Disclosures: Percival reports no relevant financial disclosures.
September 23, 2021
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The present and future of flu vaccine production technologies

Disclosures: Percival reports no relevant financial disclosures.
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According to the CDC, manufacturers expect to deliver 188 million to 200 million doses of influenza vaccine in the United States this year.

The CDC was unable to estimate the efficacy of last season’s vaccine due to a mild season with low numbers of infections. In addition, fewer virus specimens from last season made it more difficult to characterize the circulating virus and prepare for this influenza season.

Kelly M. Percival
Kelly M. Percival

The influenza A strains are both different from those included in last season’s vaccine, whereas the influenza B strains remain the same. Each strain was selected based on whether it is an egg-based, cell-based or recombinant production method. The exact virus strains vary between production methods because not all viruses are ideal for the different production systems, resulting in different viruses with similar properties selected for timely vaccine production.

This year’s quadrivalent vaccines contain the following virus strains:

  • A/Victoria/2570/2019 (H1N1) pdm09-like virus for egg-based vaccines;
  • A/Wisconsin/588/2019 (H1N1) pdm09-like virus for cell- or recombinant-based vaccines;
  • A/Cambodia/e0826360/2020 (H3N2)-like virus;
  • B/Washington/02/2019-like virus (B/Victoria lineage); and
  • B/Phuket/3073/2013-like virus (B/Yamagata lineage).

Currently, influenza vaccines are produced with three different technologies: an egg-based, cell-based, or recombinant formulation. This year’s U.S. supply is composed of approximately 82% egg-based and 18% cell-based or recombinant technology. Egg-based methods are dominant, but the CDC has a long-term goal to reduce reliance on egg-based methods and to embrace newer vaccine technologies that allow for a quicker response to novel influenza outbreaks and pandemics.

Egg-based manufacturing

Egg-based manufacturing is most common and has been used for more than 70 years. The production process begins with candidate vaccine viruses (CVVs), provided by CDC or WHO, grown in eggs by private sector manufacturers. Theses CVVs are then injected into fertilized hen’s eggs and incubated for several days for replication, followed by extraction, inactivation or weakening and purification for vaccine production. Then comes quality testing, filling and distribution. The process takes approximately 6 months, allowing time for viruses to drift. Egg adaptation also can occur, leading to reduced vaccine efficacy. Egg adaptation occurs when viruses adapt to avian cell receptors, which are different from receptors on mammalian cells. This adaptation occurs on the influenza virus in the same region that is dominant antigenically, and as the virus adapts to grow in eggs, it can differ antigenically from circulating viruses. This may lead to less effective egg-based vaccines compared with non-egg-adapted vaccines.

In addition to the long manufacturing time, the process requires many chicken eggs, which presents challenges. Each dose of quadrivalent inactivated vaccine needs four eggs, requiring the production of more than 100 million embryonated chicken eggs in flocks that must be pathogen free. Lapses in hygiene can result in the rejection of large amounts of vaccine. Additionally, the H3N2 strains do not grow well in embryonated hen eggs because they are not the ideal substrate for all virus strains.

Cell-based manufacturing

Cell-based influenza vaccine production, approved by the FDA in 2012, was the first non-egg-based production technology. Initially, the process also began with egg-based CVVs, but in 2016, the FDA issued an approval to begin using cell-grown CVVs. The CDC provides these cell-based CVVs to the manufacturer, which then replicates the virus inside Madin-Darby canine kidney (MDCK) cells instead of fertilized chicken eggs, shortening the production time. This process eliminates the potential for egg-adapted changes and grows viruses more like the circulating strain, which increases its efficacy.

Observational studies from the severe 2017-2018 season — an H3N2 predominant year — showed greater protection against influenza or influenza-like illness among those who received cell-based vaccine vs. standard egg-based vaccine. Additionally, this process is not dependent on egg supply, and MDCK cells can be frozen and banked in large quantities, allowing for production to be scaled up easily and quickly if needed for a pandemic. Currently, Flucelvax, manufactured by Seqirus, is the only approved cell-based influenza vaccine.

Recombinant vaccines

Recombinant influenza vaccines are produced using recombinant technology that does not require egg-grown vaccine virus. Flublok, manufactured by Sanofi, is currently the only FDA-approved recombinant vaccine. Recombinant vaccines do not require having a CVV sample for production because the vaccines are created synthetically. This occurs by taking antigens from WHO- or CDC-supplied viruses and transcribing them into DNA. The influenza hemagglutinin (HA) DNA is combined with baculovirus, a virus that infects invertebrates, to result in a recombinant virus. The recombinant baculovirus are placed into cells of Spodoptera frugiperda (commonly called the fall armyworm), which expresses both baculovirus and HA protein. The expressed influenza HA protein is then collected, purified and packaged into the influenza vaccine. This process is the fastest of currently available production methods and can produce some vaccine quantities in 6 to 8 weeks.

Because it is not dependent on selection of vaccine viruses adapted for growth in eggs or the development of cell-based vaccine viruses, this process could be advantageous in the event of a pandemic or egg shortage.

Experimental vaccines

The Department of Defense is currently conducting a large study with 15,000 participants randomly assigned in a 1:1:1 ratio to receive cell-culture-based vaccine, recombinant vaccine or egg-based vaccine over three influenza seasons. The study, which will compare the effectiveness of egg-based vs. non-egg-based vaccines, is anticipated to end in May 2022 and will hopefully provide valuable insight into the effectiveness of the different vaccines.

The future of influenza vaccine production technology might be messenger RNA vaccines, which introduce engineered single-stranded mRNA molecules that provide biological instructions for cells to produce proteins that trigger an immune response, which include antibody production. The potential use of mRNA influenza vaccines was already under evaluation but is now being propelled by the success of COVID-19 vaccines.

The mRNA vaccines are produced more quickly, which is important in improving the ability of influenza vaccination to target the dominant strain that year. Furthermore, there is hope that this technology can be used to make combination vaccines to target multiple respiratory viruses, such as influenza, SARS-CoV-2 and respiratory syncytial virus.

Sanofi Pasteur and Moderna have both begun trials testing mRNA influenza vaccines. Sanofi and Translate Bio announced on June 22 the initiation of a phase 1 clinical trial with up to 280 participants. It anticipates having interim data by the end of 2021. Moderna announced on July 7 that the first participants had been dosed in its phase 1/2 study of its investigational mRNA influenza vaccine, which will enroll about 180 people.

The possibility of a non-mRNA combination influenza and COVID-19 vaccine is being explored by Novavax, which announced on May 10 data from a preclinical animal study of its combination quadrivalent seasonal influenza and COVID-19 vaccine, which includes a quadrivalent nanoparticle influenza vaccine formulated together with a recombinant SARS-CoV-2 spike protein vaccine and matrix-M adjuvant. Clinical studies of the combination vaccine are expected to begin by the end of this year.

As more data become available on the efficacy of egg-based compared with other production method-based vaccines, it is likely the percentage of yearly influenza vaccines that are egg based will decrease and combination respiratory vaccines may become a reality. Because these less-used, non-egg-based and experimental platforms can be made more quickly and efficiently, not only is it possible to see increased efficacy but also an improved response to influenza outbreaks and pandemics.