In the Journals: Narcolepsy and the 2009 Pandemic Influenza Vaccine

The science behind development of narcolepsy following receipt of one version of the 2009 pandemic influenza vaccine

In 1976, due to a feared pandemic of swine flu, about 40 million Americans were immunized with a swine flu vaccine. Although the pandemic never materialized, the feeling at the time was that it was better to be safe than sorry. Unfortunately, one possible consequence of the 1976 swine flu vaccine was a disease called Guillain-Barré Syndrome (GBS): An ascending paralysis that can lead to respiratory compromise. The vaccine was thought to cause GBS in as many as 1 in 100,000 vaccine recipients. In the book, "FLU," by Gina Kollata, the 1976 swine flu affair was deconstructed, raising the hypothesis that the association between swine flu vaccine and GBS might have been an example of selection bias. In any case, the notion that vaccines could cause autoimmunity, when the body reacts against itself, was born.

Perhaps the single clearest evidence that vaccines can cause autoimmunity occurred in 2009, associated with another swine flu pandemic. This time the pandemic materialized and the vaccine given in advance clearly saved tens of thousands of lives. In Europe, however, the vaccine also caused a problem.

One of the vaccines given in Europe was called PandemRix®, a combination of swine flu vaccine adjuvanted with squalene (squalene adjuvant has never been used in the United States). As a consequence of vaccination, about 1,300 people developed a disease called narcolepsy: A debilitating condition that causes overpowering daytime sleepiness accompanied by sudden muscle weakness. The disease is caused by a decrease in production of a hypocretin, a molecule produced by the hypothalamus that regulates wakefulness.

In the July 2015 issue of Science Translational Medicine, researchers from Stanford and GlaxoSmithKline showed why narcolepsy followed receipt of the squalene-adjuvanted 2009 swine flu vaccine in Europe (Ahmed SS, Valkmuth W, Duca J, et al. Antibodies to influenza nucleoprotein cross-react with human hypocretin receptor 2. Sci Transl Med. 2015 Jul 1;7(294):294ra105). The authors found that, in certain genetically susceptible individuals, antibodies directed against the influenza virus nucleoprotein cross-reacted with a protein on the surface of hypocretin-secreting cells. Further, they found that an influenza vaccine that contained larger quantities of nucleoprotein was more likely to induce these cross-reactive antibodies than an influenza vaccine that contained much less of this protein.

The onset of narcolepsy in swine flu vaccine appeared to require the confluence of three events:

1. The presence of influenza nucleoprotein in the vaccine
2. A powerful adjuvant, like squalene, and 
3. A particular major histocompatibility complex (MHC) genetic background in the recipient