Momentum builds for cell-culture flu vaccines

Jun 27, 2005 (CIDRAP News) – You've got to gather a lot of eggs to supply the world with influenza vaccine, but that might change before long.

As governments and scientists wrestle with how best to protect people from the annual onslaught of typical flu and the unpredictable attack of pandemic flu, they're seeking alternatives to egg-based vaccines.

A production method common to other vaccines, cell culture, is increasingly gaining currency. Cell-culture technology involves growing key vaccine components in human, monkey, canine, insect, or other cells in enclosed vats.

The process has been used for vaccines such as polio, hepatitis A, chickenpox, and shingles, said Robin Robinson, PhD, senior project officer for the Office of Public Health Emergency Preparedness in the US Department of Health and Human Services (HHS).

Growing flu vaccines in cell cultures would mark a huge departure from the traditional method.

The decades-old production method used today involves growing vaccines in fertilized chicken eggs. It depends on the availability of hundreds of millions of eggs and requires adapting the virus strain to grow in eggs. The production process takes at least 6 months, according to the National Institute of Allergy and Infectious Diseases. And in the event of an emergency, there is no way to quickly scale up the supply, since eggs must be ordered in advance.

With cell-culture methods, the virus does not need to be adapted for growth in eggs, and in an emergency, manufacturers could boost production without waiting for chickens to lay enough eggs. Although estimates vary as to how much time would be saved with cell-culture production, experts familiar with both methods say it could shorten the process by at least a month.

Besides being faster, production of cell-culture vaccines is considered safer and cleaner than egg-based systems because it uses a closed system of bioreactors.

An improving climate
Despite the disadvantages of egg-based vaccines, however, there has been little pressure to pursue cell culture. The functional egg-based infrastructure, the relatively low profits for flu vaccines, and the challenges of adapting the flu virus for cell culture production have slowed research and development, authorities say.

Egg-based vaccines "have always been a very cheap product, and there was never a real incentive in the industry to change that process," explained Manon Cox, DrS, MBA, chief operating officer of Protein Sciences Corp. in Meriden, Conn., in a recent interview. Protein Sciences is developing a cell-culture flu vaccine using caterpillar cells.

The climate for cell-culture flu vaccines is improving because of shortages in the US vaccine supply and the growing fear that the next pandemic could be brewing right now in Southeast Asia.

While some companies have been researching cell-culture techniques for years, others now have incentives to join the push. The United States has worked in the last year and a half to encourage a number of contracts to "secure, expand, and diversify the influenza vaccine supply in the United States" for both seasonal and pandemic flu, Robinson said.

HHS in April awarded vaccine maker Sanofi Pasteur a $97 million, 5-year contract to develop cell-culture technology. The contract is for developing the technology and design for a facility to manufacture at least 300 million doses of vaccine for use in a pandemic.

HHS has already issued another request for proposals to boost flu vaccine research and development, Robinson said. The contracts call for producing a pandemic flu–like vaccine that must go through phase 1 and 2 clinical trials "so they have a candidate that will be both safe and immunogenic," he said.

Bruce Gellin, director of the National Vaccine Program at HHS, explained why it's important to end the era of the egg in testimony before a congressional subcommittee on Apr 12:

"Using a cell culture approach to producing influenza vaccine offers a number of benefits. Vaccine manufacturers can bypass the step needed to adapt the virus strains to grow in eggs. In addition, cell culture–based influenza vaccines will help meet surge capacity needs in the event of a pandemic or shortage. US licensure and manufacture of influenza vaccines produced in cell culture will also provide security against risks associated with egg-based production, such as the potential for egg supplies to be contaminated by various poultry-based diseases."

Cell-based techniques would allow manufacturers to double or triple vaccine production, from, say, 10 million doses a week to perhaps 20 million or 30 million, Robinson said.

In addition, safety could be greatly improved with cell-culture vaccines, he noted. Egg-based vaccine production involves open systems, whereas cell-culture production involves a bioreactor, which is a closed system. Cell-culture technology far safer from contamination by pathogens, which would be of crucial importance in the event of a pandemic, he said.

Caterpillar cells as vaccine factories
Sanofi Pasteur is but one of several companies working to develop cell-culture flu vaccine, according to a list Robinson compiled. They include Solvay Pharmaceuticals of the Netherlands, Baxter in Austria, Chiron in Germany, GlaxoSmithKline in Belgium, ID Biomedical of Canada, and Medimmune in the United States. None of the vaccines is on the market yet.

"Today everybody is trying to do this," said Cox, of Protein Sciences.

Protein Sciences is betting on the baculovirus system for its cell culture flu vaccine. The baculovirus has a reputation in nature for easily infecting insect cells, Cox said.

Protein Sciences' process starts with recombinant hemagglutinin (rHA), she said. Hemagglutinin (H) and neuraminidase (N) are the surface proteins of the flu virus. H helps the virus bind to and enter host cells, and N enables new copies of the virus to leave a cell so they can infect others.

