Cited by 11Protein purification and stabilityInfluenza Virus Research StudiesViral Infectious Diseases and Gene Expression in Insects

Membrane Chromatography-Based Downstream Processing for Cell-Culture Produced Influenza Vaccines

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Yang, Zeyu, Xu, Xingge, Silva, Cristina A. T., Farnos, Omar, Venereo-Sanchez, Alina, Toussaint, Cécile, Dash, Shantoshini, González-Domínguez, Irene +3 more·2022·Vaccines

Abstract

New influenza strains are constantly emerging, causing seasonal epidemics and raising concerns to the risk of a new global pandemic. Since vaccination is an effective method to prevent the spread of the disease and reduce its severity, the development of robust bioprocesses for producing pandemic influenza vaccines is exceptionally important. Herein, a membrane chromatography-based downstream processing platform with a demonstrated industrial application potential was established. Cell culture-derived influenza virus H1N1/A/PR/8/34 was harvested from benchtop bioreactor cultures. For the clarification of the cell culture broth, a depth filtration was selected as an alternative to centrifugation. After inactivation, an anion exchange chromatography membrane was used for viral capture and further processing. Additionally, two pandemic influenza virus strains, the H7N9 subtype of the A/Anhui/1/2013 and H3N2/A/Hong Kong/8/64, were successfully processed through similar downstream process steps establishing optimized process parameters. Overall, 41.3–62.5% viral recovery was achieved, with the removal of 86.3–96.5% host cell DNA and 95.5–99.7% of proteins. The proposed membrane chromatography purification is a scalable and generic method for the processing of different influenza strains and is a promising alternative to the current industrial purification of influenza vaccines based on ultracentrifugation methodologies.

