilities for serum-free cell and tissue culture[J]. Toxicol In Vitro, 2004, 18(1): 1-12. doi: 10.1016/j.tiv.2003.08.009 pmid: 14630056
[35]	Merten OW, Kallel H, Manuguerra JC, et al. The new medium MDSS2N, free of any animal protein supports cell growth and production of various viruses[J]. Cytotechnology, 1999, 30(1-3): 191-201. doi: 10.1023/A:1008021317639 pmid: 19003369
[36]	Merten OW, Kierulff JV, Castignolles N, et al. Evaluation of the new serum-free medium(MDSS2)for the production of different biologicals: use of various cell lines[J]. Cytotechnology, 1994, 14(1): 47-59. pmid: 7765112
[37]	Kessler N, Thomas-Roche G, Gérentes L, et al. Suitability of MDCK cells grown in a serum-free medium for influenza virus production[J]. Dev Biol Stand, 1999, 98: 13-21; discussion 73-74. pmid: 10494956
[38]	Rockman S, Laurie KL, Parkes S, et al. New technologies for influenza vaccines[J]. Microorganisms, 2020, 8(11): 1745. doi: 10.3390/microorganisms8111745 URL
[39]	Brands R, Visser J, Medema J, et al. Influvac: a safe Madin Darby Canine Kidney(MDCK)cell culture-based influenza vaccine[J]. Dev Biol Stand, 1999, 98: 93-100; discussion 111. pmid: 10494962
[40]	Mossad SB. Demystifying FluMist, a new intranasal, live influenza vaccine[J]. Cleve Clin J Med, 2003, 70(9): 801-806. doi: 10.3949/ccjm.70.9.801 URL
[41]	Bühler S, Ramharter M. Flucelvax Tetra: a surface antigen, inactivated, influenza vaccine prepared in cell cultures[J]. ESMO Open, 2019, 4(1): e000481. doi: 10.1136/esmoopen-2018-000481 URL
[42]	Lamb YN. Cell-based quadrivalent inactivated influenza virus vaccine(flucelvax^® Tetra/flucelvax quadrivalent^®): a review in the prevention of influenza[J]. Drugs, 2019, 79(12): 1337-1348. doi: 10.1007/s40265-019-01176-z
[43]	黄锭. 用于流感疫苗生产的MDCK细胞无血清单细胞悬浮培养体系的开发[D]. 上海: 华东理工大学, 2010.
	Huang D. Development of serum-free single-cell suspension culture system of MDCK cells for the production of influenza vaccines[D]. Shanghai: East China University of Science and Technology, 2010.
[44]	张良艳, 姚志东, 邢丽, 等. MDCK细胞的悬浮驯化及初步应用[J]. 生物技术通讯, 2013, 24(3): 382-384.
	Zhang LY, Yao ZD, Xing L, et al. Conversion of MDCK cell line to suspension culture and its appli cation for influenza virus production[J]. Lett Biotechnol, 2013, 24(3): 382-384.
[45]	Bissinger T, Wu YX, Marichal-Gallardo P, et al. Towards integrated production of an influenza A vaccine candidate with MDCK suspension cells[J]. Biotechnol Bioeng, 2021, 118(10): 3996-4013. doi: 10.1002/bit.27876 pmid: 34219217
[46]	赵彩红, 王美皓, 李自良, 等. 无血清悬浮培养MDCK细胞系的建立及生物反应器高密度培养[J]. 中国生物制品学杂志, 2021, 34(11): 1362-1369.
	Zhao CH, Wang MH, Li ZL, et al. Establishment of MDCK suspension cell line in serum-free medium at high cell density in bioreactors[J]. Chin J Biol, 2021, 34(11): 1362-1369.
[47]	李乐凯, 吴业红, 徐军, 等. 生物反应器高密度无血清培养全悬浮MDCK细胞和流感病毒工艺的建立[J]. 中国生物制品学杂志, 2022, 35(9): 1082-1089.
	Li LK, Wu YH, Xu J, et al. Development of a process for high-density serum-free culture of fully suspended MDCK cells and influenza virus in bioreactor[J]. Chin J Biol, 2022, 35(9): 1082-1089.
[48]	国家药品监督管理局药品审评中心[EB/OL].(2023-01-13)(2023-08-05). https://www.cde.org.cn/main/xxgk/listpage/4b5255eb0a84820cef4ca3e8b6bbe20c.
	CDE Center for drug evaluation[EB/OL].(2023-01-13)(2023-08-05). https://www.cde.org.cn/main/xxgk/listpage/4b5255eb0a84820cef4ca3e8b6bbe20c.
