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Apr 1, 2010 (Vol. 30, No. 7)

Cell Culture Moving Past Previous Technical Limits

Researchers Employ Insect and Duck Cells, Novel Media, and Next-Generation Automation Technologies

  • Click Image To Enlarge +
    CHO-K1 cells adapted to growth in a protein- and peptide-free minimal medium developed by Cell Culture Technologies.

    Spodoptera frugiperda (the fall armyworm caterpillar) and the duck are gradually replacing the chicken as the creature of choice for vaccine production. New cell-culture techniques and, particularly, recombinant technologies, are bringing faster production cycles and higher purity yields, according to researchers who will present their insights at the Bharatbook conference on “Vaccine Manufacturing” next month in London.

    Protein Sciences is about to commercialize its FluBlok™ seasonal flu vaccine, which was developed through a baculovirus protein-expression technology that uses insect cells as host cells. The Spodoptera frugiperda insect cell line (expresSF+® cells) grows in suspension culture in the absence of serum. “We will have one of the first products made in insect cells licensed in the U.S.,” reports Clifton McPherson, Ph.D., director of quality control. GlaxoSmithKline was the first, using a different insect virus.

    “We use a recombinant baculovirus in which a highly expressed gene is replaced with the hemagglutinin gene, and this recombinant baculovirus is used to infect expresSF+ cells,” Dr. McPherson explains. Using an insect cell line also reduces the potential of cross-over infections, as  few viruses can infect both insects and humans.

    Although chicken and egg technologies have been widely used for decades, they are expensive and have certain production issues. Namely, “the influenza virus is adapted to grow in eggs,” Dr. McPherson says. In contrast, “ours can be a perfect match for the virus in the wild.”

    Protein Sciences’ technology is also scalable. The company is in the process of scaling up from 500 L batches using the same bioreactors used for mAbs. It’s also safe, he adds. “We never handle live virus. We start with RNA or with the gene sequence.”

    The same technology used for FluBlok  is also being used to develop a pandemic vaccine called PanBlok™ that is in Phase II trials in partnership with UMN Pharma and with support from BARDA in the U.S.

    PanBlok is based on a purified recombinant hemagglutinin antigen from the H5N1 avian influenza. Protein Sciences is working to speed pandemic response with the goal of producing 50 million doses within six months of an outbreak. Protein Sciences’ technology allows for a rapid response, and the production volume is more assured because recombinant technology is not limited by egg production concerns.

  • Ducks

    Vivalis chose avian stem cells for its cell-culture line. There are two major advantages, according to Majid Mehtali, Ph.D., managing director and CSO. “The avian nature of the cells allows Vivalis’ EB66 cell line to be used as an alternative manufacturing platform for the production of all human and animal vaccines previously produced on chicken eggs. The use of duck instead of chicken cells prevents the risk of contamination by endogenous retroviral particles, which are common in chicken cells but not in duck cells.

    “The use of embryonic stem cells is beneficial since such cells are the only ones that are naturally immortal and genetically stable due to their naturally high levels of telomerase activity, which stabilizes the chromosome structure and length of telomeres. Consequently, EB66 cells can be grown for hundreds of generations without major changes in their biological properties.”

    A broad variety of viral vaccines can be produced in EB66, with production yields for influenza viruses that are comparable to those of mammalian cells, Dr. Mehtali reports. Because stem cells differentiate depending on the cell-culture environment, the procedure used to generate the EB66 cell line was designed for great stability and will only differentiate in harsh conditions.

    “Additionally, a strategic collaboration with SAFC-Biosciences allowed the development of custom EB66 cell culture media, which allows efficient cell growth at high cell densities (more than 30 million cells/mL) and a short population doubling time of about 15 hours without any differentiation,” Dr. Mehtali adds.

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