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Flu vaccine: What’s taking so long?
POSTED 12 NOVEMBER 2009

Still standing in line?

A purple microscopic image of round flu virus with hundreds of small hair-like receptors
Image: CDC
Those little "trees" on the surface of this H1N1 flu virus are receptor molecules that it uses to attach to cells during the infection process.

It's time for the flu shot, and not many shots are available. That's scary. We’ve just seen a report that H1N1 influenza killed 3,900 Americans between April and October. About 22 million Americans have gotten the virus, and 98,000 of them had to be hospitalized. Nine million children have been infected and 540 have died. Whether you want the regular ("seasonal") vaccine, or the pandemic ("H1N1"), the operative word seems to be mañana. Despite considerable effort, supplies of both vaccines are short -- and good protection requires both shots.

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Why the big delay? For both vaccines, the main blame seems to fall on an antiquated production process. Virology and immunology have advanced light years in recent decades, and yet flu vaccines continue to be made inside chicken eggs, a process that can take more than half a year.

Between H1N1 and bird flu, a highly lethal H5N1 virus that cannot now spread from person to person, it's looking like the future of civilization rests on something we usually scramble for breakfast.

The vaccine shortage is dangerous because flu changes so fast, and so unpredictably. It's entirely possible that a deadly new strain could break out somewhere in the world, and take a jet into cities around the world. A different respiratory virus, SARS, did that a few years ago, and was contained only with heroic measures. Still, within months 774 had died.

If a lethal flu does suddenly break out, it may be too late to use a vaccine to activate the best, cheapest and most effective defense of all -- the human immune system. Today's technology would require us to identify the virus, find and inject hundreds of millions of sterile eggs with the virus, let it grow, purify the virus and make the vaccine.

The threat of influenza, combined with the vaccine shortage, have many people thinking about faster and better ways to make vaccines, which are unquestionably one of the greatest advances in medicine.

Influenza, over easy

To understand the story, read five fast flu facts:

Influenza is a highly variable virus, continually mutating and rearranging to evade vaccines and the immune system.

A vaccine against seasonal flu won't protect against the more powerful H1N1 virus, and vice versa.

Due to the long production process, health authorities must predict which strains of virus will be present more than one-half year before flu season normally begins.

H1N1, the "swine flu" that caused so much havoc last spring, has spread to all 50 states, where it continues to disproportionately affect young, healthy people.

Influenza may be "just the flu," or a nightmare: The 1918 outbreak killed 50 million or more.

A key problem, says vaccine maker Novartis, is the "seed" virus it received earlier this year, which had "very low yields...at 23 percent as compared to average yield seen with seasonal vaccines." In mid-September, Novartis started production with a new H1N1 seed, "which provides an improved yield of 63 percent."

However, large-scale production of H1N1 vaccine is continuing. Novartis, for example, has contracted to produce 90 million units of H1N1 vaccine from a plant in the United Kingdom for the U.S. Department of Health and Human Services. On Oct. 29 the company said it had produced 42 million units, not all of which had reached patients. Novartis expects to complete that order by December.

A picture inside a shopping mall with a line of people against a wall stretched down a long hall
Photo: Nsaum75
Hunndreds line up in a mall in Texas City, Texas, to receive the H1N1 flu vaccine from the Galveston County Health Department, Oct 30, 2009.

Still scrambled after all these years

Currently, the Food and Drug Administration chooses a viral strain for the next winter in February, even though it's hard to be sure which flu strains will be active so many months in advance.

The fundamental problem arises after the seed virus is chosen: making large quantities of virus for the vaccine. Since the 1950s, flu vaccine has been made by inoculating (infecting) fertilized chicken eggs with a seed virus that reproduces. This larger amount of virus is then disabled and formed into a vaccine that can trigger the immune system without causing disease.

The process is cumbersome -- requiring hundreds of millions of pathogen-free eggs -- and slow. The eggs must be free of pathogens, says Paul Radspinner, president of FluGen, a Madison, Wis., startup company that is exploring new production methods. "You can't go to the local hennery and grab a dozen eggs. It takes six to 12 months from the time you place an order for new eggs to increase the number of eggs in the system."

With the ongoing shortages of both flu vaccines, Radspinner says, "The issues with that production system were really exposed this time." Because the H1N1 pandemic did not begin until March or April, "there was no way in the world there would be enough eggs for the seasonal and the pandemic vaccines."

Inside a laboratory, a large wheeled rack of brown eggs next to a white machineÊ
These eggs are used to grow vaccines at a Novartis plant. Even though eggs safely produce millions of doses, better ways to grow flu vaccines are clearly needed.

Hard-boiled eggs

Still, after the vaccine makers get seed virus and round up their eggs, everything may go smoothly, if:

the virus thrives in the eggs

the virus does not kill the eggs (as some H5N1 "bird flus" are prone to do)

the correct strain (or strains) of virus were chosen and another strain of virus does not break out after that choice and

most people react to the vaccine with a strong immune response

In some years, the wrong strain of flu is chosen, and the vaccine is less effective (although it still may confer some immunity). This year, although the H1N1 strain seems to be correct, two separate flu vaccines are in short supply, and it's too soon to know whether the seasonal strain was correctly chosen.

If vaccine can be made faster and cheaper, it would be easier to predict which strain will be around in flu season, there would be more time to grow another strain of virus if the prediction was wrong, and production could be ramped up quickly in the event of a severe epidemic.

And so the issue of production lies at the heart of our influenza problem.

Can we develop a faster, better method for making vaccine?
more

Terry Devitt, editor; Steve Furay, project assistant; S.V. Medaris, designer/illustrator; David Tenenbaum, feature writer; Amy Toburen, content development executive

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