Marching toward a better flu vaccine

This is a story about eggs, time and the flu. And how advances in the craft of vaccine-making might break a lot fewer eggs and help more of us dodge the flu.

With the nation already in the throes of flu season, a growing number of Americans are hunting around for an elusive dose of flu vaccine. Others are simply wondering why the medical establishment has such a spotty record of protecting us from this yearly scourge.

For now, they can blame the eggs, but it won’t always be that way.

Today chicken eggs are at the heart of a lengthy, brittle process of producing each year’s vaccine, a process that has changed little since the first flu vaccine was introduced in the 1940s.

It takes months -- as many as eight, by one authoritative count -- to collect millions of these delicate incubators from the nation’s coops and barnyards, and then use them to grow the tiny viruses that make up the next season’s vaccine. So when the flu season arrives and the virus is not exactly what health officials predicted last March, or when more people want or need to get the vaccine than originally expected, it’s too late to change the recipe or mix up a new batch.

It’s time to start collecting eggs for next year’s vaccine.

On the horizon, however, are new vaccine design and production techniques that could get around the many problems that chicken eggs pose. Two techniques in particular, reverse genetics and mammalian tissue culture, promise to accelerate the vaccine-making process.

Banishing or diminishing the role of the egg could allow pharmaceutical companies to turn out flu vaccine much more quickly. With less production lead time, the vaccine-makers could keep up with fast-changing flu viruses and even faster-changing public demand for flu vaccine.

The U.S. Department of Health and Human Services has asked Congress for $100 million this year to help develop and test these new techniques and to begin working out some of the complex legal issues their adoption would raise. That money is a down payment on U.S. plans to build what Dr. Julie Gerberding, director of the Centers for Disease Control and Prevention, last week called a “surge capacity” for flu vaccine.

If that sounds like war, it is no accident. Building “surge capacity” is key to preparing for a scenario that state and federal health officials have called “nature’s terrorist attack” -- pandemic influenza. In the world of virus-watchers, such a worldwide influenza epidemic is “the big one,” and most consider it an inevitability in the next decade or two. It could come in waves lasting as long as three years, killing millions.

Typically, pandemics involve an influenza virus that has never been seen, or that hasn’t been seen in years, so that immunity among the broad population is low -- and illness and death are rampant. The notorious Spanish flu pandemic of 1918 is thought to have killed at least 20 million worldwide. More recent pandemics occurred in 1957 and 1968, when the Asian flu and Hong Kong flu killed 70,000 and 34,000 in the United States alone.

The surprise factor of the pandemic flu virus makes shortening the vaccine-making process so important. This would not be last year’s virus with a few adjustments. Rather, it would be a bolt from the blue bearing down on an unprotected population. International health officials may not have eight months to see it coming. And so they cannot afford a cumbersome and lengthy production process to pump out a vaccine, because tens of thousands could die while vaccine-makers gather eggs.

In laying plans for pandemic preparedness, health officials feel a very real urgency: they are spurred by last year’s SARS outbreak and a pandemic scare that flared in Hong Kong in 1997, but was contained when health officials there ordered the slaughter of all chickens, the bird population that harbored the threatening virus.

Neither event turned out to be “the big one” and SARS, while caused by a previously unknown virus, wasn’t flu at all. And this year’s flu, while nasty, almost certainly won’t be catastrophic either. But these cases have lighted a fire under U.S. public health officials, who hope they can put a vaccine “surge capacity” well in place by the time it hits.

“We need to do what we can now, before we face a pandemic. We need to diversify the manufacturing technology,” says Dr. Bruce Gellin, director of the national vaccine program in the Department of Health and Human Services. “The egg-based vaccine has been quite successful for some time. But in the spirit of increasing the chances that things will go right, a different production technology may give you some advantages.”

One new approach called reverse genetics essentially shortcuts the process by which a flu virus is created for large-scale replication in a given vaccine.

Currently, virologists essentially pair two viruses -- their “best guess” for next year’s dominant flu virus and a “master virus” chosen because it is safe for humans and reproduces readily in eggs -- and then let them reproduce. It can take weeks or months to achieve, but that random process of reproduction eventually produces the desired flu virus, which is then cultured by the millions and either killed or weakened before becoming the principal ingredient in a vaccine.

By using reverse genetics, immunologists would bypass that random process and proceed from an ideal design of a flu virus. By snipping and splicing together existing lines of genetic code, they would essentially build the desired virus and proceed directly to production. Instead of hoping for a virus that reproduces itself well in eggs, they would design one that does so reliably.

In cases of flu viruses so virulent they tend to kill off the eggs that are used to culture them, reverse genetics would allow scientists to snip out the part of a viral genome that made egg-culture difficult or time-consuming. It could shave weeks or even months off the vaccine-making process.

In mammalian cell culture, a chosen flu virus (possibly one designed by reverse genetics) is first made to infect a mammalian cell line -- a “super-cell” able to replicate itself almost indefinitely. (In Europe, cell lines derived from the kidneys of African green monkeys are currently being used to develop flu vaccines.) The infected cell line replicates itself over and over in large fermenting vats filled with special growth nutrients. This production process bypasses the egg as a growth medium altogether.

Polio vaccine is made using mammalian cell culture, and reverse genetics was used earlier this year to re-create a SARS virus. But neither method has been used in any U.S. FDA-approved influenza vaccines, and the processes -- as well as their vaccine products -- would have to receive such approval before they could be used in the United States. And that, say U.S. scientists, will require extensive studies to prove the safety and effectiveness of both techniques.

In the case of mammalian cell culture, St. Jude Children’s Research Hospital virologist Richard Webby notes that while the process has worked in small flasks, the feasibility of culturing cell lines on a massive scale is still unproven.

In addition, both methods raise legal issues that pharmaceutical companies have not faced in traditional vaccine-making.

Companies would likely claim ownership of patent rights (on cell lines produced through mammalian cell culture, for instance) and intellectual property rights (on the process by which a virus is engineered through reverse genetics) when the new techniques are used. And in cases where different parties each own a part of a vaccine, how do they share liability if something goes wrong?

These are among the issues that would be teased out in the course of “pandemic preparedness planning,” if Congress approves the funding, which is likely.

Scientists such as Webby say that the fact both techniques are already in use to make other vaccines means that with enough will and research funding, they could be adopted here in just a few years. CDC’s Gerberding on Thursday said that Health and Human Services Secretary Tommy Thompson “has placed a high priority” on developing ways to modernize and speed the flu vaccine-making process.

“None of these hurdles are too great to get over,” says Webby. “It’s a matter of addressing these hurdles now rather than wait for when we face an emergency.”

But if the government’s efforts to prepare for a pandemic bear fruit, the first beneficiaries would likely be flu sufferers in years like this one is shaping up to be -- when the virus seems especially virulent, the season starts early, shortages occur, or when healthy populations, such as older children and teens, are felled in surprising numbers.

If techniques such as mammalian tissue culture and reverse genetics were in use today, Gerberding acknowledged last week, U.S. pharmaceutical companies might be able to rush more vaccine, or a better-targeted vaccine, into production before the flu season is over. If production times for flu vaccines could be cut to just a few months, international health officials could wait a few more months to discern which flu virus would dominate in the coming season. They could then order a vaccine that provided more complete immunity for those who take it.

If small batches could be made in a matter of weeks rather than months, vaccine shortages could be a thing of the past. And if a flu season reveals that unforeseen populations -- like older kids -- should have been urged to get the flu vaccine, a more flexible production process could respond with more vaccine.

That could save a lot of lives. And eggs too.