In 2009, an unusual side effect was observed in a group of European and Scandinavian people who received a swine flu vaccine that contained the adjuvant, squalene. The vaccine was called Pandemrix. Depending upon the country studied, between 1 in 16,000 doses and 1 in 50,000 doses of Pandemrix was complicated by the development of narcolepsy: a disorder characterized by excessive sleepiness during the day, a sudden loss of muscle tone and strength, and rapid eye movement abnormalities.

Two important facts are known about narcolepsy. First, it’s caused by a loss of cells in the hypothalamus that make a peptide called hypocretin, which is responsible for wakefulness. Second, the disease is far more common in people who have a particular genetic background (HLA-DQB1). What wasn’t known was why people who received the squalene-adjuvanted vaccine, Pandemrix, developed narcolepsy. Until now (Ahmed SS, et al. Antibodies to influenza nucleoprotein cross-react with human hypocretin receptor 2. Sci Transl Med. 2015 Jul 1;7(294):294ra105).

Ahmed and coworkers examined the sera of patients who developed narcolepsy following vaccination and compared it with sera from patients who 1) received Pandemrix and didn’t develop narcolepsy, 2) received a different vaccine, Focetria (another squalene-adjuvanted swine flu vaccine that wasn’t associated with narcolepsy), or 3) didn’t receive any vaccine. They found that people who developed narcolepsy following Pandemrix developed antibodies against the influenza virus nucleoprotein; these antibodies cross-reacted with a receptor for hypocretin, blocking the effect of the peptide. On the other hand, people who received Focetria didn’t develop these cross-reactive antibodies.

The reason that people developed narcolepsy following administration of Pandemrix but not Focetria (both of which were squalene-adjuvanted swine flu vaccines) was that Pandemrix contained more influenza nucleoprotein than Focetria. The good news is that protective immune responses against influenza are based largely on the response to the influenza hemagglutinin, not the nucleoprotein. So the solution to the problem of narcolepsy following influenza vaccination is simply to make sure that influenza vaccines contain little to no nucleoprotein.

We need a better influenza vaccine. One way to achieve better immune responses to the influenza vaccine is to use an adjuvant like squalene (a natural product that is part of normal cholesterol metabolism). The concern with the European experience with Pandemrix was that squalene might be too dangerous to include in an influenza vaccine. But now we know that we can make safer influenza vaccines by excluding influenza virus nucleoprotein when squalene is used as an adjuvant.     

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