Cell culture-derived flu vaccine: Present and future

ABSTRACT The benefit of influenza vaccines is difficult to estimate due to the complexity of accurately assessing the burden of influenza. To improve the efficacy of influenza vaccines, vaccine manufacturers have developed quadrivalent influenza vaccine (QIV) formulations for seasonal vaccination by including both influenza B lineages. Three parallel approaches for producing influenza vaccines are attracting the interest of many vaccine manufacturing companies. The first and oldest is the conventional egg-derived influenza vaccine, which is used by the current licensed influenza vaccines. The second approach is a cell culture-derived influenza vaccine, and the third and most recent is synthetic vaccines. Here, we analyze the difficulties with vaccines production in eggs and compare this to cell culture-derived influenza vaccines and discuss the future of cell culture-derived QIVs.Keywords: Influenza vaccine, cell culture-derived, quadrivalent.

[1]  J. Bourdon,et al.  Influenza A viruses alter the stability and antiviral contribution of host E3-ubiquitin ligase Mdm2 during the time-course of infection , 2018, Scientific Reports.

[2]  M. Gunzer,et al.  Respiratory Influenza A Virus Infection Triggers Local and Systemic Natural Killer Cell Activation via Toll-Like Receptor 7 , 2018, Front. Immunol..

[3]  E. Montomoli,et al.  Egg-Independent Influenza Vaccines and Vaccine Candidates , 2017, Vaccines.

[4]  P. Buck,et al.  A review of the value of quadrivalent influenza vaccines and their potential contribution to influenza control , 2017, Human vaccines & immunotherapeutics.

[5]  M. Postma,et al.  A systematic review of the health economic consequences of quadrivalent influenza vaccination , 2017, Expert review of pharmacoeconomics & outcomes research.

[6]  G. Zuccotti,et al.  Safety and tolerability of cell culture-derived and egg-derived trivalent influenza vaccines in 3 to <18-year-old children and adolescents at risk of influenza-related complications. , 2016, International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases.

[7]  M. R. Capeding,et al.  Safety and tolerability of a cell culture derived trivalent subunit inactivated influenza vaccine administered to healthy children and adolescents: A Phase III, randomized, multicenter, observer-blind study. , 2016, Vaccine.

[8]  Steve Di Lonardo,et al.  Incidence of medically attended influenza during pandemic and post-pandemic seasons through the Influenza Incidence Surveillance Project, 2009-13. , 2015, The Lancet. Respiratory medicine.

[9]  L. Brammer,et al.  Epidemiological and virological characteristics of influenza B: results of the Global Influenza B Study , 2015, Influenza and other respiratory viruses.

[10]  N. Hegde Cell culture-based influenza vaccines: A necessary and indispensable investment for the future , 2015, Human vaccines & immunotherapeutics.

[11]  D. Levy-bruhl,et al.  Characteristics and practices of National Immunisation Technical Advisory Groups in Europe and potential for collaboration, April 2014. , 2015, Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin.

[12]  Amine A. Kamen,et al.  Current and Emerging Cell Culture Manufacturing Technologies for Influenza Vaccines , 2015, BioMed research international.

[13]  A. Pérez-Rubio,et al.  [Burden of influenza virus type B and mismatch with the flu vaccine in Spain]. , 2015, Revista espanola de quimioterapia : publicacion oficial de la Sociedad Espanola de Quimioterapia.

[14]  R. Rappuoli,et al.  Vaccines, new opportunities for a new society , 2014, Proceedings of the National Academy of Sciences.

[15]  A. Sheikh,et al.  Prevalence of common food allergies in Europe: a systematic review and meta‐analysis , 2014, Allergy.

[16]  C. Davis,et al.  Performance characteristics of qualified cell lines for isolation and propagation of influenza viruses for vaccine manufacturing , 2014, Vaccine.

[17]  U. Reichl,et al.  Production of high-titer human influenza A virus with adherent and suspension MDCK cells cultured in a single-use hollow fiber bioreactor. , 2014, Vaccine.

[18]  C. Vinnemeier,et al.  Immunogenicity and safety of an inactivated 2012/2013 trivalent influenza vaccine produced in mammalian cell culture (Optaflu®) , 2014, Human vaccines & immunotherapeutics.

