Flu vaccine helps unravel complex causes of narcolepsy

It was as unexpected as it was tragic: children in Northern Europe who got one particular vaccine against the 2009 swine flu pandemic were at a much higher risk of developing narcolepsy, a lifelong disorder in which people fall asleep involuntarily and experience spells of muscle weakness. Exposure to swine flu itself could also lead to the disorder: after the pandemic, China saw a fourfold rise in narcolepsy in children who didn't receive any flu vaccine. New research has now revealed the link between the two: part of a surface protein on the pandemic virus looks very similar to part of a brain protein that helps keep people awake. When a person's immune system learns to recognise and fight the virus, it mistakes the brain protein for an invader, too. The discovery could make flu vaccines safer and might also make narcolepsy the first autoimmune disease to have its complex causes picked apart. Some 200 children in Sweden and Finland developed narcolepsy after receiving Pandemrix, a flu vaccine made by GlaxoSmithKline and now withdrawn. A study of eight European countries confirmed the link in Sweden and Finland, but not in the UK, Ireland or the Netherlands, although there were some reports of vaccine-linked narcolepsy in those countries. The disease was very rare, affecting at most one in 15,000 vaccinated children in the Nordic countries, where most young people were vaccinated. Fewer were vaccinated elsewhere, so there may not have been enough narcolepsy cases to detect statistically, says Miriam Sturkenboom of Erasmus Medical Centre in Rotterdam, the Netherlands, who led the study. Neurons destroyed Narcolepsy develops when the immune system destroys 70,000 neurons in a brain region called the hypothalamus that produce hypocretin – a neurotransmitter that carries a "waking" signal to other parts of the brain. How Pandemrix might be involved in this process was not clear, although some researchers suspected the involvement of the vaccine's novel adjuvant, a chemical that stimulates the immune reaction to a vaccine. To pin down the link between the vaccine and narcolepsy, Emmanuel Mignot at Stanford University School of Medicine looked at the activity of CD4 cells, part of the immune system, in children who received Pandemrix during the 2009 flu pandemic. He tested 39 narcoleptic children and their siblings – their identical twin siblings in four cases – who also received the vaccine but did not get narcolepsy. He found that the children with narcolepsy had CD4 cells that reacted to both hypocretin and a particular bit of the HA surface protein unique to the flu virus involved in the 2009 pandemic. CD4s from the children that did not have narcolepsy did not react to either. CD4 surge Narcoleptic children who were given ordinary 2012 flu vaccine – which, like Pandemrix, contains the HA protein from the 2009 virus – also responded with a surge in CD4s that attack hypocretin and the cells that make it. So immunity to the 2009 HA protein, either in Pandemrix or in flu itself, says Mignot, had unexpected consequences for hypocretin production. "People blamed the adjuvant for the narcolepsy cases," says Mignot, "but the problem was their immune reaction to the HA protein. The adjuvant just strengthened it." Vaccines might be made safer, he says, by removing the troublesome bit of the HA. Not vaccinating could increase narcolepsy risk, because flu itself can trigger it. Why some people's immune systems mistake hypocretin for part of a viral protein when others' do not is not yet clear. The differences in immune response may be due to exposure to different infections or random immune cell changes. This presents an enormous opportunity, says Mignot. "For the first time we have a clear environmental factor leading to an autoimmune process in some people," he says. Genetics, immune history and environment have been hard to unravel in complex autoimmune conditions like diabetes, he says. This system, he hopes, could lead to progress far beyond narcolepsy.