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Sci Transl Med. 2015 Jul 1;7(294):294ra105. doi: 10.1126/scitranslmed.aab2354.

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

Author information

1
Global Clinical Sciences, Novartis Vaccines Srl, Siena 53100, Italy. sohail.q.ahmed@gsk.com steinman@stanford.edu.
2
Informatics and Information Technology, Atreca Inc., Redwood City, CA 94063, USA.
3
Computer-Aided Drug Discovery, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
4
Formulation Analytics, Novartis Vaccines Srl, Siena 53100, Italy.
5
In Vitro Cell Biology, Novartis Vaccines Srl, Siena 53100, Italy.
6
Integrated Biologics Profiling Unit, Novartis Pharma AG, Basel 4057, Switzerland.
7
Quantitative Sciences, Novartis Vaccines Srl, Siena 53100, Italy.
8
Research, Novartis Vaccines Srl, Siena 53100, Italy.
9
Development, Novartis Vaccines, Cambridge, MA 02139, USA.
10
National Institute for Health and Welfare (THL), Helsinki 00300, Finland. Virology, University of Turku, Turku 20520, Finland.
11
National Institute for Health and Welfare (THL), Helsinki 00300, Finland.
12
Internal Medicine, Policlinico Santa Maria alle Scotte, Azienda Ospedaliera Universitaria Senese, Siena 53100, Italy. Medical Science, Surgery, and Neuroscience, University of Siena, Siena 53100, Italy.
13
Molecular and Developmental Medicine, University of Siena, Siena 53100, Italy. VisMederi Srl, Siena 53100, Italy.
14
Molecular and Developmental Medicine, University of Siena, Siena 53100, Italy.
15
Stanford University Mass Spectrometry, Stanford University School of Medicine, Palo Alto, CA 94305 USA.
16
Immunology, Stanford University School of Medicine, Palo Alto, CA 94305, USA.
17
Neurology and Neuroscience, Stanford University School of Medicine, Stanford, CA 94305, USA. sohail.q.ahmed@gsk.com steinman@stanford.edu.

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.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT01079273.

PMID:
26136476
DOI:
10.1126/scitranslmed.aab2354
[Indexed for MEDLINE]

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