Correction to This Article
This article incorrectly identified Michael T. Osterholm, director of the Center for Infectious Disease Research and Policy, as a physician. He has a doctorate in environmental health and a master's degree in public health.
Is there a history lesson from the swine flu of '76?

By David Brown
Saturday, November 28, 2009; A03

As more and more people receive the H1N1 shot, an earlier vaccine is casting a mysterious shadow over the attempt to immunize 200 million people in the next few months.

A vaccine made in 1976 in response to a different strain of H1N1 influenza led to an outbreak of a rare form of paralysis. Of the 43 million people who were vaccinated, about 400 developed Guillain-Barré syndrome (GBS), and 25 died.

Whether an equally unexpected surprise might be lurking in this year's swine flu shot is a big -- although not publicly acknowledged -- question hanging over the current immunization effort. That possibility is why the Centers for Disease Control and Prevention routinely reports, as it did Wednesday, on whether any notable side effects to the new vaccine have been discovered. (None have.)

Unlike today's bug, the 1976 virus never took off from where it originated at an army base in New Jersey. With nothing to be gained from vaccination, the widespread campaign was halted after less than three months.

For the 15 years after the "swine flu affair," scientists sought to nail down whether and how much the 1976 vaccine increased a person's risk of GBS. Almost nothing, however, was done to figure out how and why the flu shot had that effect. It's an oversight some public health officials are coming to regret.

"We should have made an exhaustive attempt to understand what happened from a biological standpoint," said Michael T. Osterholm, a physician who heads the Center for Infectious Disease Research and Policy.

Both the 1976 strain and the new H1N1 strain are closely related to viruses carried by pigs, making some wonder whether that "swinishness" makes their vaccines more likely to cause unusual effects.

"That is the right question to ask," said Peter Palese, an influenza virologist at Mount Sinai School of Medicine in New York. "And I would like to say that no one really knows."

Researchers stopped looking back at 1976, Osterholm said, when there were no subsequent problems with flu vaccines. "After we had a couple of seasons under our belt when there was no unusual risk to regular flu vaccines, we just let it go," he said.

Today's H1N1 vaccine is made, tested and administered the same way the seasonal flu vaccine is. There's no reason to think it's any more dangerous than the regular flu shot, whose risk of serious side effects is essentially zero.

But that was true of the 1976 vaccine, too.

A spike in cases?

Named after two French physicians who described it in 1916, Guillain-Barré [GEE-yan bah-RAY] syndrome causes weakness and tingling that starts in the legs, but over weeks can affect most of the body's muscles. The symptoms occur because the insulation on the outside of nerve fibers breaks down, damaging the normal conduction of impulses.

In normal times, GBS occurs at a rate of roughly 2 cases per 100,000 people per year. Although only about 5 percent die, up to a third spend time in an intensive care unit on a ventilator before they get better. Nearly a third still have some weakness three years later.

After the 1976 vaccination campaign was halted on Dec. 16 of that year, much work went into figuring out whether the increase in GBS cases was real, or just a random upward blip.

Careful counting in defined populations -- most important, the entire states of Minnesota and Michigan -- proved beyond doubt that it was real: The risk of developing the condition rose four- to seven-fold in the six weeks after getting the swine flu shot. The number of cases attributable to the vaccine ranged from 5 to 12 per million people vaccinated.

Studies of vaccines before they go on the market have too few people in them to uncover adverse events occurring at such very low frequency. That's why the GBS risk was not detected in the testing of the 1976 vaccine -- and why it would not be caught in this year's testing, either.

Researchers looked for spikes in GBS among people vaccinated for flu in subsequent seasons and did not find any. The only exceptions were 1992-93 and 1993-94. When those two seasons were combined, people getting flu shots had a slightly higher risk of GBS -- about 1 extra case per million. The conclusion was that 1976 was a fluke, unlikely to happen again.

Comparing the vaccines

There's some evidence that the 1976 vaccine may have triggered GBS through a mechanism known as molecular mimicry.

About two-thirds of cases of GBS arise after an intestinal or respiratory infection (including flu). The biggest cause is a bacterium responsible for food-borne illness, Campylobacter jejuni. Campylobacter can stimulate the immune system to make antibodies against a nerve-sheath substance called ganglioside, and that presumably leads to the condition.

However, not all people with the syndrome have nerve-attacking antibodies, and millions of people get Campylobacter infections without getting GBS. So clearly there are unknown factors -- some almost certainly genetic -- involved in the disease. The 1976 vaccine may have triggered GBS in much the way that Campylobater does. The evidence comes from experiments done by Irving Nachamkin, a microbiologist at the University of Pennsylvania, and published last year.

Nachamkin had access to a few unopened vials of the 1976 vaccine, which he tested for the presence of Campylobacter bacteria. He found none, putting to rest the theory that the 1976 GBS cases were the consequence of contaminated vaccine. He then injected the vaccine into mice. All developed antibodies against GM1, a form of ganglioside.

"We were just as surprised as anyone when we found this," Nachamkin said. "The real question is: Is it relevant to Guillain-Barré syndrome?"

What's confusing is that animals injected with flu vaccines from 1991 and 2004 also developed the anti-GM1 antibodies ( as did some animals infected with the even more distantly related H5N1 bird flu strain). Furthermore, none developed muscle weakness. Researchers at CDC are hunting down blood samples from people who got the 1976 vaccine to see if they contain antibodies to ganglioside, or hold any other hints as to what might have made that flu shot have that rare side effect.

Today, both the federal government's epidemiologists and pretty much every neurologist in America have eyes wide open for cases of GBS.

As of last week, six cases of GBS in people who had gotten the H1N1 vaccine had been reported to the federal government's Vaccine Adverse Event Reporting System. (Four more are under investigation.) The six people with confirmed cases live in Maryland, Virginia, New York, Connecticut, Florida and Illinois. In each case, the person came down with neurological symptoms within two days being vaccinated -- almost certainly too soon to be a consequence of the vaccine.

"At this point, we are not seeing any evidence there is an increase in Guillain-Barre syndrome," said James J. Sejvar, the physician leading CDC's surveillance for it.

A survey by the Harvard School of Public Health earlier in the fall found that about half of American adults have no plans to get the pandemic flu vaccine. Only one-third said they thought it was "very safe" for most people.

Even if there were to be a slight increase in GBS, some public health officials believe it would still be worth getting vaccinated.

"I think the numbers of people who would be saved from serious illness or death would be far greater," said Palese.

The emerging picture of the 2009 pandemic seems to bear out that hunch.

For every 100,000 people vaccinated, the 1976 vaccine was responsible for just under 1 case of GBS. A CDC analysis this month revealed that out of every 100,000 people who come down with the pandemic flu, 18 die from it.

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