Impact of cultivation conditions on N-glycosylation of influenza virus a hemagglutinin produced in MDCK cell culture

Biotechnology and Bioengineering

Volumn 110, Issue 6, 2013, Pages 1691-1703

  Rödig, Jana Verena ^a   Rapp, Erdmann ^a   Bohne, Jana ^b   Kampe, Michael ^a   Kaffka, Helene ^a   Bock, Andreas ^a   Genzel, Yvonne ^a   Reichl, Udo ^a,c  

^a MAX PLANCK INSTITUTE FOR DYNAMICS OF COMPLEX TECHNICAL SYSTEMS   (Germany)

^b Novartis Vaccines and Diagnostics GmbH   (Germany)

^c OTTO VON GUERICKE UNIVERSITY   (Germany)

Author keywords

Capillary gel electrophoresis; CGE LIF; Cultivation conditions; HA, hemagglutinin; Influenza virus A PR 8 34 (H1N1); N glycosylation; N glycosylation pattern analysis

Indexed keywords

CAPILLARY GEL ELECTROPHORESIS; CGE-LIF; CULTIVATION CONDITIONS; HA, HEMAGGLUTININ; INFLUENZA VIRUS; N-GLYCOSYLATION; PATTERN ANALYSIS;

BODY FLUIDS; CAPILLARY ELECTROPHORESIS; CELL CULTURE; CELLS; CULTIVATION; GLYCOPROTEINS; GLYCOSYLATION; POLYSACCHARIDES; VACCINES; VIRUSES;

ESTERIFICATION;

INFLUENZA VIRUS HEMAGGLUTININ;

ADAPTATION; ADHERENT CELL; ANIMAL CELL; ARTICLE; CELL CULTURE; CELL DENSITY; CONTROLLED STUDY; GEL ELECTROPHORESIS; HOST CELL; INFLUENZA VIRUS A; MDCK CELL; NONHUMAN; PROTEIN GLYCOSYLATION; TEMPERATURE; VIRUS CULTURE; VIRUS INACTIVATION; VIRUS REPLICATION;

ANIMALS; CULTURE MEDIA, SERUM-FREE; DOGS; GLYCOSYLATION; HEMAGGLUTININS; INFLUENZA A VIRUS, H1N1 SUBTYPE; MADIN DARBY CANINE KIDNEY CELLS; TEMPERATURE; TRYPSIN; VIRUS CULTIVATION;

INFLUENZAVIRUS A; MAMMALIA;

EID: 84876764826     PISSN: 00063592     EISSN: 10970290     Source Type: Journal    
DOI: 10.1002/bit.24834     Document Type: Article

References (69)