[19]  Danielle H W Vlecken,et al.  Comparison of initial feasibility of host cell lines for viral vaccine production. , 2013, Journal of virological methods.

[20]  Sarah Cobey,et al.  Improving influenza vaccine virus selection: report of a WHO informal consultation held at WHO headquarters, Geneva, Switzerland, 14–16 June 2010 , 2013, Influenza and other respiratory viruses.

[21]  C. Bauch,et al.  Comparing influenza vaccine efficacy against mismatched and matched strains: a systematic review and meta-analysis , 2013, BMC Medicine.

[22]  M. Lucero,et al.  Global and regional burden of hospital admissions for severe acute lower respiratory infections in young children in 2010: a systematic analysis , 2013, The Lancet.

[23]  Wen-Ta Chiu,et al.  Surveillance and Vaccine Effectiveness of an Influenza Epidemic Predominated by Vaccine-Mismatched Influenza B/Yamagata-Lineage Viruses in Taiwan, 2011−12 Season , 2013, PloS one.

[24]  M. Decker,et al.  Safety and immunogenicity of a quadrivalent inactivated influenza vaccine compared to licensed trivalent inactivated influenza vaccines in adults. , 2013, Vaccine.

[25]  M. Kieny,et al.  Global production capacity of seasonal influenza vaccine in 2011. , 2013, Vaccine.

[26]  P. Schlagenhauf,et al.  A prospective observational safety study on MF59(®) adjuvanted cell culture-derived vaccine, Celtura(®) during the A/H1N1 (2009) influenza pandemic. , 2012, Vaccine.

[27]  K. Matsushita,et al.  Assessment of the immunogenicity and safety of varying doses of an MF59®-adjuvanted cell culture-derived A/H1N1 pandemic influenza vaccine in Japanese paediatric, adult and elderly subjects. , 2012, Vaccine.

[28]  G. D. Cioppa,et al.  A randomised, single-blind, dose-range study to assess the immunogenicity and safety of a cell-culture-derived A/H1N1 influenza vaccine in adult and elderly populations. , 2012, Vaccine.

[29]  P. Tambyah,et al.  Preflucel®: a Vero-cell culture-derived trivalent influenza vaccine , 2012, Expert review of vaccines.

[30]  A. Nowak‐Wegrzyn,et al.  In vitro assessment of the allergenicity of novel MF59-adjuvanted pandemic H1N1 influenza vaccine produced in dog kidney cells , 2012, Human vaccines & immunotherapeutics.

[31]  H. Ehrlich,et al.  Clinical development of a Vero cell culture-derived seasonal influenza vaccine. , 2012, Vaccine.

[32]  A. Izu,et al.  Safety assessment and immunogenicity of a cell-culture-derived influenza vaccine in adults and elderly subjects over three successive influenza seasons , 2012, Human vaccines & immunotherapeutics.

[33]  E. Montomoli,et al.  Cell culture-derived influenza vaccines from Vero cells: a new horizon for vaccine production , 2012, Expert review of vaccines.

[34]  T. Vesikari,et al.  Immunogenicity, Safety and Reactogenicity of a Mammalian Cell-Culture–Derived Influenza Vaccine in Healthy Children and Adolescents Three to Seventeen Years of Age , 2012, The Pediatric infectious disease journal.

[35]  M. Callegari,et al.  Instrumental Robots Design with Applications to Manufacturing 7.1 Introduction the Design Cycle for Instrumental Robots 7.2 the Design of Function-oriented Robots Conceptual Design of Task-driven Robot-arms @bullet Conceptual Design of Work-constrained Robot-arms @bullet Computer Aids Based on Funct , 2001 .

[36]  M. Levin,et al.  The rationale for quadrivalent influenza vaccines , 2012, Human vaccines & immunotherapeutics.

[37]  A. Nicoll,et al.  The importance of influenza prevention for public health , 2012, Human vaccines & immunotherapeutics.

[38]  N. Ferguson,et al.  Improving influenza vaccine virus selectionReport of a WHO informal consultation held at WHO headquarters, Geneva, Switzerland, 14–16 June 2010 , 2011, Influenza and other respiratory viruses.