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  1. [1]Pereyaslov D. Zemtsova G. Gruessner C. Daniels R.S. McCauley J.W. Brown C.S. Improving the representativeness of influenza viruses shared within the WHO Global Influenza Surveillance and Response System Influenza Other Respir. Viruses 2016 10 68 75 10.1111/irv.12362 26589132 PMC4746561 · DOI
  2. [2]Kim Y.H. Hong K.J. Kim H. Nam J.H. Influenza vaccines: Past, present, and future Rev. Med. Virol. 2022 32 e2243 10.1002/rmv.2243 33949021 PMC8209895 · DOI
  3. [3]Manceur A.P. Zou W. Marcil A. Paquet E. Gadoury C. Jaentschke B. Li X. Petiot E. Durocher Y. Baardsnes J. Generation of monoclonal pan-hemagglutinin antibodies for the quantification of multiple strains of influenza PLoS ONE 2017 12 e0180314 10.1371/journal.pone.0180314 28662134 PMC5491208 · DOI
  4. [4]Sharabi S. Drori Y. Micheli M. Friedman N. Orzitzer S. Bassal R. Glatman-Freedman A. Shohat T. Mendelson E. Hindiyeh M. Epidemiological and Virological Characterization of Influenza B Virus Infections PLoS ONE 2016 11 e0161195 10.1371/journal.pone.0161195 27533045 PMC4988634 · DOI
  5. [5]Tong S. Zhu X. Li Y. Shi M. Zhang J. Bourgeois M. Yang H. Chen X. Recuenco S. Gomez J. New World Bats Harbor Diverse Influenza A Viruses PLoS Pathog. 2013 9 e1003657 10.1371/journal.ppat.1003657 24130481 PMC3794996 · DOI
  6. [6]Lamb R.A. Takeda M. Death by influenza virus protein Nat. Med. 2001 7 1286 1288 10.1038/nm1201-1286 11726965 · DOI
  7. [7]Yuan W.M. Krug R.M. Influenza B virus NS1 protein inhibits conjugation of the interferon (IFN)-induced ubiquitin-like ISG15 protein Embo J. 2001 20 362 371 10.1093/emboj/20.3.362 11157743 PMC133459 · DOI
  8. [8]Couch R.B. Keitel W.A. Cate T.R. Quarles J.A. Taber L.A. Glezen W.P. Prevention of influenza virus infections by current inactivated influenza virus vaccines Proceedings of the 3rd International Conference on Options for the Control of Influenza Cairns, Australia 4–9 May 1996 97 106
  9. [9]Gubareva L.V. Kaiser L. Hayden F.G. Influenza virus neuraminidase inhibitors Lancet 2000 355 827 835 10.1016/S0140-6736(99)11433-8 10711940 · DOI
  10. [10]Mifsud E.J. Hayden F.G. Hurt A.C. Antivirals targeting the polymerase complex of influenza viruses Antivir. Res. 2019 169 104545 10.1016/j.antiviral.2019.104545 31247246 · DOI
  11. [11]Krammer F. Smith G.J.D. Fouchier R.A.M. Peiris M. Kedzierska K. Doherty P.C. Palese P. Shaw M.L. Treanor J. Webster R.G. Influenza Nat. Rev. Dis. Primers 2018 4 3 10.1038/s41572-018-0002-y 29955068 PMC7097467 · DOI
  12. [12]Kiso M. Mitamura K. Sakai-Tagawa Y. Shiraishi K. Kawakami C. Kimura K. Hayden F.G. Sugaya N. Kawaoka Y. Resistant influenza A viruses in children treated with oseltamivir: Descriptive study Lancet 2004 364 759 765 10.1016/S0140-6736(04)16934-1 15337401 · DOI
  13. [13]Jang Y.H. Seong B.L. The Quest for a Truly Universal Influenza Vaccine Front. Cell. Infect. Microbiol. 2019 9 344 10.3389/fcimb.2019.00344 31649895 PMC6795694 · DOI
  14. [14]Trombetta C.M. Marchi S. Manini I. Lazzeri G. Montomoli E. Challenges in the development of egg-independent vaccines for influenza Expert Rev. Vaccines 2019 18 737 750 10.1080/14760584.2019.1639503 31265333 · DOI
  15. [15]Silva C.A.T. Kamen A.A. Henry O. Recent advances and current challenges in process intensification of cell culture-based influenza virus vaccine manufacturing Can. J. Chem. Eng. 2021 99 2525 2535 10.1002/cjce.24197 · DOI
  16. [16]Bialy D. Shelton H. Functional neuraminidase inhibitor resistance motifs in avian influenza A(H5Nx) viruses Antivir. Res. 2020 182 104886 10.1016/j.antiviral.2020.104886 32750468 PMC7534037 · DOI
  17. [17]Nuñez I.A. Ross T.M. A review of H5Nx avian influenza viruses Ther. Adv. Vaccines Immunother. 2019 7 2515135518821625 10.1177/2515135518821625 30834359 PMC6391539 · DOI
  18. [18]Sparrow E. Adetifa I. Chaiyakunapruk N. Cherian T. Fell D.B. Graham B.S. Innis B. Kaslow D.C. Karron R.A. Nair H. WHO preferred product characteristics for monoclonal antibodies for passive immunization against respiratory syncytial virus (RSV) disease in infants—Key considerations for global use Vaccine 2022 40 3506 3510 10.1016/j.vaccine.2022.02.040 35184927 PMC9176315 · DOI
  19. [19]Hegde N.R. Cell culture-based influenza vaccines: A necessary and indispensable investment for the future Hum. Vaccines Immunother. 2015 11 1223 1234 10.1080/21645515.2015.1016666 PMC4514150 25875691 · DOI
  20. [20]Tzeng T.T. Lai C.C. Weng T.C. Cyue M.H. Tsai S.Y. Tseng Y.F. Sung W.C. Lee M.S. Hu A.Y. The stability and immunogenicity of inactivated MDCK cell-derived influenza H7N9 viruses Vaccine 2019 37 7117 7122 10.1016/j.vaccine.2019.03.024 31383484 · DOI
  21. [21]Chia M.Y. Hu A.Y. Tseng Y.F. Weng T.C. Lai C.C. Lin J.Y. Chen P.L. Wang Y.F. Chao S.R. Chang J.Y. Evaluation of MDCK cell-derived influenza H7N9 vaccine candidates in ferrets PLoS ONE 2015 10 e0120793 10.1371/journal.pone.0120793 25799397 PMC4370571 · DOI
