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Comparison of Pandemrix and Arepanrix,two pH1N1 AS03-adjuvanted vaccines differentially associated with narcolepsy development

ISSN:0889-1591
2015年第47卷第期
1. Center for Sleep Sciences and Medicine, Stanford School of Medicine, Palo Alto, CA, USA;2. Stanford University Mass Spectrometry, Palo Alto, CA, USA;1. Medical Informatics, Erasmus Medical Center, Rotterdam, The Netherlands;2. Medicines Evaluation Board, Utrecht (CBG-MEB), The Netherlands;3. European Medicines Agency (EMA), London, United Kingdom;1. Department Safety of Medicinal Products and Medical Devices, Paul-Ehrlich-Institut, Federal Institute for Vaccines and Biomedicines, Langen, Germany;2. Hephata-Klinik, Schlafzentrum, Schwalmstadt-Treysa, Germany;3. Sleep Disorders Center, Department of Psychiatry, University of Regensburg, Regensburg, Germany;1. Helsinki Sleep Clinic, Vitalmed Research Centre, Helsinki, Finland;2. Department of Clinical Neurosciences, University of Helsinki, Helsinki, Finland;3. Molecular Sleep Laboratory, Department of Diagnostics, Glostrup Hospital, Glostrup, Denmark;4. Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy;5. IRCCS Istituto delle Scienze Neurologiche, Bologna, Italy;6. Danish Center for Sleep Medicine, Department of Clinical Neurophysiology, University of Copenhagen, Glostrup Hospital, Glostrup, Denmark;7. Department of Virology, University of Turku, Turku, Finland;8. Department of Infectious Disease Surveillance and Control, National Institute for Health and Welfare, Helsinki, Finland;9. Department of Vaccines and Immune Protection, National Institute for Health and Welfare, Helsinki, Finland;1. AP-HP, Pediatric Sleep Center, CHU Robert-Debré, Paris, France;2. National Reference Centre for Orphan Diseases, Narcolepsy, Idiopathic Hypersomnia and Kleine-Levin Syndrome (CNR narcolepsie-hypersomnie), France;3. Inserm UMS20, Centre d’Immunologie Humaine (CIH) Institut Pasteur, France;4. Inserm U1061, Montpellier, France;5. Université Montpellier 1, Montpellier, France;6. Sleep Disorders Center, Department of Neurology, Gui-de-Chauliac Hospital, CHU Montpellier, France;7. Sleep Disorders Unit, Pitié-Salpêtrière University Hospital, AP-HP, France;8. Brain Research Institute (CRICM-UPMC-Paris6; Inserm UMR_S 975; CNRS UMR 7225), Sorbonne Universities, UPMC Univ Paris 06, Paris, F-75005, France;9. Aviesan/Institut Multi-Organismes Immunologie, Hématologie et Pneumologie (ITMO IHP), France;1. Stanford University Center for Sleep Sciences, Palo Alto, CA 94304, USA;2. Department of Pulmonary Medicine, Peking University People’s Hospital, 100044 Beijing, China;3. Department of Biostatistics, University of Washington, PO box 357232, Seattle, WA 98195, USA;4. Department of Biomedical and Neuromotor Sciences, University of Bologna, Via Ugo Foscolo 7, 40123 Bologna, Italy;5. IRCCS Institute of Neurological Sciences, 40139 Bologna, Italy;6. INSERM U1061, Reference Center for Narcolepsy, Sleep-Wake Disorders Center, Department of Neurology, Gui-de-Chauliac Hospital, Centre Hospitalier Régional Universitaire Montpellier, 34090 Montpellier, France;7. Department of Psychiatry, St. Vincent’s Hospital, The Catholic University of Korea, 442-723 Suwon, Korea;8. Danish Center for Sleep Medicine, Department of Clinical Neurophysiology, University of Copenhagen, Glostrup Hospital, 2600 Glostrup, Denmark;9. Norwegian Resource Center for ADHD, TS, and Narcolepsy, Oslo University Hospital, 0450 Ullevål, Norway;10. Molecular Sleep Laboratory, Department of Diagnostics, Glostrup Hospital, 2600 Glostrup, Denmark;11. Department of Pathology, Stanford University School of Medicine, Stanford, CA 94304, USA;12. Sleep Disorder Unit, Pitié-Salpêtrière Hospital, Assistance Publique – Hopitaux de Paris, 75013 Paris, France;13. Department of Neurology, Medical University of Innsbruck, 6020 Innsbruck, Austria;14. Mater Private Hospital, Dublin 7, Ireland;15. Helsinki Sleep Clinic, Vitalmed Research Centre, 00420 Helsinki, Finland;16. Department of Clinical Neurosciences, University of Helsinki, 00100 Helsinki, Finland;17. Chang Gung Memorial Hospital and University, Taipei 10591, Taiwan;18. Department of Sleep Medicine, Strasbourg University Hospital, Strasbourg University, 67084 Strasbourg, France;19. Institute of Clinical Medicine, University of Helsinki, 00100 Helsinki, Finland;20. Center for Advanced Research in Sleep Medicine, Hôpital du Sacré-Coeur and Department of Neurosciences, University of Montreal, Montreal, QC H3T 1J4, Canada;21. Center for Advanced Research in Sleep Medicine, Hôpital du Sacré-Coeur and Department of Psychiatry, University of Montreal, Montreal QC H3T 1J4, Canada;22. Children’s Hospital Oakland Research Institute, 5700 Martin Luther King Junior Way, Oakland, CA 94609-1673, USA;23. Stanford Genome Technology Center, Stanford University, Palo Alto, CA 94304, USA;1. Department of Psychiatry, Eulji Addiction Institute, Gangnam Eulji Hospital, Eulji University, Seoul, South Korea;2. Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul, South Korea;3. Department of Psychiatry, The Armed Forces Capital Hospital, Seongnam, Gyeonggi, South Korea;4. Department of Psychiatry, Yonsei University College of Medicine, Seoul, South Korea;5. Sleep Health Center, Severance Hospital, Seoul, South Korea;6. Department of Internal Medicine, The Armed Forces Capital Hospital, Seongnam, Gyeonggi, South Korea;7. Department of Internal Medicine, Korea University College of Medicine, Seoul, South Korea;8. Department of Internal Medicine, Chungbuk National University, Cheongju, Chungbuk, South Korea

