In an attempt to battle the 2009 swine flu pandemic, two separate pharmaceutical companies developed vaccines for the causative H1N1 strain: Pandemrix, produced by GlaxoSmithKline (GSK), and Focetria, created by Novartis. But the former left GSK with their own battle – with its dissemination came a peculiar rise in cases of narcolepsy, a chronic and incurable brain disorder that disrupts sleep-wake cycles. No such relationship was observed in populations that received Focetria, which was manufactured using a different H1N1 strain.
The association was too strong to ignore and after its acknowledgement, GSK began coughing up compensation money to affected families. Finally, scientists may have an explanation for this bizarre situation, which has also furthered our understanding of the condition. According to a new study published in Science Translational Medicine, the vaccine triggered the generation of antibodies that targeted both the virus and a population of brain cells critical to the regulation of sleep-wake cycles.
This intriguing finding supports earlier suggestions that narcolepsy may be the result of an autoimmune reaction, where the body accidentally attacks itself. These suspicions were aroused after scientists discovered that a significant portion of disease sufferers possess a genetic variation within a family of immune molecules that serve to help distinguish foreign invaders from the self. Additionally, narcoleptics seem to generate higher levels of antibodies to pathogens following infection.
Another important observation is that the brains of narcolepsy patients seem to have fewer neurons responsible for the generation of a signaling chemical called hypocretin that, when attached to its corresponding receptor, helps maintain wakefulness. Consequently, narcoleptics also have less hypocretin in their brains.
So what could it be that is joining all of these dots? Researchers from Stanford University hoped to find out, and began poking around. Interestingly, they found that a chunk of one of H1N1’s proteins closely resembles a portion of the hypocretin receptor. While this protein was found in both vaccines, it was present in significantly higher concentrations in Pandemrix.
This led to the intriguing possibility that the antibodies generated as a result of the vaccine could be cross-reactive, meaning they stuck to both their viral target and the hypocretin receptor. If this turned out to be the case, it could mean that the antibodies were triggering an autoimmune reaction.
To probe this hypothesis further, the researchers examined the blood of 20 individuals who developed narcolepsy following immunization with Pandemrix and compared them to six controls vaccinated with Focetria. Piecing together the clues, they found that 17 of those in the Pandemrix group had abnormally high levels of hypocretin receptor antibodies, whereas the controls did not.
The team therefore proposes that in those genetically predisposed to the condition, the H1N1 protein that was present in high levels in Pandemrix, but not Focetria, successfully triggered the production of antibodies to the virus, but that these also bind to the hypocretin receptor. This could ultimately drive a targeted immune response towards the hypocretin cells, triggering their destruction and thus disrupting the regulation of sleep-wake cycles.
While this is an unfortunate situation, the vaccine was withdrawn following the apparent observations. Furthermore, the researchers point out that even with the increased risk of narcolepsy, the benefits of the vaccine outweighed the cost, given that almost 12,500 died of H1N1 in the U.S. alone.