  22. [22]Chen P.L. Tzeng T.T. Hu A.Y. Wang L.H. Lee M.S. Development and Evaluation of Vero Cell-Derived Master Donor Viruses for Influenza Pandemic Preparedness Vaccines 2020 8 626 10.3390/vaccines8040626 33113866 PMC7712210 · DOI
  23. [23]Nestola P. Peixoto C. Silva R.R. Alves P.M. Mota J.P. Carrondo M.J. Improved virus purification processes for vaccines and gene therapy Biotechnol. Bioeng. 2015 112 843 857 10.1002/bit.25545 25677990 · DOI
  24. [24]Venereo-Sanchez A. Gilbert R. Simoneau M. Caron A. Chahal P. Chen W. Ansorge S. Li X. Henry O. Kamen A. Hemagglutinin and neuraminidase containing virus-like particles produced in HEK-293 suspension culture: An effective influenza vaccine candidate Vaccine 2016 34 3371 3380 10.1016/j.vaccine.2016.04.089 27155499 · DOI
  25. [25]Thompson C.M. Petiot E. Mullick A. Aucoin M.G. Henry O. Kamen A.A. Critical assessment of influenza VLP production in Sf9 and HEK293 expression systems BMC Biotechnol. 2015 15 31 10.1186/s12896-015-0152-x 25981500 PMC4432999 · DOI
  26. [26]Tseng Y.F. Weng T.C. Lai C.C. Chen P.L. Lee M.S. Hu A.Y. A fast and efficient purification platform for cell-based influenza viruses by flow-through chromatography Vaccine 2018 36 3146 3152 10.1016/j.vaccine.2017.03.016 28342667 · DOI
  27. [27]Rathore A.S. Agarwal H. Sharma A.K. Pathak M. Muthukumar S. Continuous Processing for Production of Biopharmaceuticals Prep. Biochem. Biotechnol. 2015 45 836 849 10.1080/10826068.2014.985834 25674930 · DOI
  28. [28]González-Domínguez I. Lorenzo E. Bernier A. Cervera L. Gòdia F. Kamen A. A Four-Step Purification Process for Gag VLPs: From Culture Supernatant to High-Purity Lyophilized Particles Vaccines 2021 9 1154 10.3390/vaccines9101154 34696262 PMC8539588 · DOI
  29. [29]Carvalho S.B. Silva R.J.S. Moreira A.S. Cunha B. Clemente J.J. Alves P.M. Carrondo M.J.T. Xenopoulos A. Peixoto C. Efficient filtration strategies for the clarification of influenza virus-like particles derived from insect cells Sep. Purif. Technol. 2019 218 81 88 10.1016/j.seppur.2019.02.040 · DOI
  30. [30]Grein T.A. Michalsky R. Vega López M. Czermak P. Purification of a recombinant baculovirus of Autographa californica M nucleopolyhedrovirus by ion exchange membrane chromatography J. Virol. Methods 2012 183 117 124 10.1016/j.jviromet.2012.03.031 22521717 · DOI
  31. [31]Kutner R.H. Puthli S. Marino M.P. Reiser J. Simplified production and concentration of HIV-1-based lentiviral vectors using HYPERFlask vessels and anion exchange membrane chromatography BMC Biotechnol. 2009 9 10 10.1186/1472-6750-9-10 19220915 PMC2649911 · DOI
  32. [32]Davidoff A.M. Ng C.Y.C. Sleep S. Gray J. Azam S. Zhao Y. McIntosh J.H. Karimipoor M. Nathwani A.C. Purification of recombinant adeno-associated virus type 8 vectors by ion exchange chromatography generates clinical grade vector stock J. Virol. Methods 2004 121 209 215 10.1016/j.jviromet.2004.07.001 15381358 · DOI
  33. [33]Sarsenbayeva G. Volgin Y. Kassenov M. Issagulov T. Bogdanov N. Nurpeisova A. Sagymbay A. Abitay R. Stukova M. Sansyzbay A. A novel preservative-free seasonal influenza vaccine safety and immune response study in the frame of preclinical research J. Med. Virol. 2017 89 1168 1173 10.1002/jmv.24771 28160490 · DOI
  34. [34]Yang H. Establishing acceptable limits of residual DNA PDA J. Pharm. Sci. Technol. 2013 67 155 163 10.5731/pdajpst.2013.00910 23569076 · DOI · Paper page
  35. [35]Kapteyn J.C. Porre A.M. de Rond E.J.P. Hessels W.B. Tijms M.A. Kessen H. Slotboom A.M.E. Oerlemans M.A. Smit D. van der Linden J. HPLC-based quantification of haemagglutinin in the production of egg- and MDCK cell-derived influenza virus seasonal and pandemic vaccines Vaccine 2009 27 1468 1477 10.1016/j.vaccine.2008.11.113 19110022 · DOI
  36. [36]Wolf M.W. Reichl U. Downstream processing of cell culture-derived virus particles Expert Rev. Vaccines 2011 10 1451 1475 10.1586/erv.11.111 21988309 PMC7103681 · DOI
  37. [37]Kalbfuss B. Wolff M. Geisler L. Tappe A. Wickramasinghe R. Thom V. Reichl U. Direct capture of influenza A virus from cell culture supernatant with Sartobind anion-exchange membrane adsorbers J. Membr. Sci. 2007 299 251 260 10.1016/j.memsci.2007.04.048 · DOI
  38. [38]Reimer C.B. Baker R.S. vanFrank R.M. Newlin T.E. Cline G.B. Anderson N.G. Purification of Large Quantities of Influenza Virus by Density Gradient Centrifugation J. Virol. 1967 1 1207 1216 10.1128/jvi.1.6.1207-1216.1967 5621490 PMC375411 · DOI
  39. [39]Asanzhanova N.N. Ryskeldinova S.Z. Chervyakova O.V. Khairullin B.M. Kasenov M.M. Tabynov K.K. Comparison of Different Methods of Purification and Concentration in Production of Influenza Vaccine Bull. Exp. Biol. Med. 2017 164 229 232 10.1007/s10517-017-3964-y 29177903 · DOI
  40. [40]Weigel T. Solomaier T. Peuker A. Pathapati T. Wolff M.W. Reichl U. A flow-through chromatography process for influenza A and B virus purification J. Virol. Methods 2014 207 45 53 10.1016/j.jviromet.2014.06.019 24992667 · DOI
  41. [41]Wolff M.W. Reichl U. Downstream Processing: From Egg to Cell Culture-Derived Influenza Virus Particles Chem. Eng. Technol. 2008 6 846 857 10.1002/ceat.200800118 PMC7162065 32313385 · DOI