Narcolepsy onset in children has been associated with the 2009 influenza A H1N1 pandemic and vaccination with Pandemrix. However it was not clearly observed with other adjuvanted pH1N1 vaccines such as Arepanrix or Focetria. Our aim was to characterize the differences between Pandemrix and Arepanrix that might explain the risk for narcolepsy after Pandemrix vaccination using 2D-DIGE and mass spectrometry (MS). We found that Pandemrix (2009 batch) and Arepanrix (2010 batch) showed 5 main viral proteins: hemagglutinin HA1 and HA2 subunits, neuraminidase NA, nucleoprotein NP, and matrix protein MA1 and non-viral proteins from the Gallus gallus growth matrix used in the manufacturing of the vaccines. Latticed patterns of HA1, HA2 and NA indicated charge and molecular weight heterogeneity, a phenomenon likely caused by glycosylation and sulfation. Overall, Pandemrix contained more NP and NA, while Arepanrix displayed a larger diversity of viral and chicken proteins, with the exception of five chicken proteins (PDCD6IP, TSPAN8, H-FABP, HSP and TUB proteins) that were relatively more abundant in Pandemrix. Glycosylation patterns were similar in both vaccines. A higher degree of deamidation and dioxidation was found in Pandemrix, probably reflecting differential degradation across batches. Interestingly, HA1 146N (residue 129N in the mature protein) displayed a 10-fold higher deamidation in Arepanrix versus Pandemrix. In recent vaccine strains and Focetria, 146N is mutated to D which is associated with increased production yields suggesting that 146N deamidation may have also occurred during the manufacturing of Arepanrix. The presence of 146N in large relative amounts in Pandemrix and the wild type virus and in lower relative quantities in Arepanrix or other H1N1 vaccines may have affected predisposition to narcolepsy.

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ISSN:0889-1591
2015年第47卷第期

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