Improved poliovirus d-antigen yields by application of different Vero cell cultivation methods

Thomassen, Yvonne E.; Rubingh, Olaf; Wijffels, René H.; Pol, Leo A. van der; Bakker, Wilfried A.M.

doi:10.1016/j.vaccine.2014.02.022

Cited by 32 publications

(29 citation statements)

References 21 publications

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“…Although similar to the recirculation strategy followed by Thomassen et al ( 2014 ), a special case has been reported for the proliferation of both adherent and suspension MDCK cells in a single-used hollow fiber bioreactor for propagation of pandemic influenza virus (Tapia et al 2014 ). Here, cell concentrations of about 3.0 × 10 7 cells/mL were obtained by recirculation of fresh medium through the hollow fibers providing nutrients to the cells and diluting accumulated toxic compounds.…”

Section: Virus Production At High Cell Densitiesmentioning

confidence: 97%

“…In another example, the proliferation of bovine kidney (BK) cells on Cytodex 3 for the propagation of Parapoxvirus ovis up to 7.0 × 10 6 cells/mL was carried out using a periodic medium exchange (Pohlscheidt et al 2008 ) based on the minimum glucose concentration measured. Finally, a recirculation-based feeding mode was applied for the propagation of Vero cells grown on microcarriers at about 6.0 × 10 6 cells/mL for subsequent infection with various poliovirus serotypes (Thomassen et al 2014 ). In this process, a fresh medium of an STR was circulated through the cultivation bioreactor at increasing rates depending on cultivation time.…”

Section: Virus Production At High Cell Densitiesmentioning

confidence: 99%

“…In addition, an optimal supply of nutrients at toi is required (Aunins 2003 ). The latter can be achieved by a complete medium exchange prior to addition of the virus seed (Bock et al 2011 ; Pohlscheidt et al 2008 ) or by an intensive medium renewal during the cell proliferation phase (Thomassen et al 2014 ). The use of a perfusion rate of two reactor volumes per day starting immediately after virus infection also helped to improve adenovirus yields in HEK293 cells (Henry et al 2004 ).…”

Section: Virus Production At High Cell Densitiesmentioning

confidence: 99%

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Bioreactors for high cell density and continuous multi-stage cultivations: options for process intensification in cell culture-based viral vaccine production

Tapia

Vázquez-Ramírez

Genzel

et al. 2016

Appl Microbiol Biotechnol

123

111

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With an increasing demand for efficacious, safe, and affordable vaccines for human and animal use, process intensification in cell culture-based viral vaccine production demands advanced process strategies to overcome the limitations of conventional batch cultivations. However, the use of fed-batch, perfusion, or continuous modes to drive processes at high cell density (HCD) and overextended operating times has so far been little explored in large-scale viral vaccine manufacturing. Also, possible reductions in cell-specific virus yields for HCD cultivations have been reported frequently. Taking into account that vaccine production is one of the most heavily regulated industries in the pharmaceutical sector with tough margins to meet, it is understandable that process intensification is being considered by both academia and industry as a next step toward more efficient viral vaccine production processes only recently. Compared to conventional batch processes, fed-batch and perfusion strategies could result in ten to a hundred times higher product yields. Both cultivation strategies can be implemented to achieve cell concentrations exceeding 107 cells/mL or even 108 cells/mL, while keeping low levels of metabolites that potentially inhibit cell growth and virus replication. The trend towards HCD processes is supported by development of GMP-compliant cultivation platforms, i.e., acoustic settlers, hollow fiber bioreactors, and hollow fiber-based perfusion systems including tangential flow filtration (TFF) or alternating tangential flow (ATF) technologies. In this review, these process modes are discussed in detail and compared with conventional batch processes based on productivity indicators such as space-time yield, cell concentration, and product titers. In addition, options for the production of viral vaccines in continuous multi-stage bioreactors such as two- and three-stage systems are addressed. While such systems have shown similar virus titers compared to batch cultivations, keeping high yields for extended production times is still a challenge. Overall, we demonstrate that process intensification of cell culture-based viral vaccine production can be realized by the consequent application of fed-batch, perfusion, and continuous systems with a significant increase in productivity. The potential for even further improvements is high, considering recent developments in establishment of new (designer) cell lines, better characterization of host cell metabolism, advances in media design, and the use of mathematical models as a tool for process optimization and control.