[49]	Xu W, Du SW, Li LT, et al. IFITM3 promotes NiV envelope protein-mediated entry into MDCK cells and interacts with the fusion subunit of the F protein[J]. Int J Biochem Cell Biol, 2022, 153: 106325. doi: 10.1016/j.biocel.2022.106325 URL
[50]	Li X, Ahmad US, Huang YY, et al. Desmoglein-3 acts as a pro-survival protein by suppressing reactive oxygen species and doming whilst augmenting the tight junctions in MDCK cells[J]. Mech Ageing Dev, 2019, 184: 111174. doi: 10.1016/j.mad.2019.111174 URL
[51]	Ganguly M, Yeolekar L, Tyagi P, et al. Evaluation of manufacturing feasibility and safety of an MDCK cell-based live attenuated influenza vaccine(LAIV)platform[J]. Vaccine, 2020, 38(52): 8379-8386. doi: 10.1016/j.vaccine.2020.10.092 pmid: 33229107
[52]	Ma GL, Qiao ZL, He D, et al. Establishment of a low-tumorigenic MDCK cell line and study of differential molecular networks[J]. Biologicals, 2020, 68: 112-121. doi: 10.1016/j.biologicals.2020.07.003 URL
[53]	Doroshenko A, Halperin SA. Trivalent MDCK cell culture-derived influenza vaccine Optaflu(Novartis Vaccines)[J]. Expert Rev Vaccines, 2009, 8(6): 679-688. doi: 10.1586/erv.09.31 pmid: 19485748
[54]	Qiu ZY, Guo SQ, Liu G, et al. TGM2 inhibits the proliferation, migration and tumorigenesis of MDCK cells[J]. PLoS One, 2023, 18(4): e0285136. doi: 10.1371/journal.pone.0285136 URL
[55]	Gopal SK, Greening DW, Zhu HJ, et al. Transformed MDCK cells secrete elevated MMP1 that generates LAMA5 fragments promoting endothelial cell angiogenesis[J]. Sci Rep, 2016, 6: 28321. doi: 10.1038/srep28321 pmid: 27324842
[56]	Watanabe H, Ishibashi K, et al. Mutant p53-expressing cells undergo necroptosis via cell competition with the neighboring normal epithelial cells[J]. Cell Rep, 2018, 23(13): 3721-3729. doi: S2211-1247(18)30862-3 pmid: 29949757
[57]	Castosa R, Martinez-Iglesias O, Roca-Lema D, et al. Hakai overexpression effectively induces tumour progression and metastasis in vivo[J]. Sci Rep, 2018, 8(1): 3466. doi: 10.1038/s41598-018-21808-w pmid: 29472634
[58]	Shukla P, Vogl C, Wallner B, et al. High-throughput mRNA and miRNA profiling of epithelial-mesenchymal transition in MDCK cells[J]. BMC Genomics, 2015, 16: 944. doi: 10.1186/s12864-015-2036-9 pmid: 26572553
[59]	Rasmussen RN, Christensen KV, Holm R, et al. Transcriptome analysis identifies activated signaling pathways and regulated ABC transporters and solute carriers after hyperosmotic stress in renal MDCK I cells[J]. Genomics, 2019, 111(6): 1557-1565. doi: S0888-7543(18)30394-X pmid: 30389539
[60]	Mayuramart O, Poomipak W, Rattanaburi S, et al. IRF7-deficient MDCK cell based on CRISPR/Cas9 technology for enhancing influenza virus replication and improving vaccine production[J]. PeerJ, 2022, 10: e13989. doi: 10.7717/peerj.13989 URL
[61]	Onions D, Egan W, Jarrett R, et al. Validation of the safety of MDCK cells as a substrate for the production of a cell-derived influenza vaccine[J]. Biologicals, 2010, 38(5): 544-551. doi: 10.1016/j.biologicals.2010.04.003 pmid: 20537553
[62]	Zhang JY, Nian XX, Liu B, et al. Development of MDCK-based quadrivalent split seasonal influenza virus vaccine with high safety and immunoprotection: a preclinical study[J]. Antiviral Res, 2023, 216: 105639. doi: 10.1016/j.antiviral.2023.105639 URL
[63]	Bart S, Cannon K, Herrington D, et al. Immunogenicity and safety of a cell culture-based quadrivalent influenza vaccine in adults: a Phase III, double-blind, multicenter, randomized, non-inferiority study[J]. Hum Vaccin Immunother, 2016, 12(9): 2278-2288. doi: 10.1080/21645515.2016.1182270 URL
[64]	Yeolekar LR, Ganguly M, Tyagi P, et al. Immunogenicity and efficacy of the monovalent, trivalent and quadrivalent intranasal live attenuated influenza vaccines containing different pdmH1N1 strains[J]. Vaccine, 2018, 36(46): 6944-6952. doi: S0264-410X(18)31354-9 pmid: 30322745
[65]	Chia MY, Lin CY, Chen PL, et al. Characterization and immunogenicity of influenza H7N9 vaccine antigens produced using a serum-free suspension MDCK cell-based platform[J]. Viruses, 2022, 14(9): 1937. doi: 10.3390/v14091937 URL

年份 Year	商品名 Product name	细胞名称 Cell name	国家 Country	制造商 Manufacturer	适用人群 Suitable for the croud	参考文献Reference
2001	Influvac^®	MDCK	Netherlands	Solvay	Adult	[39]
2007	Optaflu^®	MDCK-33016PF	Switzerland	Novartis	Adult	[12]
2012	Flumist^®	MDCK	USA	GSK	Adult	[40]
2015	SKY Cellflu^®	MDCK-SKY3851	Korea	SK Chemicals	Children and adults over 4 years old	[38]
2016	Flucelvax Tetra^®	MDCK	EU	CSL-Seqirus	Children and adults over 4 years old	[41]
2019	Flucelvax Quadriskent^®	MDCK	USA	CSL-Seqirus	Children and adults over 9 years old	[42]

年份 Year	商品名 Product name	细胞名称 Cell name	国家 Country	制造商 Manufacturer	适用人群 Suitable for the croud	参考文献Reference
2001	Influvac^®	MDCK	Netherlands	Solvay	Adult	[39]
2007	Optaflu^®	MDCK-33016PF	Switzerland	Novartis	Adult	[12]
2012	Flumist^®	MDCK	USA	GSK	Adult	[40]
2015	SKY Cellflu^®	MDCK-SKY3851	Korea	SK Chemicals	Children and adults over 4 years old	[38]
2016	Flucelvax Tetra^®	MDCK	EU	CSL-Seqirus	Children and adults over 4 years old	[41]
2019	Flucelvax Quadriskent^®	MDCK	USA	CSL-Seqirus	Children and adults over 9 years old	[42]