Narcolepsy Linked to Pandemrix Flu Vaccine

A link between narcolepsy and the influenza vaccine was uncovered in 2009, after an immunization campaign in Europe. Children vaccinated with GlaxoSmithKline's Pandemrix vaccine were found to have an increased risk of developing narcolepsy. Recent research published in Science Translational Medicine1 supports the autoimmune connection between narcolepsy and the GSK influenza vaccine. Ahmed et al. identified a peptide from the influenza virus nucleoprotein A that has a high homology to the hypocretin receptor, and is found in higher abundance in GSK's Pandemrix vaccine than the Novartis Focetria vaccine. Hypocretin is a neurotransmitter that helps keep people awake, and a lack of hypocretins causes narcolepsy with cataplexy (sudden physical collapse)2.
Hypocretins are produced by neurons located in the hypothalamus, which is located behind the eyes and between the ears. During wakefulness, hypocretins are released and bind to hypocretin receptors on target neurons, which causes an increase in the activity of these neurons and suppresses rapid eye movement (REM) sleep. Narcolepsy with cataplexy is caused by a lack of hypocretins, resulting from the death of the hypocretin-producing neurons. As a result, narcoleptic patients have poorly-regulated REM sleep2.
In the study by Ahmed et al.1, the authors found that patients who were vaccinated with Pandemrix had more antibodies that bound both the nucleoprotein A peptide, as well as the hypocretin receptor, in their blood than in the blood of Focetria-vaccinated patients. When the blood of patients who were immunized with Pandemrix and subsequently developed narcolepsy was tested, antibodies that recognized the hypocretin receptor and nucleoprotein A peptides bound to human cell lines that expressed the hypocretin receptor. The authors also tested the blood of patients immunized with Focetria and did not find these antibodies. However, the same antibodies were found in a small portion of samples from patients infected with the 2009 swine flu, and some of the patients that tested positive for the antibodies did not have narcolepsy. This suggests that the antibodies may not be targeting the hypocretin receptor specifically, but that there is a non-specific reaction to the loss of hypocretin-producing neurons.
There was an earlier study that found a link between narcolepsy and flu vaccines from the Mignot group at the Stanford University School of Medicine, where the authors found spikes in narcolepsy incidents in China following flu seasons3. It is thought that a component of the influenza virus or vaccine causes an autoimmune reaction to the body’s hypocretin response. In their 2009 study, De la Herran-Arita et al.4 found that T cells taken from immunized patients who had narcolepsy were reactive to hypocretin peptides displayed by HLAs, while their twins that did not have narcolepsy did not have hypocretin-reactive T cells. However, when the authors couldn’t replicate the results of this study, they retracted the paper.
There have been numerous examples of autoimmune diseases being caused by infectious agents. It is thought that they stimulate autoimmunity via molecular mimicry, when the host immune system recognizes antigenic determinants of microbes as being similar to antigenic determinants of the self. Viral infections are associated with Guillain-Barré syndrome, for example, and the condition has also been linked with bacterial and viral vaccines. It is also possible to have molecular mimicry by T cell recognition of peptides bound to MHC molecules. This was first demonstrated in an animal model of multiple sclerosis, where a hepatitis B virus polymerase peptide caused autoimmune encephalitis in rabbits. Another example is the autoimmune disease herpes simplex keratitis, which is caused by CD4 T cells that are activated by herpes simplex virus 1 infection. It is difficult to demonstrate that a vaccine caused an autoimmune disease without clinical trials or epidemiologic studies with a very large sample size. These studies are costly and difficult to coordinate, limiting their availability.
The Pandemrix vaccine was only used for one flu season in Europe (2009-2010) and is no longer used there6. The Pandemrix vaccine was never used in the United States.

The correlation between the flu vaccine and narcolepsy is still being explored, and it is not clear whether the link is antibody- or T-cell mediated, or whether there is a yet to be discovered mechanism. Do you have any thoughts on the possibility of an autoimmune component to narcolepsy? Let us know at tech@biolegend.com.

Just when I thought I got the hang of science...
Contributed by Rea Dabelic, PhD.
References:
  1. Antibodies to influenza nucleoprotein cross-react with human hypocretin receptor 2
  2. What is narcolepsy?
  3. Narcolepsy onset is seasonal and increased following the 2009 H1N1 pandemic in china
  4. CD4+ T Cell Autoimmunity to Hypocretin/Orexin and Cross-Reactivity to a 2009 H1N1 Influenza A Epitope in Narcolepsy
  5. Vaccination and autoimmune disease: what is the evidence?
  6. CDC statement on narcolepsy following Pandemrix influenza vaccination in Europe
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