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Section: Virus Production At High Cell Densitiesmentioning

confidence: 97%

Section: Virus Production At High Cell Densitiesmentioning

confidence: 99%

Section: Virus Production At High Cell Densitiesmentioning

confidence: 99%

See 1 more Smart Citation

Bioreactors for high cell density and continuous multi-stage cultivations: options for process intensification in cell culture-based viral vaccine production

Tapia

Vázquez-Ramírez

Genzel

et al. 2016

Appl Microbiol Biotechnol

123

111

View full text Add to dashboard Cite

show abstract

“…More recently, improvements in virus yield compared to conventional static systems have been achieved. Examples of recently developed large-scale application can be found for vaccines against poliomyelitis [39,90] and influenza (H5N1) diseases [91]. The investigated process was performed in a wave bioreactor (10 l working volume), which replaced a total of 600 RBs (1750 cm 2 ) due to its higher productivity [22].…”

Section: Adherent Cells On Microcarriersmentioning

confidence: 99%

“…For instance, media exchange and nutrient feeding strategies were used to increase concentration of Vero cells grown on Cytodex-1 microcarriers by 80%, while polio virus type 1, 2 and 3 D-antigen yields were improved by 100, 64 and 76%, respectively, in comparison to batch cultures [90]. This facilitates the establishment of advanced process operations to improve cell growth and to increase virus yields.…”

Section: Adherent Cells On Microcarriersmentioning

confidence: 99%

Bioreactor concepts for cell culture-based viral vaccine production

Gallo-Ramirez

Nikolay²,

Genzel

et al. 2015

Expert Review of Vaccines

124

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Authors contributed equallyVaccine manufacturing processes are designed to meet present and upcoming challenges associated with a growing vaccine market and to include multi-use facilities offering a broad portfolio and faster reaction times in case of pandemics and emerging diseases. The final products, from whole viruses to recombinant viral proteins, are very diverse, making standard process strategies hardly universally applicable. Numerous factors such as cell substrate, virus strain or expression system, medium, cultivation system, cultivation method, and scale need consideration. Reviewing options for efficient and economical production of human vaccines, this paper discusses basic factors relevant for viral antigen production in mammalian cells, avian cells and insect cells. In addition, bioreactor concepts, including static systems, single-use systems, stirred tanks and packed-beds are addressed. On this basis, methods towards process intensification, in particular operational strategies, the use of perfusion systems for high product yields, and steps to establish continuous processes are introduced.

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Bioreactor production of rVSV‐based vectors in Vero cell suspension cultures

Kießlich

Kim

Shen

et al. 2021

Biotech & Bioengineering

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The Vero cell line is the most used continuous cell line in viral vaccine manufacturing. This adherent cell culture platform requires the use of surfaces to support cell growth, typically roller bottles, or microcarriers. We have recently compared the production of rVSV-ZEBOV on Vero cells between microcarrier and fixed-bed bioreactors. However, suspension cultures are considered superior with regard to process scalability. Therefore, we further explore the Vero suspension system for recombinant vesicular stomatitis virus (rVSV)-vectored vaccine production. Previously, this suspension cell line was only able to be cultivated in a proprietary medium. Here, we expand the adaptation and bioreactor cultivation to a serum-free commercial medium. Following small-scale optimization and screening studies, we demonstrate bioreactor productions of highly relevant vaccines and vaccine candidates against Ebola virus disease, HIV, and coronavirus disease 2019 in the Vero suspension system. rVSV-ZEBOV, rVSV-HIV, and rVSV Ind -msp-S F -Gtc can replicate to high titers in the bioreactor, reaching 3.87 × 10 7 TCID 50 /ml, 2.12 × 10 7 TCID 50 /ml, and 3.59 × 10 9 TCID 50 /ml, respectively. Furthermore, we compare cell-specific productivities, and the quality of the produced viruses by determining the ratio of total viral particles to infectious viral particles.

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Improved poliovirus d-antigen yields by application of different Vero cell cultivation methods

Cited by 32 publications

References 21 publications

Bioreactors for high cell density and continuous multi-stage cultivations: options for process intensification in cell culture-based viral vaccine production

Bioreactors for high cell density and continuous multi-stage cultivations: options for process intensification in cell culture-based viral vaccine production

Bioreactor concepts for cell culture-based viral vaccine production

Bioreactor production of rVSV‐based vectors in Vero cell suspension cultures

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