1. Abdel-Motal UM, Guay HM, Wigglesworth K, Welsh RM, Galili U. 2007. Immunogenicity of influenza virus vaccine is increased by anti-gal-mediated targeting to antigen-presenting cells. J Virol 81(17): 9131-9141.
2. Abe Y, Takashita E, Sugawara K, Matsuzaki Y, Muraki Y, Hongo S. 2004. Effect of the addition of oligosaccharides on the biological activities and antigenicity of influenza A/H3N2 virus hemagglutinin. J Virol 78(18): 9605-9611.
3. Andersen DC, Bridges T, Gawlitzek M, Hoy C. 2000. Multiple cell culture factors can affect the glycosylation of Asn-184 in CHO-produced tissue-type plasminogen activator. Biotechnol Bioeng 70(1): 25-31.
4. Andersen DC, Goochee CF. 1994. The effect of cell-culture conditions on the oligosaccharide structures of secreted glycoproteins. Curr Opin Biotechnol 5(5): 546-549.
5. Aumiller JJ, Mabashi-Asazuma H, Hillar A, Shi X, Jarvis DL. 2012. A new glycoengineered insect cell line with an inducibly mammalianized protein N-glycosylation pathway. Glycobiology 22(3): 417-428.
6. Bock A, Schulze-Horsel J, Schwarzer J, Rapp E, Genzel Y, Reichl U. 2011. High-density microcarrier cell cultures for influenza virus production. Biotechnol Prog 27(1): 241-250.
7. Borys MC, Linzer DI, Papoutsakis ET. 1993. Culture pH affects expression rates and glycosylation of recombinant mouse placental lactogen proteins by Chinese hamster ovary (CHO) cells. Biotechnology (NY) 11(6): 720-724.
8. Borys MC, Linzer DI, Papoutsakis ET. 1994. Ammonia affects the glycosylation patterns of recombinant mouse placental lactogen-I by chinese hamster ovary cells in a pH-dependent manner. Biotechnol Bioeng 43(6): 505-514.
9. Chee Furng Wong D, Tin Kam Wong K, Tang Goh L, Kiat Heng C, Gek Sim Yap M. 2005. Impact of dynamic online fed-batch strategies on metabolism, productivity and N-glycosylation quality in CHO cell cultures. Biotechnol Bioeng 89(2): 164-177.
10. Chen Z, Aspelund A, Jin H. 2008. Stabilizing the glycosylation pattern of influenza B hemagglutinin following adaptation to growth in eggs. Vaccine 26(3): 361-371.
11. de Vries RP, de Vries E, Bosch BJ, de Groot RJ, Rottier PJ, de Haan CA. 2010. The influenza A virus hemagglutinin glycosylation state affects receptor-binding specificity. Virology 403(1): 17-25.
12. de Vries RP, Smit CH, de Bruin E, Rigter A, de Vries E, Cornelissen LA, Eggink D, Chung NP, Moore JP, Sanders RW, Hokke CH, Koopmans M, Rottier PJ, de Haan CA. 2012. Glycan-dependent immunogenicity of recombinant soluble trimeric hemagglutinin. J Virol 86(21): 11735-11744.
13. Doroshenko A, Halperin SA. 2009. Trivalent MDCK cell culture-derived influenza vaccine Optaflu (Novartis Vaccines). Expert Rev Vaccines 8(6): 679-688.
14. Eilers PH, Boelens HFM. 2005. Baseline correction with assymetric Least Squares Smoothing. Leiden University Medical Centre Report.
15. Gawlitzek M, Estacio M, Furch T, Kiss R. 2009. Identification of cell culture conditions to control N-glycosylation site-occupancy of recombinant glycoproteins expressed in CHO cells. Biotechnol Bioeng 103(6): 1164-1175.
16. Genzel Y, Behrendt I, Konig S, Sann H, Reichl U. 2004. Metabolism of MDCK cells during cell growth and influenza virus production in large-scale microcarrier culture. Vaccine 22(17-18): 2202-2208.
17. Genzel Y, Dietzsch C, Rapp E, Schwarzer J, Reichl U. 2010. MDCK and Vero cells for influenza virus vaccine production: A one-to-one comparison up to lab-scale bioreactor cultivation. Appl Microbiol Biotechnol 88(2): 461-475.
18. Genzel Y, Reichl U. 2009. Continuous cell lines as a production system for influenza vaccines. Expert Rev Vaccines 8(12): 1681-1692.
