In 2010, following the H1N1 pandemic and the vaccination campaign to reduce its impact, researchers noted a significant increase in a rare neurological disorder, narcolepsy, in Sweden and Finland. Since then researchers have been studying a possible association between a specific H1N1 flu vaccine, Pandemrix by Glaxo-Smith-Kline (GSK) and a sudden onset of the sleep disorder narcolepsy. In those two countries the association seems strong, but the full story is still complicated with many unknowns.
Narcolepsy is a neurological disorder marked by excessive sleepiness, cataplexy (sudden loss of muscle tone, usually triggered by emotions) and disordered sleep. Almost all cases are associated with low levels of hypocretin in the hypothalamus – this is a hormone involved in sleep regulation. Further there is a strong HLA (human leukocyte antigen) association – specifically DQB1*0602. HLA is a group of proteins involved in regulating immune activity. An HLA association strongly suggests that narcolepsy may be an auto-immune disease.
The current synthesis of this information is that narcolepsy occurs in genetically susceptible individuals after some environmental trigger, such as in infection, that causes the immune system to attack and destroy hypocretin cells in the brain.
It is currently not known what the precise mechanism is for the increase in narcolepsy in the two “signal countries,” Sweden and Finland. Possibilities include immune stimulation from the vaccine itself, increased immune activity from the adjuvant ASO3, immune activation from H1N1 infection, or a combination of these factors, perhaps with some other infection present at the time.
Epidemiologically, at this time it seems that the increase in narcolepsy in Finland and Sweden among children <20 (but not in adults) is a fairly strong signal and has been reasonably confirmed. This does not establish by itself a specific cause and effect, but other factors such as timing and the relative risk of vaccinated vs unvaccinated children make a causal link to the Pandemrix vaccine plausible. The increased risk from the Swedish data is about 1 case of narcolepsy per 27,800 vaccinations.
The Pandemrix vaccine was used throughout Europe and Scandinavia, and in a few South American countries, but not in the US (which used a vaccine without adjuvant). A related vaccine was used in Canada during the H1N1 outbreak. It is still uncertain whether other European countries also had an increase in narcolepsy. Data from France is conflicting. A 2011 study found no reports of narcolepsy following the vaccine through June 2010. A later report found a possible increase, but the pattern does not match the patterns seen in Sweden and Finland, with more adults affected in France.
There is still a debate as to whether there is a signal of increased narcolepsy in other countries that received the Pandemrix vaccine, but as yet this has not been confirmed. A recent review of the evidence concluded:
According to the strictest primary analysis, the kind of assessment designed to avoid most biases like media and diagnostic awareness biases, no significant risk was found in children and adolescents in other countries included in the study – Denmark, Italy, France, the Netherlands, Norway and the United Kingdom (non-signalling countries).
But there may be a signal when only data from prior to media attention are considered. This likely means that if there were an effect, it is much smaller than what was seen in Finland and Sweden. This leads to the question of why such a dramatic difference in different countries receiving the same vaccine. This cannot be explained by genetics alone, although this is a likely factor. This suggests that other environmental factors may be important, and even necessary, for narcolepsy risk to occur. There also may be confounding factors that have not yet been identified.
It now seems likely that some combination of factors, including but not limited to the Pandemrix vaccine, led to a spike in narcolepsy cases among children but not adults in Finland and Sweden. The same effect has not been confirmed in other countries, but a smaller effect has not been ruled out.
Use of Pandemrix has been suspended because of this concern, which is appropriate. It must be emphasized, however, that this effect, if confirmed, has no relevance to the flu vaccine in general. It has led to increased surveillance for narcolepsy following vaccination, to be cautious, but at present there is no reason to be concerned about this risk with the seasonal flu vaccine, even those targeting H1N1.
Depending on the results of further investigation, this episode might lead to genetic typing for the DQB1*0602 variant and vaccine recommendations based upon this genetic type. It must be recognized, however, that infection can also trigger narcolepsy in susceptible individuals, and therefore all factors will be considered in making recommendations. At present there are still too many unknown variable to say what the implications of the Finland and Sweden experience are.