Egg-based influenza vaccine remains the market leader, but biotech firms are examining alternatives.
Respiratory season is almost upon us, and with it, tests, doctor visits and vaccines. Though the targeted strains of flu vaccine change every year, the way those vaccines are produced and sold do not. But that might be changing.
Every respiratory season has the public health community atwitter about eggs. That’s because the most common method used to produce each year’s seasonal flu vaccine involves a laborious, time-consuming process, according to the National Institute of Allergy and Infectious Diseases (NIAID). Scientists select vaccine strains months in advance of the upcoming flu season and then grow the selected flu virus strains in chicken eggs. Sometimes an existing but unexpected flu strain becomes prevalent during flu season, making the vaccine a poor match to the circulating strains.
Providing protection against the H5N1 bird flu virus may lead to further complications, as it will call for more eggs. Many of them. The Administration for Strategic Preparedness and Response of the U.S. Department of Health and Human Services reports that officials are moving forward with a plan to produce 4.8 million doses of H5N1 avian flu vaccine for pandemic preparedness.
Despite its drawbacks, the egg-based influenza vaccine remains by far the market leader. It’s a known entity and it’s effective. But following the development of mRNA-based COVID vaccines from Pfizer and Moderna, the federal government, public health officials and pharmaceutical companies are exploring a variety of options, including mRNA for influenza vaccine and vaccine produced in mammalian and insect cell lines that don’t pose the same risks as egg-based shots (e.g., allergic reactions).
Cell-based vaccines
A cell-culture-based production process for flu vaccines was approved by FDA in 2012. Originally, this production process also began with chicken-egg-grown candidate vaccine viruses (CVVs). But in 2016, the FDA issued an approval for Seqirus, the sole FDA-approved cell-culture-based flu vaccine manufacturer in the United States, to begin using cell culture-grown CVVs. Currently, cell culture-based manufacturing is used to make inactivated flu vaccines (e.g., flu shots), not LAIV (nasal spray flu vaccine).
The process of creating cell culture-based flu vaccines involves several steps. First, CDC or one of its laboratory partners uses influenza viruses that have been grown in cultured mammalian cells to make CVVs, which are then provided to the vaccine manufacturer. Next, the vaccine manufacturer inoculates the CVVs into cultured mammalian cells (instead of into chicken eggs) and allows the CVVs to replicate (i.e., make copies) for a few days. Then, the virus-containing fluid is collected from the cells and the virus antigen is purified. The manufacturing process continues with purification, virus inactivation, and testing. Finally, FDA tests and approves the vaccines prior to release and shipment.
NIAID and industry partners are exploring ways to move away from both the egg-based and cell-based flu vaccine production methods toward recombinant DNA manufacturing for flu vaccines. This method does not require an egg-grown vaccine virus. Instead, manufacturers isolate a certain protein from a naturally occurring (“wild type”) recommended flu vaccine virus. These proteins are then combined with portions of another virus that grows well in insect cells. The resulting “recombinant” vaccine virus is then mixed with insect cells and allowed to replicate. The flu surface protein called hemagglutinin is then harvested from these cells and purified. Flublok Quadrivalent by Sanofi is an example of a recombinant flu vaccine.
Scientists are also developing novel influenza vaccine platforms that could be produced more efficiently. NIAID’s Vaccine Research Center is developing DNA or gene-based vaccines against seasonal and pandemic influenza that have been tested in clinical trials. A DNA vaccine contains a small, circular piece of DNA that includes genes that code for proteins of a flu virus. When the vaccine is injected into the body, cells read the genes and make virus proteins, which self-assemble into virus-like particles. The body then mounts an immune response to these particles.
mRNA
While protein-based vaccines deliver a virus-like protein (antigen) ready-made, directly to the immune system, mRNA vaccines deliver genetic material (created in a laboratory) that instructs the body’s cells to produce the antigen, according to biotech firm Novavax. That antigen in turn triggers an immune response. mRNA vaccines do not contain any live virus and cannot cause infection.
Compared to protein-based vaccines, mRNA vaccines are relatively new. While the first mRNA flu vaccine was tested on mice in the 1990s, it wasn’t until 2011 that the first mRNA vaccines were tested in humans. This delay was because the mRNA immediately degraded before it could be translated into the antigen protein. That issue was solved by advances in vaccine nanotechnology, which helped protect the mRNA as it is delivered to the cell. The first mRNA vaccines to complete all stages of clinical trials and be licensed for use were for COVID-19.
But because mRNA technology can be used to produce vaccines more quickly than conventional vaccine manufacturing technologies, scientists expect it can help create a shot that better matches the season’s flu strains and as a result, offer better protection, according to Pfizer. Another key benefit of mRNA technology is its flexibility, which may allow scientists to quickly “edit” vaccines. For viruses like the flu that are constantly changing and require vaccines that must be updated each year, once a path is established with the FDA or other regulatory authorities, scientists may be able to swap out the mRNA instructions to match with the then-circulating variants.
Despite its promise, it’s unlikely mRNA influenza vaccines will make a big dent in the market, at least in the immediate future.
“I’m not of the opinion that mRNA will be that groundbreaking or paradigm-shifting, as other researchers believe it will,” says Doug Campos-Outcalt, M.D., MPA, adjunct senior lecturer, Public Health Practice, Policy and Transitional Research Department, Mel & Enid Zuckerman College of Public Health, University of Arizona. “The COVID vaccines are very effective to start with, but immunity wanes fairly quickly, and we’re not sure of the vaccine’s long-term implications. What’s more, mRNA vaccines can be reactogenic; people do not like the reactions. We’ll probably get down to an annual or every-six-month shot based on the circulating strain. So mRNA isn’t a huge advantage over other technologies.
“Yes, producing egg-based vaccines is a slow process. That’s the main problem with it. But we have other technologies – recombinant, cell-based and other methods coming through the pipeline. I don’t think mRNA will be the only option for flu vaccine.”
COVID-19/flu combo vaccine in the works
Moderna, Pfizer and BioNTech, and Novavax continue to work on developing a combination COVID-19/influenza vaccine.
In June, Moderna announced that its Phase 3 trial of mRNA-1083, an investigational combination vaccine against influenza and COVID-19, met its primary endpoints, eliciting a higher immune response than comparison vaccines used in the trial.
“Combination vaccines have the potential to reduce the burden of respiratory viruses on health systems and pharmacies, as well as offer people more convenient vaccination options that could improve compliance and provide stronger protection from seasonal illnesses,” CEO Stéphane Bancel said in a statement. The company will engage with regulators on next steps.
Meanwhile, in May, Novavax and Sanofi announced a licensing agreement granting a license to Novavax’s adjuvanted COVID-19 vaccine for use in combination with Sanofi’s flu vaccines while Novavax develops its own COVID-19-Influenza Combination vaccine candidate.
“Our new partnership combines Novavax’s proprietary recombinant protein and nanoparticle technologies, Matrix™ adjuvant and R&D expertise, with Sanofi’s world-class leadership in launching and commercializing innovative vaccines,” said Novavax President and CEO John C. Jacobs in a statement.