19. Gershman H, Robbins PW. 1981. Transitory effects of glucose starvation on the synthesis of dolichol-linked oligosaccharides in mammalian cells. J Biol Chem 256(15): 7774-7780.
20. Gillmeister MP, Tomiya N, Jacobia SJ, Lee YC, Gorfien SF, Betenbaugh MJ. 2009. An HPLC-MALDI MS method for N-glycan analyses using smaller size samples: Application to monitor glycan modulation by medium conditions. Glycoconj J 26(9): 1135-1149.
21. Govorkova EA, Kodihalli S, Alymova IV, Fanget B, Webster RG. 1999. Growth and immunogenicity of influenza viruses cultivated in Vero or MDCK cells and in embryonated chicken eggs. Dev Biol Stand 98: 39-51; discussion 73-74.
22. Gregersen JP, Schmitt HJ, Trusheim H, Broker M. 2011. Safety of MDCK cell culture-based influenza vaccines. Future Microbiol 6(2): 143-152.
23. Hakimi J, Atkinson PH. 1980. Growth-dependent alterations in oligomannosyl glycopeptides expressed in Sindbis virus glycoproteins. Biochemistry 19(24): 5619-5624.
24. Hayter PM, Curling EM, Baines AJ, Jenkins N, Salmon I, Strange PG, Tong JM, Bull AT. 1992. Glucose-limited chemostat culture of Chinese hamster ovary cells producing recombinant human interferon-gamma. Biotechnol Bioeng 39(3): 327-335.
25. Heynisch B, Frensing T, Heinze K, Seitz C, Genzel Y, Reichl U. 2010. Differential activation of host cell signalling pathways through infection with two variants of influenza A/Puerto Rico/8/34 (H1N1) in MDCK cells. Vaccine 28(51): 8210-8218.
26. Hooker AD, Goldman MH, Markham NH, James DC, Ison AP, Bull AT, Strange PG, Salmon I, Baines AJ, Jenkins N. 1995. N-glycans of recombinant human interferon-gamma change during batch culture of Chinese hamster ovary cells. Biotechnol Bioeng 48(6): 639-648.
27. Howard MK, Kistner O, Barrett PN. 2008. Pre-clinical development of cell culture (Vero)-derived H5N1 pandemic vaccines. Biol Chem 389(5): 569-577.
28. Hütter J, Rödig JV, Höper D, Reichl U, Seehofer PH, Rapp E, Lepenies B. 2012. Toward animal cell culture-based influenza vaccine design: Viral hemagglutinin N-glycosylation markedly impacts immunogenicity. J Immunol 190(1): 220-230.
29. Kalbfuss B, Knochlein A, Krober T, Reichl U. 2008. Monitoring influenza virus content in vaccine production: Precise assays for the quantitation of hemagglutination and neuraminidase activity. Biologicals 36(3): 145-161.
30. Kistner O, Barrett PN, Mundt W, Reiter M, Schober-Bendixen S, Dorner F. 1998. Development of a mammalian cell (Vero) derived candidate influenza virus vaccine. Vaccine 16(9-10): 960-968.
31. Kistner O, Howard MK, Spruth M, Wodal W, Bruhl P, Gerencer M, Crowe BA, Savidis-Dacho H, Livey I. Reiter M. and others. 2007. Cell culture (Vero) derived whole virus (H5N1) vaccine based on wild-type virus strain induces cross-protective immune responses. Vaccine 25(32): 6028-6036.
32. Klenk HD, Wagner R, Heuer D, Wolff T. 2002. Importance of hemagglutinin glycosylation for the biological functions of influenza virus. Virus Res 82(1-2): 73-75.
33. Kobata A. 1988. Structures, function, and transformational changes of the sugar chains of glycohormones. J Cell Biochem 37(1): 79-90.
34. Kunkel JP, Jan DC, Butler M, Jamieson JC. 2000. Comparisons of the glycosylation of a monoclonal antibody produced under nominally identical cell culture conditions in two different bioreactors. Biotechnol Prog 16(3): 462-470.
35. Kunkel JP, Jan DC, Jamieson JC, Butler M. 1998. Dissolved oxygen concentration in serum-free continuous culture affects N-linked glycosylation of a monoclonal antibody. J Biotechnol 62(1): 55-71.
