Patients with a history of vaccination with the pandemic influenza vaccine Pandemrix and narcolepsy were found to have antibodies to hypocretin receptor 2, possibly explaining this association after the 2009 (H1N1) pandemic.

The development of narcolepsy is associated with HLA-DQB1*0602 haplotype, loss of hypothalamic cells, and decrease production of hypocretin, a neuropeptide also known as orexin.

After the 2009 H1N1 influenza pandemic, there were increased reports of narcolepsy associated with the Pandemrix vaccine in Europe. Studies of this association found a 12.7-fold increased risk of narcolepsy within 8 months of Pandemrix vaccination. However, Focetria, the other H1N1 vaccine used in Europe in the 2009 pandemic, does not currently have a reported increased risk. Likewise, studies in China indicate an increased risk of narcolepsy after infection with the 2009 pandemic H1N1 influenza virus.

“We hypothesized that differences between the ‘adjuvanted’ A(H1N1)pdm09 vaccines Pandemrix and Focetria explain the association of narcolepsy with Pandemrix vaccinated subjects,” Dr. Syed Ahmed of Novartis Vaccines, Siena, Italy, and colleagues reported ( Sci. Transl. Med. 2015;7:294ra105 ).

The researchers conducted a retrospective analysis of sera from narcoleptic individuals vaccinated with Pandemrix and a history of H1N1 infection as well as children from Finland without a history of narcolepsy and a history of Focetria vaccination. The samples were randomized and the investigators were blinded.

By aligning protein sequences of influenza strains, the researchers were able to identify an influenza nucleoprotein peptide similar to the hypocretin receptor. ELISA assays detected antibodies to hypocretin receptor 2 in a significantly higher percentage of sera samples from patients with a history of Pandemrix vaccination, HLA-DQB1*0602 haplotype, and narcolepsy (17 of 20), compared with patients with a history of Focetria vaccination (0 of 6; P < .001) or H1N1 infection (5 of 20; P < .001).

Furthermore, mass spectrometry indicated Focetria contained 72.7% less nucleoprotein than did Pandemrix. ELISA assays detected fewer nucleoprotein antibodies in individuals vaccinated with Focetria than in those infected with H1N1. Dr. Ahmed and his colleagues concluded that a possible mechanism for influenza and vaccine associated narcolepsy involves nucleoprotein antigen development after vaccination or infection and cross reaction with the hypocretin receptor 2. Furthermore, the difference in nucleoprotein content of the two vaccine types may further explain the association of Pandemrix vaccination with narcolepsy.


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