Monday, July 6, 2015

H1N1 vaccine and narcolepsy

Researchers think they might have solved a mystery -- why one of the vaccines against the 2009-2010 pandemic influenza was associated with an increased risk of narcolepsy.
The adjuvanted vaccine Pandemrix, manufactured by GlaxoSmithKline, was first linked to narcolepsy among children in Finland, where it was the only vaccine used during the H1N1 flu pandemic...

Epidemiologists in Europe estimated that the number of cases of narcolepsy increased 17- to 25-fold, although the absolute numbers of people affected remained small.

But the other major adjuvanted vaccine used at the same time, dubbed Focetria, was never associated with the rare condition, which is characterized by disturbed sleep at night and bouts of sleepiness during the day.

Neither vaccine was used in the U.S. according to the CDC, and vaccines that were used showed no association with narcolepsy.

Steinman and colleagues hypothesized that differences between the vaccines, which were made differently, would explain why one was associated with narcolepsy and the other was not.
Indeed, they reported in the July 1 issue of Science Translational Medicine, analysis showed that the Pandemrix vaccine contained a fragment of influenza nucleoprotein A that mimics a protein involved in narcolepsy.

The journal described the findings as a case of "immunological mistaken identity."

Blood samples from narcolepsy patients in Finland with a history of Pandemrix vaccination, Steinman and colleagues found, had antibodies that reacted to both the influenza protein and the narcolepsy protein, human hypocretin receptor 2.

In contrast, blood from unvaccinated people who came down with the pandemic flu or those who were vaccinated with Focetria did not show such antibodies...

In an accompanying focus article, Wekerle argued that the researchers have shown that "in rare cases, vaccines can accidentally trigger autoimmune-like brain disease."

But exactly how such an effect can occur remains obscure, he argued. In particular, it's not clear what role is played by the genetic underpinning of the disease, the narcolepsy-associated HLA-DQB1*06:02 gene variant.

In sporadic cases, narcolepsy is linked to the HLA-DQB1*06:02 haplotype, which is involved in dysregulation of the pathway connecting the neuropeptide hypocretin (also known as orexin) and its receptors.

Studies have shown that patients with narcolepsy and associated cataplexy have a loss of hypothalamic cells that leads to a deficiency in hypocretin in the cerebrospinal fluid, Steinman and colleagues noted.
On the other hand, Wekerle commented, changes in the hypocretin receptors themselves have yet not been reported in patients with sporadic narcolepsy...

For the vaccine-related cases, Steinman and colleagues proposed a pathogenic cascade that begins when a vaccine component triggers antibodies that also can bind to parts of a molecule in the brain, in this case the hypocretin receptor 2.

In genetically susceptible people, a subsequent secondary event, such as an infection, might alter the blood-brain barrier and allow the antibodies to interfere with the hypocretin pathway, leading to clinical narcolepsy.


See:  Ahmed SS, Volkmuth W, Duca J, Corti L, Pallaoro M, Pezzicoli A, Karle A, Rigat
F, Rappuoli R, Narasimhan V, Julkunen I, Vuorela A, Vaarala O, Nohynek H, Pasini
FL, Montomoli E, Trombetta C, Adams CM, Rothbard J, Steinman L. Antibodies to
influenza nucleoprotein cross-react with human hypocretin receptor 2. Sci Transl
Med. 2015 Jul 1;7(294):294ra105.

Also:  Wekerle H. Vaccination and narcolepsy: Immune link found? Sci Transl Med. 2015
Jul 1;7(294):294fs27.

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