Authors
Yang, Z., Xu, X., Silva, C. A. T., Farnos, O., Venereo-Sanchez, A., Toussaint, C., Dash, S., González-Domínguez, I., Bernier, A., Henry, O., & Kamen, A.
Affiliations
  • McGill University (CA)
  • Polytechnique Montréal (CA)
  • Viral Vectors and Vaccines Bioprocessing Group, Department of Bioengineering, McGill University, Montreal, QC H3A 0G4, Canada
Corresponding author
Kamen, Amine
Venue
Vaccines
Publisher
MDPI AG
Published
2022-08-13
Volume
10
Issue
8
Pages
1310
ISSN
2076-393X (ISSN-L)
OpenAlex
W4292182981
Cited by
11
References
40
Citations by year
2026: 1 · 2025: 2 · 2024: 5 · 2023: 3
FWCI
0.82
Type
journal article
Language
en
Open access
Locations
  • Vaccines (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • PolyPublie (École Polytechnique de Montréal) (submittedVersion)
Funders
  • the Canadian Institutes of Health Research (CIHR) (CPG-151958, CHRPJ-508335-17, CRC-240394)
  • the Natural Sciences and Engineering Research Council (NSERC) (CPG-151958, CHRPJ-508335-17, CRC-240394)
  • Canada Research Chair (CPG-151958, CHRPJ-508335-17, CRC-240394)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein purification and stability
  • Health Sciences › Medicine › Epidemiology › Influenza Virus Research Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Viral Infectious Diseases and Gene Expression in Insects
Keywords
influenza vaccine production, membrane chromatography, downstream processing, anion exchange chromatography, depth filtration, viral capture, H1N1 PR8, H7N9, H3N2, pandemic influenza, host cell DNA removal, virus inactivation

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