Pandemic Flu Spurs Race for New Vaccine Methods

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A molecular virologist holds up an egg that is being used to grow the H5N1 bird flu vaccine strain.

A molecular virologist holds up an egg that is being used to grow the H5N1 bird flu vaccine strain. Paul Hackett/Reuters/Corbis hide caption

itoggle caption Paul Hackett/Reuters/Corbis
Howard Pien, chair of vaccine-maker Chiron Corporation.

Howard Pien, chair of vaccine-maker Chiron Corporation. Chiron currently uses a 50-year-old method to make flu vaccine, but is investigating the potential of cell-based vaccines. Corbis hide caption

itoggle caption Corbis

If a deadly new strain of flu were suddenly to emerge, one of the most important lines of defense would be a vaccine. But today's flu vaccines are manufactured using hens' eggs, and this 50-year old technology is not very nimble. With governments and global health organizations taking the threat of a flu pandemic seriously, a big push is on to develop new and faster ways to make flu vaccines.

Comparing Flu Vaccines

Flu vaccines provide protection against the influenza virus by presenting the human body with something that looks like the flu virus but that does not cause disease. Our immune systems recognize this material and produce antibodies to it. If we are exposed to an actual flu virus, those antibodies will neutralize the virus and protect us.

   

The pros and cons of various vaccine methods, either being used today or in development:

   

STANDARD VACCINE

   

Pros: Millions of Americans receive this vaccine every year. It's safe and well tolerated. Its production begins in hens' eggs — a tried and true technology for 50 years.

   

Cons: The production method requires a great deal of planning. Eggs must be ordered many months in advance. Each dose of vaccine requires one egg, so millions of doses require millions of eggs. Also, it may be more difficult to make a bird flu vaccine using bird eggs.

   

LIVE-ATTENUATED VACCINE

   

Pros: This newer method of production results in a vaccine that has a flu virus that is crippled, so it can't cause disease. But the virus is not killed, as is the case in the standard vaccine. The vaccine also can be given as a nasal spray (FluMist is the brand name).

   

Cons: More expensive than standard vaccine, and also produced in eggs. Not approved for young children or older people.

   

CELL-BASED VACCINE

   

Pros: This vaccine can be produced in giant vats of living cells (for flu, in dog kidney cells). Such a production method means it can be scaled up much faster than egg-based vaccines, making it more useful in a pandemic. Several versions have been tested successfully in people. One product is approved in the Netherlands.

   

Cons: Won't be widely available for a few years. The Food and Drug Administration is still assessing its safety. The dog cells, when injected in animals, can cause tumors. However, the vaccine itself does not contain any dog cells.

   

DNA VACCINE

   

Pros: Instead of injecting flu virus proteins into people, this concept involves injecting just the DNA from a flu virus. Human cells then "read" this DNA and create proteins that act as a vaccine. Manufacture of DNA could be much faster than that of conventional vaccines.

   

Cons: The method is being tested in human clinical trials, but development could still take years, and it may not prove to be safe and effective.

   

UNIVERSAL VACCINE

   

Pros: Scientists would like to develop a flu vaccine that can be given just once and last for life, as is the case for some childhood vaccines. Current vaccines have to be tailored to protect against specific strains of flu viruses. This one, ideally, would protect against them all.

   

Cons: This is currently more a concept than an actual product, though scientists do have some strategies that could ultimately lead to a universal vaccine.

Health officials estimate a flu pandemic would last about a year and millions of lives would be at risk. Howard Pien, head of vaccine-maker Chiron Corporation, says a vaccine for such a new, deadly strain would take at least four or five months to develop.

At that point, a pandemic could already have spread around the world. Even then, there wouldn't be enough vaccine to go around, unless there's a new way to make vaccines — and the capacity to make billions of doses in a hurry.

"These are big issues of the day," says Pien, "and if we have another year or two years or three years, we better not squander the time."

Harold Slevin, from Solvay Pharmaceuticals, says his company's current reliance on millions of chicken eggs for vaccine manufacture makes him nervous.

"If the pandemic strain of flu comes out of birds, part of the issue is that many of those strains cannot be grown in chicken eggs, because they kill the chicken egg."