[39]  H. Ehrlich,et al.  Efficacy, safety, and immunogenicity of a Vero-cell-culture-derived trivalent influenza vaccine: a multicentre, double-blind, randomised, placebo-controlled trial , 2011, The Lancet.

[40]  T. Vesikari,et al.  Clinical efficacy of cell culture–derived and egg‐derived inactivated subunit influenza vaccines in healthy adults. , 2010, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[41]  R. Belshe The need for quadrivalent vaccine against seasonal influenza. , 2010, Vaccine.

[42]  U. Reichl,et al.  A new MDCK suspension line cultivated in a fully defined medium in stirred-tank and wave bioreactor. , 2010, Vaccine.

[43]  U. Reichl,et al.  MDCK and Vero cells for influenza virus vaccine production: a one-to-one comparison up to lab-scale bioreactor cultivation , 2010, Applied Microbiology and Biotechnology.

[44]  A. Nowak‐Wegrzyn,et al.  In vitro assessment of the allergenicity of a novel influenza vaccine produced in dog kidney cells in individuals with dog allergy. , 2010, Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology.

[45]  Jonathan Liu,et al.  Comparison of egg and high yielding MDCK cell-derived live attenuated influenza virus for commercial production of trivalent influenza vaccine: In vitro cell susceptibility and influenza virus replication kinetics in permissive and semi-permissive cells☆ , 2010, Vaccine.

[46]  B. Seong,et al.  Reverse genetic platform for inactivated and live-attenuated influenza vaccine , 2010, Experimental & Molecular Medicine.

[47]  S. Mittal,et al.  Egg-independent vaccine strategies for highly pathogenic H5N1 influenza viruses , 2010, Human vaccines.

[48]  K. Hoschler,et al.  Trial of 2009 influenza A (H1N1) monovalent MF59-adjuvanted vaccine. , 2009, The New England journal of medicine.

[49]  R. Schwartz,et al.  Use of MDCK cells for production of live attenuated influenza vaccine. , 2009, Vaccine.

[50]  K. Neuzil,et al.  Influenza vaccine manufacture: keeping up with change. , 2009, The Journal of infectious diseases.

[51]  K. Reisinger,et al.  Subunit influenza vaccines produced from cell culture or in embryonated chicken eggs: comparison of safety, reactogenicity, and immunogenicity. , 2009, The Journal of infectious diseases.

[52]  R. Bugarini,et al.  Safety and immunogenicity of a novel influenza subunit vaccine produced in mammalian cell culture. , 2009, The Journal of infectious diseases.

[53]  I. Donatelli,et al.  A phase I clinical trial of a PER.C6 cell grown influenza H7 virus vaccine. , 2009, Vaccine.

[54]  R. Webster,et al.  The Influenza Virus Enigma , 2009, Cell.

[55]  M. Tashiro,et al.  Timely production of A/Fujian-like influenza vaccine matching the 2003-2004 epidemic strain may have been possible using Madin-Darby canine kidney cells. , 2008, Vaccine.

[56]  A. Aguzzi,et al.  Canine MDCK cell lines are refractory to infection with human and mouse prions. , 2008, Vaccine.

[57]  J. Gregersen A risk-assessment model to rate the occurrence and relevance of adventitious agents in the production of influenza vaccines , 2008, Vaccine.

[58]  S. Abe,et al.  Purification and cDNA cloning of a novel protease inhibitor secreted into culture supernatant by MDCK cells. , 2008, Biologicals : journal of the International Association of Biological Standardization.

[59]  D. Alexander,et al.  An overview of the epidemiology of avian influenza. , 2007, Vaccine.

[60]  S. Ellenberg Food and Drug Administration (FDA) , 2005 .

[61]  J. Wood,et al.  Generation of influenza vaccine viruses on Vero cells by reverse genetics: an H5N1 candidate vaccine strain produced under a quality system. , 2005, Vaccine.

[62]  T. Toner,et al.  Comparative study of influenza virus replication in Vero and MDCK cell lines. , 2004, Journal of virological methods.

