By Deborah Borfitz 

November 10, 2021 | Cell-based vaccines, initially developed to add speed and scale to pandemic response efforts and reduce dependency on chickens in the vaccine manufacturing process, have over the past few years also shown to be more reliably effective than traditional, egg-based products, according to Professor Terry Nolan, head of the Vaccine and Immunization Research Group at the Murdoch Children’s Research Institute and the Peter Doherty Institute for Infection and Immunity at the University of Melbourne.

Currently, most flu vaccines are made in chicken eggs, and this has been standard practice for decades, he says.  Australian scientist and Nobel Prize winner Sir Frank Macfarlane Burnet pioneered the technique of growing influenza in chick eggs almost 70 years ago. 

Up until about 15 years ago, children allergic to eggs were often advised either not to get the vaccine or to do so under the watch of a healthcare provider who recognizes and treats severe allergic reactions, adds Nolan. The reassuring truth, as recent studies have demonstrated, is that by the time an egg embryo culture reaches the vaccine stage there is no residual egg protein. At the University of Melbourne, “there has never been a case of a child vaccinated with an egg embryo-generated vaccine having a reaction, and that’s the real proof that it hasn’t been doing any [harm].” 

Still, a “mind-boggling” number of eggs are required for large-scale flu vaccination campaigns, Nolan says. The vaccine also needs to be reformulated year after year because egg-adapted changes create a mismatch between the viruses they carry and those in circulation that are infecting people.

Unlike influenza viruses grown in the yolk of fertilized hen eggs, flu vaccines developed from mammalian cell lines produce an exact match to the World Health Organization’s selected influenza strains, he continues. “Biologically, they are less likely to drift from the target strains.” They also permit a shorter response time when a new flu virus emerges. 

Nolan was lead investigator on a study, newly published in the New England Journal of Medicine (DOI: 10.1056/NEJMoa2024848), which found a cell-based influenza vaccine— Flucelvax Quadrivalent, manufactured by U.K.-based Seqirus—effectively protected against flu in children and adolescents. It was the first non-egg-based vaccine showing sufficient immune response in children as young as two years of age. 

The U.S. Food and Drug Administration (FDA) only weeks ago approved Flucelvax Quadrivalent for use in children as young as six months old, based on findings of a phase 3 comparison study with a U.S.-licensed quadrivalent influenza vaccine. The vaccine was initially approved by the FDA in 2016 for people four years of age and older.

The study population of six months up to age four was to fulfill an FDA post-marketing requirement following accelerated approval of Flucelvax Quadrivalent for use in persons four years of age and older, says Jon Edelman, vice president of clinical development at Seqirus. “The commitment to FDA was part of our obligations under the Pediatric Study Plan, as required for new influenza vaccines.” 

Flucelvax Quadrivalent (aka Flucelvax TETRA or Flucelvax QUAD) is also available in Austria, Australia, Canada, Germany, Greece, Italy, Spain, Taiwan, and the U.K., reports Stefan Merlo, vice president of commercial development at Seqirus. “Specific approved age groups vary among regions based on local regulatory guidelines, and Seqirus continues to seek regulatory approvals for expanded age indications of Flucelvax down to six months in countries beyond the U.S.” 

Study Particulars

In the newly published study, the overall vaccine efficacy was 54.6% and benefit was seen against all three strains of the flu virus—A/H1N1 (80.7%), A/H3N2 (42.1%), and B (47.6%)—across three influenza seasons, Nolan reports. H3N2 proved to be “very difficult” to vaccinate against, as has been the case for flu vaccines in general. 

The COVID-19 pandemic has created a world of armchair immunologists with high expectations for vaccine effectiveness, he says. But when it comes to kids and the flu, “something around 50% is considered very good and, because flu is so prevalent, modest efficacy… translates into a big population effect.”

Adults and children typically get the same dose of a cell-based vaccine (0.5 milliliter in the case of Flucelvax Quadrivalent), says Nolan, excepting high-dose vaccines intended for the elderly. It is also now customary for flu vaccine trials to use a comparator vaccine rather than a placebo, which is considered unethical in countries where public health officials make flu vaccine recommendations. 