It could be tough to find a strain of virus that will grow well in eggs — and be the makings of a good vaccine. And Slevin sees an even bigger problem: The possibility there won't be enough chickens during a pandemic.

"Various governments have stepped in and are destroying their whole chicken population: no chicken, no eggs, no vaccine under today's technology."

Slevin's company has developed a new way to produce flu vaccines. This relies on a line of immortal cells, harvested from a cocker spaniel's kidney way back in 1958 and kept alive ever since. This approach is called cell-based technology.

Slevin explains the process: "You take a little vial of cells out of the freezer, you put them in your bioreactor, provide the various nutrients to grow them, and inoculate them with the virus, and in principle, you can grow an infinite supply of the virus that makes your vaccine."

The bioreactor is essentially a large tank, not too much different from what's used to brew beer. So production of flu vaccine is limited only by how many tanks are built, not how many chickens are available to lay eggs. Solvay Pharmaceuticals has a head start. It has a plant built in Holland to produce flu vaccines using this technology, and it has approval to sell that vaccine in the Netherlands.

But Solvay's competition is not far behind.

A Chiron plant in Germany has already produced cell-based flu vaccines that have been tested for safety on 3,000 people in Europe. This factory won't satisfy demand even within Europe, but Rino Rappuoli, chief scientist at Chiron, says the company is making exact copies of the equipment to expand production capacity.

"We are preparing to clone that facility in the U.S. if our discussions with the government go in the right direction," says Rappuoli.

The U.S. government is involved because companies don't have an economic incentive to go it alone. A flu pandemic would require what's called "surge capacity" — the ability to make extra vaccine in a short period of time.

"We as manufacturers always have this problem," explains Rappuoli. "We need to respond to public health and social needs, which are very important questions. But for a company, it is difficult to be social, a company needs to provide returns to investors."

Those discussions are just the backdrop for a recent FDA meeting. The issue is whether the next generation of vaccines will be effective, and whether they will be safe enough to be given to hundreds of millions of Americans. FDA advisory committee member David Markovitz, from the University of Michigan, says it's a real balancing act, moving quickly in the face of a possible pandemic, but not cutting corners on safety. The new approach got a favorable reception at this non-binding advisory meeting.

"I think the overall feeling is that this is the way things are going to go and the question is just how fast," says Markovitz. "I am convinced enough to think that relatively rapidly would be good. I think other members of the committee might want to go a little bit more slowly."

Just about everyone agrees on one point: They would be happier if this discussion took place years ago. That's because it may be another three to five years before new plants are built, vaccines are approved, and manufacturing is fully up to speed. In the meantime, the federal government's plan is to create a relatively small stockpile of experimental vaccine to protect health care workers and others at the highest risk.

At the National Institutes of Health, in Bethesda, Md., Gary Nabel runs one of the nation's premier vaccine labs.

The cell-based vaccine would solve one problem, says Nabel: It would guarantee that vaccine production can be scaled up to protect as many people as possible. But it doesn't solve the other problem: Getting a vaccine in hand quickly enough to nip a pandemic in the bud.

"I think we could do much much better than we are doing today," he says.

Ideally, says Nabel, we shouldn't need to wait for a new flu virus to emerge to spur research. Nabel's lab is exploring the possibility of a vaccine that doesn't need to be specially tailored to any particular strain of flu — even a pandemic strain.

"Universal means we just get it once and we would have protection against all of the flu strains that there are in the world," he explains. "Or if we are not able to develop a universal flu strain, might there be some pattern of immunization that we follow like we all did for our childhood vaccines, where you vaccinate for a certain set of flu viruses one year, another set the next year, and a third set the last year. Then you're done for life."

This work now has a high priority, because of a possible flu pandemic. Nabel wishes the push had started before a potential crisis appeared on the horizon: "We don't at this point know whether the pandemic will come or not. But at the very least it's been a wake up call to us that we need to re-examine the problem and see if we are taking the best approaches, to dealing not just with pandemic flu but with yearly flu."

Yearly flu kills about 36,000 Americans; the current vaccine system only protects about a third of the people most at risk. So ideally, Nabel says, all the effort to do something about a possible pandemic flu could pay off with new products and new vaccination routine that will help us all, every year.

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