36. Ljunggren J, Haggstrom L. 1994. Catabolic control of hybridoma cells by glucose and glutamine limited fed batch cultures. Biotechnol Bioeng 44(7): 808-818.
37. Lohr V, Genzel Y, Behrendt I, Scharfenberg K, Reichl U. 2010. A new MDCK suspension line cultivated in a fully defined medium in stirred-tank and wave bioreactor. Vaccine 28(38): 6256-6264.
38. Lohr V, Rath A, Genzel Y, Jordan I, Sandig V, Reichl U. 2009. New avian suspension cell lines provide production of influenza virus and MVA in serum-free media: Studies on growth, metabolism and virus propagation. Vaccine 27(36): 4975-4982.
39. Nam JH, Zhang F, Ermonval M, Linhardt RJ, Sharfstein ST. 2008. The effects of culture conditions on the glycosylation of secreted human placental alkaline phosphatase produced in Chinese hamster ovary cells. Biotechnol Bioeng 100(6): 1178-1192.
40. Nyberg GB, Balcarcel RR, Follstad BD, Stephanopoulos G, Wang DI. 1999. Metabolic effects on recombinant interferon-gamma glycosylation in continuous culture of Chinese hamster ovary cells. Biotechnol Bioeng 62(3): 336-347.
41. Pau MG, Ophorst C, Koldijk MH, Schouten G, Mehtali M, Uytdehaag F. 2001. The human cell line PER.C6 provides a new manufacturing system for the production of influenza vaccines. Vaccine 19(17-19): 2716-2721.
42. Rapp E, Hennig R, Borowiak M, Kottler R, Reichl U. 2011. High-throughput glycosylation pattern analysis of glycoproteins utilizing a multiplexing capillary-DNA-sequencer. Glycoconjug J 28: 234-235.
43. Restelli V, Wang MD, Huzel N, Ethier M, Perreault H, Butler M. 2006. The effect of dissolved oxygen on the production and the glycosylation profile of recombinant human erythropoietin produced from CHO cells. Biotechnol Bioeng 94(3): 481-494.
44. Robertson JS, Bootman JS, Newman R, Oxford JS, Daniels RS, Webster RG, Schild GC. 1987. Structural changes in the haemagglutinin which accompany egg adaptation of an influenza A(H1N1) virus. Virology 160(1): 31-37.
45. Rödig J, Rapp E, Djeljadini S, Lohr V, Genzel Y, Jordan I, Sandig V, Reichl U. 2011a. Impact of influenza virus adaptation status on HA N-glycosylation patterns in cell culture-based vaccine production. J Carbohydr Chem 30: 281-290.
46. Rödig J, Rapp E, Hennig R, Schwarzer J, Reichl U. 2011b. Optimized CGE-LIF-Based Glycan Analysis for High-Throughput Applications. Proceedings of the 21st Annual Meeting of the European Society for Animal Cell Technology (ESACT), June 7-10, 2009. Dublin, Ireland: Springer Science+Business Media B.V.
47. Roedig JV, Rapp E, Genzel Y, Reichl U. 2011a. Impact of different influenza cultivation conditions on HA N-Glycosylation. BMC Proc 5(Suppl. 8): P113.
48. Roedig JV, Rapp E, Hoper D, Genzel Y, Reichl U. 2011b. Impact of host cell line adaptation on quasispecies composition and glycosylation of influenza A virus hemagglutinin. PLoS ONE 6(12): e27989.
49. Ruhaak LR, Hennig R, Huhn C, Borowiak M, Dolhain RJ, Deelder AM, Rapp E, Wuhrer M. 2010. Optimized workflow for preparation of APTS-labeled N-glycans allowing high-throughput analysis of human plasma glycomes using 48-channel multiplexed CGE-LIF. J Proteome Res 9(12): 6655-6664.
50. Saito T, Nakaya Y, Suzuki T, Ito R, Saito T, Saito H, Takao S, Sahara K, Odagiri T, Murata T, Usui T, Suzuki Y, Tashiro M. 2004. Antigenic alteration of influenza B virus associated with loss of a glycosylation site due to host-cell adaptation. J Med Virol 74(2): 336-343.
51. Schild GC, Oxford JS, de Jong JC, Webster RG. 1983. Evidence for host-cell selection of influenza virus antigenic variants. Nature 303(5919): 706-709.