In his study of Flucelvax Quadrivalent, children in the control group were able to receive the meningococcal ACWY vaccine because it was conducted in eight countries—Australia, Thailand, Estonia, Finland, Lithuania, Poland, Spain and the Philippines—where flu vaccines for children were not formally recommended at the time. Since the study, vaccination of children under the age of five against the flu is now funded as part of the National Immunization Program in Australia, he says. 

The U.S. was excluded from the study for this reason. It is one of few countries in the world that has embraced flu vaccination for many years, backed by a federally funded program aimed at children, says Nolan. 

The timing couldn’t be better with winter approaching in the Northern Hemisphere and concerns growing about COVID-19 and influenza co-infection, particularly in children. Months of pandemic-related lockdowns made last year’s flu season virtually disappear, meaning this year could be a “bumper flu year” with more severe infections because people’s immunity will be lower, says Nolan. 

In Australia, where winter runs from June to August, cases of the flu were the “lowest on record” last year, he notes. This year, the numbers ticked up but only modestly—a reflection of the country’s strict lockdown restrictions that is also credited with keeping COVID-related deaths significantly below that in the U.S. 

Vaccine Scalability 

Cell-based culture, or other forms of non-egg-based culturing, has been used for many recombinant protein vaccines in adults, Nolan says. These include the COVID-19 vaccine of Novavax, a candidate for use in the U.S. via Emergency Use Authorization by the FDA. The protein-based vaccine combines the spike protein of the SARS-CoV-2 virus with a company-made adjuvant to enhance immune response and stimulate high levels of neutralizing antibodies.

“Generally, anything that is a recombinant protein can be produced through some sort of cell system,” he notes. The list includes Merck’s Gardasil human papillomavirus vaccine for the prevention of cervical cancer and Sanofi’s influenza vaccine Flublok, both marketed in the U.S. Many protein vaccines are amenable to a cell-based manufacturing process or a variant of it, he adds. 

The scalability of cell-based vaccines depends primarily on the speed at which their manufacturer can make the product to meet market demand, says Nolan. Up to now, Seqirus has been manufacturing cell-based vaccines only in the U.S. and U.K., but is now building a new facility in Australia—the first of its kind in the Southern Hemisphere—which is expected to be operational by 2026.

In the interim, truckloads of eggs continue arriving daily to produce cultures for the traditional manufacturing process, Nolan says. Unlike in the U.S., where cell-based flu vaccines have been in use for about a decade, they are new to Australia and meeting rigorous good manufacturing practice requirements of the Therapeutic Goods Administration is part of the catch-up process. 

Seqirus produces cell-based influenza vaccines at its manufacturing facility in Holly Springs, North Carolina, which was “purpose-built in partnership with the U.S. Biomedical Advanced Research and Development Authority to combat pandemic threats,” says Merlo. “While egg-based manufacturing requires large quantities of chicken eggs to be produced at the time of manufacturing, the cells used to manufacture Flucelvax Quadrivalent are kept frozen and ‘banked,’ which helps ensure an adequate supply of cells to quickly ramp up vaccine production.” 

Broad Potential

Nolan’s interest in vaccines extends well beyond those for flu. He and his colleagues are about to launch a phase 1 study of two, second-generation beta variant COVID-19 vaccines, one using mRNA and the other a recombinant protein, he says. If successful, the hope is that a big vaccine manufacturer will license the technology. 

Separately, the academic research team is working with Moderna on clinical trials for some of its non-COVID mRNA vaccines aimed at a variety of infectious, immuno-oncology, rare, and autoimmune diseases. These include vaccines against the human immunodeficiency virus, congenital anomalies and intellectual disabilities in children, and the common and highly contagious respiratory syncytial virus, says Nolan.  

“There is a lot going on at the moment in the world of vaccines and… what we’ve learned from COVID is going to benefit many other conditions as well.”