The rHA is essentially zipped up like DNA, creating a more stable, less shift-prone blueprint, Cox said. The rHA is inserted into a baculovirus, and the baculovirus is added to caterpillar cells.

"The rest happens on its own," Cox said. "There's an infection, the baculovirus infects the insect cells, and it sets about producing the product of interest [baculovirus copies containing rHA]. The insect cell is a little factory, which is now starting to produce whatever that baculovirus wants it to produce."

"Vaccine manufacturers have recognized that this baculovirus system is an enormously powerful system to make vaccines against viral or parasitic diseases," she said. "We need to convince venture capitalists and other partners that this is indeed the product to go for," she added. It will probably be 3 years before the company seeks FDA approval.

The company's efforts may have taken a stride forward with the announcement in mid-June of preliminary results from its initial field efficacy study of the FluBlOk vaccine, made through the process described above.

The study included 460 healthy people aged 18 to 49 at three US sites, according to a news release from the company. Subjects were injected with one of two different formulations of FluBlOk, with the same amount of H3 antigen but two different amounts of H1 and influenza B antigens, or with a placebo. The 135-microgram dose was 100% efficacious in preventing culture-positive influenza compared with the placebo, the company said. In addition, the vaccine groups had a 50% lower rate of flu-like illness than the placebo group.

The trial showed safety and induced strong antibody responses against influenza in all vaccinated subjects, the company said, adding that final assessments are still under way.

Seeking licensing in the Netherlands, US
The Dutch company Solvay Pharmaceuticals has been working on a cell-culture flu vaccine since the early 1990s, according to Bram Palache, MSC, PhD, biochemist and global medical affairs director for influenza vaccines.

Solvay's vaccine is made in canine cells, a line that has been approved for use in the Netherlands, although it wasn't approved when Solvay selected it, Palache said. The company is in the process of validating its factory, and hopes to make clinical lots there this year. From there it's a relatively short step to final licensure of the flu vaccine for use in the Netherlands, he added.

Solvay is seeking US Food and Drug Administration approval of the flu vaccine and the cell line used to produce it, Palache said. He was not ready to speculate on how long it might be before the vaccine would be available in the US.

The importance of alternatives to eggs for vaccine production came home to Solvay in 2003, when the company lost chickens during an outbreak of H7N7 avian flu in the Netherlands. The company had to scramble to get approval to bring in eggs from disease-free areas so it could produce flu vaccine on time.

"We had a real-life situation where the vulnerability of eggs for the production of influenza vaccines was really making the difference between having vaccine and having no vaccine," Palache said. "There's nothing wrong with egg production per se. But once the cell-culture vaccine is implemented . . . more companies will come in, using that technology. Ultimately it will replace the current production technology."

Cell culture just part of US strategy
Robinson cautioned that in the flu vaccine arena, there are more pressing short-term goals than developing cell-culture technology. "We approach it in two phases. One is preparedness to hopefully have stockpiles of a virus that is as close as we think it can be to the [potential pandemic] threat. And then to have the manufacturers ready to go with virus seed strain. And then to have the capacity."

The short-term US goals are aimed at improving the current flu vaccine production processes to improve yield and making the available vaccine supplies stretch further, he said. The goals include developing adjuvants to boost immune response and finding alternative methods for injecting the vaccine.

Robinson said he wants the nation to have the surge capacity to produce at least 20 million doses of monovalent vaccine per week by 2009.

Ultimately, what the United States would need for a pandemic flu strain is 600 million doses of vaccine—two doses for every American. Compare that with the numbers for the 2004-05 flu season: Authorities hoped to have 100 million doses available, but obtained only 61 million. The leap from the unmet goal of 100 million doses to 600 million is so daunting that even experts such as Robinson break down the numbers.

"That's why we like to talk about it in terms of weeks," he said.

And while cell-culture technology may improve flu vaccine production capacity, it is not a panacea for the challenge of a flu pandemic. A vaccine cannot be specifically tailored to a pandemic virus until the virus emerges, so even with cell-culture technology, an optimal vaccine would not be available for the first several months of a pandemic.

Moreover, only nine countries have the capacity to produce flu vaccine on a commercial scale. The advent of cell-culture technology does not automatically solve the problem that current global annual production capacity is fewer than 1 billion doses of flu vaccine in a world of more than 6 billion people—or the challenge of actually administering vaccine to billions of people in a pandemic situation. And even if the United States could eventually secure enough doses for its own population, the nation would not be immune to the global economic disruption that a pandemic would cause.

Aside from pandemic-related concerns, Palache said that switching production methods won't address a key problem with flu vaccine: demand.

"[Neither] Solvay nor any other company will produce three times as much vaccine just because they can do it if by the end of the day it isn't sold. Flu vaccines can't be put on the shelf for the next year," he said. "Whether they're eggs or cells, demand drives supply."

See also:

Transcript of Bruce Gellin's testimony
http://www.hhs.gov/asl/testify/t050412.html

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