[63]  J. Oxford,et al.  Non-responders to egg grown influenza vaccine seroconvert after booster immunization with MDCK cell grown vaccine. , 2003, Vaccine.

[64]  H. Katinger,et al.  Distinct host range of influenza H3N2 virus isolates in Vero and MDCK cells is determined by cell specific glycosylation pattern. , 2003, Virology.

[65]  R. Zeiger Current issues with influenza vaccination in egg allergy. , 2002, The Journal of allergy and clinical immunology.

[66]  Yan Li,et al.  Reappearance and global spread of variants of influenza B/Victoria/2/87 lineage viruses in the 2000-2001 and 2001-2002 seasons. , 2002, Virology.

[67]  M. Hilleman,et al.  Realities and enigmas of human viral influenza: pathogenesis, epidemiology and control. , 2002, Vaccine.

[68]  J. Treanor,et al.  Safety and immunogenicity of a trivalent, inactivated, mammalian cell culture-derived influenza vaccine in healthy adults, seniors, and children. , 2002, Vaccine.

[69]  S. Halperin,et al.  Safety and immunogenicity of a new influenza vaccine grown in mammalian cell culture. , 1998, Vaccine.

[70]  R. Webster,et al.  Immunogenicity and Protective Efficacy in Mice of Influenza B Virus Vaccines Grown in Mammalian Cells or Embryonated Chicken Eggs , 1998, Journal of Virology.

[71]  A. Palache,et al.  Immunogenicity and reactogenicity of influenza subunit vaccines produced in MDCK cells or fertilized chicken eggs. , 1997, The Journal of infectious diseases.

[72]  V. Fernández-Baca,et al.  Comparison of Madin-Darby canine kidney cells (MDCK) with a green monkey continuous cell line (Vero) and human lung embryonated cells (MRC-5) in the isolation of influenza A virus from nasopharyngeal aspirates by shell vial culture , 1997, Journal of clinical microbiology.

[73]  T. Kok,et al.  The use of MDCK, MEK and LLC-MK2 cell lines with enzyme immunoassay for the isolation of influenza and parainfluenza viruses from clinical specimens. , 1993, Journal of virological methods.

[74]  J. Oxford,et al.  Structural changes in the haemagglutinin which accompany egg adaptation of an influenza A(H1N1) virus. , 1987, Virology.

[75]  R. Couch,et al.  Comparison of different tissue cultures for isolation and quantitation of influenza and parainfluenza viruses , 1979, Journal of clinical microbiology.

[76]  A. Pérez-Rubio,et al.  Impacto del virus gripal tipo B y divergencia con la cepa B incluida en la vacuna antigripal en España , 2015 .

[77]  B. Baudner,et al.  Influenza Cell-Culture Vaccine Production , 2014 .

[78]  R. Evans European Centre for Disease Prevention and Control. , 2014, Nursing standard (Royal College of Nursing (Great Britain) : 1987).

[79]  J. Cappelleri Expert Review of Pharmacoeconomics & Outcomes Research , 2013 .

[80]  Kathy Hancock Influenza A Virus , 2020, Definitions.

[81]  D. Martens,et al.  Adaptation of a Madin-Darby canine kidney cell line to suspension growth in serum-free media and comparison of its ability to produce avian influenza virus to Vero and BHK21 cell lines. , 2011, Journal of virological methods.

[82]  R. J. Webby,et al.  Influenza vaccines , 2009, Vaccine.

[83]  T. Mabrouk,et al.  A Phase I, randomized controlled clinical trial to study the reactogenicity and immunogenicity of a new split influenza vaccine derived from a non-tumorigenic cell line. , 1999, Developments in biological standardization.

[84]  J. Manuguerra,et al.  Production of influenza virus in cell cultures for vaccine preparation. , 1996, Advances in experimental medicine and biology.

[85]  Cell culture as a substrate for the production of influenza vaccines: memorandum from a WHO meeting. , 1995, Bulletin of the World Health Organization.

[86]  K. Jenpanich,et al.  [Drug administration]. , 1976, Thai journal of nursing.

[87]  K. Shadan,et al.  Available online: , 2012 .