Antibodies to influenza nucleoprotein cross-react with human hypocretin receptor 2.

Abstract

The sleep disorder narcolepsy is linked to the HLA-DQB1*0602 haplotype and dysregulation of the hypocretin ligand-hypocretin receptor pathway. Narcolepsy was associated with Pandemrix vaccination (an adjuvanted, influenza pandemic vaccine) and also with infection by influenza virus during the 2009 A(H1N1) influenza pandemic. In contrast, very few cases were reported after Focetria vaccination (a differently manufactured adjuvanted influenza pandemic vaccine). We hypothesized that differences between these vaccines (which are derived from inactivated influenza viral proteins) explain the association of narcolepsy with Pandemrix-vaccinated subjects. A mimic peptide was identified from a surface-exposed region of influenza nucleoprotein A that shared protein residues in common with a fragment of the first extracellular domain of hypocretin receptor 2. A significant proportion of sera from HLA-DQB1*0602 haplotype-positive narcoleptic Finnish patients with a history of Pandemrix vaccination (vaccine-associated narcolepsy) contained antibodies to hypocretin receptor 2 compared to sera from nonnarcoleptic individuals with either 2009 A(H1N1) pandemic influenza infection or history of Focetria vaccination. Antibodies from vaccine-associated narcolepsy sera cross-reacted with both influenza nucleoprotein and hypocretin receptor 2, which was demonstrated by competitive binding using 21-mer peptide (containing the identified nucleoprotein mimic) and 55-mer recombinant peptide (first extracellular domain of hypocretin receptor 2) on cell lines expressing human hypocretin receptor 2. Mass spectrometry indicated that relative to Pandemrix, Focetria contained 72.7% less influenza nucleoprotein. In accord, no durable antibody responses to nucleoprotein were detected in sera from Focetria-vaccinated nonnarcoleptic subjects. Thus, differences in vaccine nucleoprotein content and respective immune response may explain the narcolepsy association with Pandemrix.

• Authors: Syed Sohail Ahmed, Wayne Volkmuth, José Duca, Lorenzo Corti, Michele Pallaoro, Alfredo Pezzicoli, Anette Karle, Fabio Rigat, Rino Rappuoli, Vas Narasimhan, Ilkka Julkunen, Arja Vuorela, Outi Vaarala, Hanna Nohynek, Franco Laghi Pasini, Emanuele Montomoli, Claudia Trombetta, Christopher M Adams, Jonathan Rothbard, Lawrence Steinman
• Journal: Science translational medicine (Sci Transl Med) Vol. 7 Issue 294 Pg. 294ra105 (Jul 01 2015) ISSN: 1946-6242 [Electronic] United States
• PMID: 26136476 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2015, American Association for the Advancement of Science.

Chemical References

• Antibodies, Viral
• Immunoglobulin G
• Influenza Vaccines
• NP protein, Influenza A virus
• Nucleocapsid Proteins
• Orexin Receptors
• Peptides
• RNA-Binding Proteins
• Viral Core Proteins
• focetria
• pandemrix

Topics

• Amino Acid Sequence
• Antibodies, Viral (immunology)
• Cell Line
• Child
• Cross Reactions (immunology)
• Humans
• Immunity
• Immunoglobulin G (blood)
• Influenza Vaccines (immunology)
• Influenza, Human (immunology, virology)
• Mass Spectrometry
• Molecular Sequence Data
• Narcolepsy (immunology)
• Nucleocapsid Proteins
• Orexin Receptors (chemistry, immunology)
• Peptides (chemistry, immunology)
• RNA-Binding Proteins (chemistry, immunology)
• Reassortant Viruses (immunology)
• Seasons
• Sequence Alignment
• Vaccination
• Viral Core Proteins (chemistry, immunology)