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Cause of 2009 swine-flu-vaccine association with narcolepsy revealed?

syringesBack in 2001, in the wacko cinematic tour de farce "Rat Race," British actor Rowan Atkinson - a.k.a. the iconic "Mr. Bean" - put a humorous face on narcolepsy, a rare, chronic, incurable and lifelong sleep disorder that can strike at any time, even in the heat of a foot race.

In 2009, narcolepsy suddenly became, for a time, not quite so rare.

The swine flu pandemic sweeping the world that year was no joke. In the United States alone, the H1N1 strain of influenza virus responsible for that pandemic resulted in 274,304 hospitalizations and 12,469 deaths, as mentioned in our news release on a just-published study in Science Translational Medicine.

There probably would have been far more hospitalizations and deaths had not several vaccines tailored to that particular influenza strain been rushed to the market. Two vaccines in particular — Focetria, manufactured by Novartis, and Pandemrix, made by GlaxoSmithKline — are credited with saving a lot of lives in Europe. But there was a dark side. As our news release notes:

Populations that had been immunized with GlaxoSmithKline’s Pandemrix vaccine showed an increase in narcolepsy, but those immunized with Novartis’ Focetria did not.

That's not news; it's been known for some time. But the findings in the new study, whose senior author is Stanford neuroimmunologist Larry Steinman, MD, may explain why.

Vaccines work by presenting a kind of "mug shot" of an infectious organism to the immune system. They contain proteins, or bits of proteins, found on viral or bacterial surfaces. Circulating immune cells become acutely attuned to the distinctive molecular "shapes" of these protein bits, and on encountering them they launch an attack.

Both Pandemrix and Focetria contained proteins encoded by the H1N1 strain. However, as the study shows, Pandemrix contained nearly four times as much of one protein in particular as Focetria did. And a part of that protein's structure, it turns out, mimics a portion of a human protein found in the brain and called the hypocretin receptor. This receptor's interactions with hypocretin are responsible for keeping us awake.

These lookalike situations are bound to arise from time to time. Ordinarily, our immune systems are trained not to attack proteins found on our own tissues, even after they've encountered a lookalike foreign object. But as Stanford immunologist Mark Davis, PhD, has shown, these restraints can break down if the immune system is overwhelmed with concurrent inflammatory signals, as happens in an influenza infection.

Steinman and his colleagues speculate that the high levels of the suspect protein in Pandemrix could have been enough to mislead some of its recipients' immune systems into launching a hit-and-run attack on some recipients' hypocretin receptors, interfering enough with their activation by hypocretin  to result in narcolepsy.

But it's important to make three things clear: First, Pandemrix has been discontinued. Second, even the three- to five-fold uptick in reported narcolepsy cases in Europe (and elsewhere) means a relatively small absolute increases in cases of this disease.

And third, the H1N1 flu strain itself also triggers narcolepsy, albeit at a lower rate — as one would expect if, indeed, one of its most immunogenic proteins has a section that resembles part of the human hypocretin receptor.

"In people who are genetically susceptible to narcolepsy, there is potentially far greater risk of getting narcolepsy with influenza infection compared to influenza vaccination," Steinman told me.

In short, don't misinterpret what I've written as a case for not getting your annual flu shot. The 2009 swine-flu epidemic was bad and could have been much, much worse, and some new influenza pandemic lurking somewhere over the horizon could make the devastating 1918 "Spanish flu" epidemic look like a walk in the park.

Previously: Adult humans harbor lots of risky autoreactive immune cells, study finds, Can a series of DNA shots halt type-1 diabetes progression? and Does influenza trigger narcolepsy?
Photo by I woz ere

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