Abstract
BackgroundNarcolepsy results from immune-mediated destruction of hypocretin secreting neurons in hypothalamus, however the triggers and disease mechanisms are poorly understood. Vaccine-attributable risk of narcolepsy reported so far with the AS03 adjuvanted H1N1 vaccination Pandemrix has been manifold compared to the AS03 adjuvanted Arepanrix, which contained differently produced H1N1 viral antigen preparation. Hence, antigenic differences and antibody response to these vaccines were investigated.Methods and FindingsIncreased circulating IgG-antibody levels to Pandemrix H1N1 antigen were found in 47 children with Pandemrix-associated narcolepsy when compared to 57 healthy children vaccinated with Pandemrix. H1N1 antigen of Arepanrix inhibited poorly these antibodies indicating antigenic difference between Arepanrix and Pandemrix. High-resolution gel electrophoresis quantitation and mass spectrometry identification analyses revealed higher amounts of structurally altered viral nucleoprotein (NP) in Pandemrix. Increased antibody levels to hemagglutinin (HA) and NP, particularly to detergent treated NP, was seen in narcolepsy. Higher levels of antibodies to NP were found in children with DQB1*06∶02 risk allele and in DQB1*06∶02 transgenic mice immunized with Pandemrix when compared to controls.ConclusionsThis work identified 1) higher amounts of structurally altered viral NP in Pandemrix than in Arepanrix, 2) detergent-induced antigenic changes of viral NP, that are recognized by antibodies from children with narcolepsy, and 3) increased antibody response to NP in association of DQB1*06∶02 risk allele of narcolepsy. These findings provide a link between Pandemrix and narcolepsy. Although detailed mechanisms of Pandemrix in narcolepsy remain elusive, our results move the focus from adjuvant(s) onto the H1N1 viral proteins.
Highlights
According to the new International Classification of Sleep Disorders (ICSD-3) narcolepsy is divided into type 1 and type 2 narcolepsy
We studied the IgG-antibody response to H1N1 viral antigen suspension using Enzyme linked solid-phase immunoassay (EIA) method, and observed that children with narcolepsy showed higher levels of IgG-antibodies binding to the Pandemrix H1N1 antigen suspension than did vaccinated healthy children from the general population (Fig. 1A )
In the group of children with narcolepsy who were homozygotic for HLA DQB1*06:02 risk allele of narcolepsy, the inhibition of IgGantibodies with Arepanrix was weaker than in the children with narcolepsy or healthy children who were heterozygotic for HLA DQB1* 06:02 (Fig. 2 B, P50.04 and P50.02, respectively), which suggests that the antibody response to the antigenic epitopes that differ between Pandemrix and Arepanrix are regulated by HLA DQB1* 06:02 restricted T-cells
Summary
According to the new International Classification of Sleep Disorders (ICSD-3) narcolepsy is divided into type 1 and type 2 narcolepsy. Type 1 narcolepsy results from an immune-mediated destruction of hypocretin secreting neurons in hypothalamus [1]. It is characterized by excessive daytime sleepiness (EDS), cataplexy and often disturbed nocturnal sleep. The association of Pandemrix vaccination and narcolepsy in children and adolescents has been reported in Sweden, Norway, Ireland, France, and U.K. Narcolepsy results from immune-mediated destruction of hypocretin secreting neurons in hypothalamus, the triggers and disease mechanisms are poorly understood. Methods and Findings: Increased circulating IgG-antibody levels to Pandemrix H1N1 antigen were found in 47 children with Pandemrix-associated narcolepsy when compared to 57 healthy children vaccinated with Pandemrix. Increased antibody levels to PLOS ONE | DOI:10.1371/journal.pone.0114361 December 15, 2014
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