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Limitations in traditional flu vaccine manufacturing methods underline the need for shifting to modern technologies.
Two years ago, deficiencies in egg-based flu vaccine manufacturing led to adverse patient responses and 79,000 deaths. Experts are calling for a shift to more reliable modern production methods based on cells and use of recombinant technology. In the 2017–2018 season, challenging strains of influenza virus reduced the effectiveness of flu vaccines, resulting in hospitalizations and deaths. The 2017–2018 flu season was particularly severe, with substantial impact on individuals in every age group within the US population, according to the US Centers for Disease Control and Prevention (CDC) (1).
The vaccines used had primarily been manufactured using the traditional chicken egg-based process, and observers have called for a move to cell-based and recombinant technology for flu vaccine production. For several years, it has been noted that the chicken egg-based approach can result in vaccines that trigger a less-than-optimal response from the human immune system. This problem has been traced to constraints in the egg substrate, within which the vaccine is constructed. When there constraints are present, the resulting vaccine ends up targeting an antigen that is different from the antigen on the surface of the influenza virus strain.
According to CDC’s influenza surveillance systems, the 2017–2018 season saw higher than normal levels of hospital outpatient visits, emergency room visits, influenza-related hospitalizations, and deaths due to pneumonia and influenza. CDC officials said that they had not seen such severe results since the flu pandemic in 2009 (1).
The agency estimates that 48.8 million flu-related illnesses occurred during the 2017–2018 season; of those 959,000 required hospitalization. In addition, 79,000 people (including 68,000 elderly individuals and 600 children) died from complications related to flu treatment, according to CDC, which analyzed results in a December 2018 webinar (1). The agency estimated that the flu vaccine that year had shown only 40% effectiveness against both influenza A and B viruses. Broken down by virus type and subtype, the influenza vaccine protected 25% against influenza A(H3N2), 65% against influenza A(H1N1), and 49% against influenza B (2).
Most influenza vaccines are still manufactured using eggs; vaccine manufacturers are given the reference viruses (specific strains of influenza that are recommended for inclusion in each’s year’s vaccine). Manufacturers grow these viruses in mass quantities in eggs to make doses of the vaccine.
Not all flu vaccines are made by the chicken egg process, however. According to the CDC, two alternative flu vaccines are currently licensed in the United States: Flublok Quadrivalent (Sanofi) and Flucelvax Quadrivalent (Sequirus). Instead of virus, Flublok features hemagglutinin, a virus surface protein, and is produced via recombinant technology, while Flucelvax contains viruses that were grown in cell culture, rather than in eggs.
The statistics resulting from the 2017–2018 flu season underscore the need for more effective vaccines to combat influenza viruses. Methods based on recombinant or cell technology avoid the constraints of egg-based vaccine manufacturing, and thus can result in vaccines that are capable of handling the circulating strains of influenza virus more effectively, according to GlobalData, a data and analytics company.
Vaccine developers and manufacturers are responding to this need. In an October 2019 report (3), GlobalData notes that the current late-stage pipeline for seasonal influenza vaccines is comprised mainly of candidates that were developed using non-egg-based production methods. In addition, the focus of today’s vaccine development is on efficacy and the improvement and development of vaccines for specific age groups, the report says. Pipeline candidates include a new plant-cell-based vaccine from Canada-based Medicago, which is a virus-like-particle (VLP) vaccine produced in plant leaves (4), and a nanoparticle-based seasonal influenza vaccine, NanoFlu, that is being developed by Novovax (5). Medicago’s vaccine candidate is in Phase III development, and Novavax’s NanoFlu is in Phase I/II development.
Meanwhile, according to a December 2018 study, cell-cultured influenza vaccines were found to be 10–11% more effective than egg-based vaccines in treating elderly patients in the US (6). According to the research, the cell-cultured vaccine was significantly more effective in preventing influenza-related hospital encounters in patients aged 65 years and older.
Currently, three cell lines have been recommended for use in commercial cell-culture-based production of influenza vaccines: Madin Darby canine kidney cells (MDCK), Vero cells-epithelial cells from the kidney of the African green monkey-and PER.C6, which is a human retina-derived cell line (7). MDCK cells and Vero cells have been shown to be promising cell-line candidates.
Sequiris, whose Flucelvax Quadrivalent is currently the only cell-culture based vaccine commercialized in the US, filed an Annual Strain Update with FDA that includes the decision to manufacture Flucelvax for the 2019/2020 flu season using a cell-based candidate vaccine virus (CVV). The CVV includes all four influenza strains recommended by the World Health Organization (WHO). This move makes the entire production process exclusively cell-based, according to Sequiris (8).
Since 2014, the company has produced Flucelvax Quadrivalent at its vaccine manufacturing facility in Holly Springs, NC, built in partnership with the US Biomedical Advanced Research and Development Authority (BARDA). Seqirus initially used egg-based CVVs in its cell-based manufacturing process, but since then, WHO began recommending cell-based CVVs. FDA approved Sequirus to use cell-based CVVs to produce its vaccines (8).
Flucelvax was made from a cell-based H3N2 MDCK-CVV for the 2017–2018 flu season. The 2019–2020 vaccine was made from cell-based CVVs for both influenza B strains. According to Seqirus, its transition to an exclusively cell-based product is completed with the inclusion of a cell-based CVV for the remaining A strain for the 2019–2020 season.
Other cell culture-derived influenza vaccines in the global market include:
1. Public Health Foundation, “CDC Webinar-How I Recommend Flu Vaccine: How to Make Recommendations that Matter to Patients (Archived Webinar),” PHF.org, Dec. 12, 2018.
2. CDC, “Summary of the 2017-2018 Influenza Season,” www.cdc.gov, accessed Oct. 23, 2019.
3. GlobalData, “Seasonal Influenza Vaccines: Global Drug Forecast and Market Analysis to 2028,” GlobalData.com, October 2019.
4. Medicago, “Production Platform,” www.medicago.com, accessed Oct. 23, 2019.
5. Novovax, “Clinical Stage Pipeline,” www.novavax.com, accessed Oct. 23, 2019.
6. H.S. Izurieta, et al., J Infect Dis 220 (8) 1255–1264 (2018).
7. A.P. Rubioa and J.M. Eirosb, Hum Vaccin Immunother. 14 (8) 1874–1882 (2018).
8. Seqiris, “Seqirus Announces Further Advances in Cell-Based Influenza Vaccine Technology,” Press Release, April 15, 2019.
Vol. 32, No. 11
When referring to this article, please cite it as F. Mirasol, “Modernizing Flu Vaccine Manufacturing,” BioPharm International 32 (11) 2019.