52. Schulze-Horsel J, Schulze M, Agalaridis G, Genzel Y, Reichl U. 2009. Infection dynamics and virus-induced apoptosis in cell culture-based influenza vaccine production-flow cytometry and mathematical modeling. Vaccine 27(20): 2712-2722.
53. Schuster M, Umana P, Ferrara C, Brünker P, Gerdes C, Waxenecker G, Wiederkum S, Schwager C, Loibner H, Himmler G, Mudde GC. 2005. Improved effector functions of a therapeutic monoclonal Lewis Y-specific antibody by glycoform engineering. Cancer Res 65(17): 7934-7941.
54. Schwarzer J, Rapp E, Hennig R, Genzel Y, Jordan I, Sandig V, Reichl U. 2009. Glycan analysis in cell culture-based influenza vaccine production: Influence of host cell line and virus strain on the glycosylation pattern of viral hemagglutinin. Vaccine 27(32): 4325-4336.
55. Schwarzer J, Rapp E, Reichl U. 2008. N-glycan analysis by CGE-LIF: Profiling influenza A virus hemagglutinin N-glycosylation during vaccine production. Electrophoresis 29(20): 4203-4214.
56. Seitz C, Frensing T, Hoper D, Kochs G, Reichl U. 2010. High yields of influenza A virus in Madin-Darby canine kidney cells are promoted by an insufficient interferon-induced antiviral state. J Gen Virol 91(Pt 7): 1754-1763.
57. Senger RS, Karim MN. 2003. Effect of shear stress on intrinsic CHO culture state and glycosylation of recombinant tissue-type plasminogen activator protein. Biotechnol Prog 19(4): 1199-1209.
58. Seo SH, Goloubeva O, Webby R, Webster RG. 2001. Characterization of a porcine lung epithelial cell line suitable for influenza virus studies. J Virol 75(19): 9517-9525.
59. Smith KA, Colvin CJ, Weber PS, Spatz SJ, Coussens PM. 2008. High titer growth of human and avian influenza viruses in an immortalized chick embryo cell line without the need for exogenous proteases. Vaccine 26(29-30): 3778-3782.
60. Stanley P. 1984. Glycosylation mutants of animal cells. Annu Rev Genet 18: 525-552.
61. Stanley P. 1989. Chinese hamster ovary cell mutants with multiple glycosylation defects for production of glycoproteins with minimal carbohydrate heterogeneity. Mol Cell Biol 9(2): 377-383.
62. Vester D, Rapp E, Kluge S, Genzel Y, Reichl U. 2010. Virus-host cell interactions in vaccine production cell lines infected with different human influenza A virus variants: A proteomic approach. J Proteomics 73(9): 1656-1669.
63. Viswanathan K, Lawrence S, Hinderlich S, Yarema KJ, Lee YC, Betenbaugh MJ. 2003. Engineering sialic acid synthetic ability into insect cells: Identifying metabolic bottlenecks and devising strategies to overcome them. Biochemistry 42(51): 15215-15225.
64. Wagner R, Heuer D, Wolff T, Herwig A, Klenk HD. 2002. N-Glycans attached to the stem domain of haemagglutinin efficiently regulate influenza A virus replication. J Gen Virol 83(Pt 3): 601-609.
65. Walsh G. 2010. Biopharmaceutical benchmarks 2010. Nat Biotechnol 28(9): 917-924.
66. Wang W, Lu B, Zhou H, Suguitan AL Jr, Cheng X, Subbarao K, Kemble G, Jin H. 2010. Glycosylation at 158N of the hemagglutinin protein and receptor binding specificity synergistically affect the antigenicity and immunogenicity of a live attenuated H5N1 A/Vietnam/1203/2004 vaccine virus in ferrets. J Virol 84(13): 6570-6577.
67. Yang M, Butler M. 2000a. Effect of ammonia on the glycosylation of human recombinant erythropoietin in culture. Biotechnol Prog 16(5): 751-759.
68. Yang M, Butler M. 2000b. Effects of ammonia on CHO cell growth, erythropoietin production, and glycosylation. Biotechnol Bioeng 68(4): 370-380.
69. Zanghi JA, Schmelzer AE, Mendoza TP, Knop RH, Miller WM. 1999. Bicarbonate concentration and osmolality are key determinants in the inhibition of CHO cell polysialylation under elevated pCO(2) or pH. Biotechnol Bioeng 65(2): 182-191.