title: Narcolepsy, 2009 A(H1N1) pandemic influenza, and pandemic influenza vaccinations: what is known and unknown about the neurological disorder, the role for autoimmunity, and vaccine adjuvants.
abstract: The vaccine safety surveillance system effectively detected a very rare adverse event, narcolepsy, in subjects receiving AS03-adjuvanted A(H1N1) pandemic vaccine made using the European inactivation/purification protocol. The reports of increased cases of narcolepsy in non-vaccinated subjects infected with wild A(H1N1) pandemic influenza virus suggest a role for the viral antigen(s) in disease development. However, additional investigations are needed to better understand what factor(s) in wild influenza infection trigger(s) narcolepsy in susceptible hosts. An estimated 31 million doses of European AS03-adjuvanted A(H1N1) pandemic vaccine were used in more than 47 countries. The Canadian AS03-adjuvanted A(H1N1) pandemic vaccine was used with high coverage in Canada where an estimated 12 million doses were administered. As no similar narcolepsy association has been reported to date with the AS03-adjuvanted A(H1N1) pandemic vaccine made using the Canadian inactivation/purification protocol, this suggests that the AS03 adjuvant alone may not be responsible for the narcolepsy association. To date, no narcolepsy association has been reported with the MF59®-adjuvanted A(H1N1) pandemic vaccine. This review article provides a brief background on narcolepsy, outlines the different types of vaccine preparations including the ones for influenza, reviews the accumulated evidence for the safety of adjuvants, and explores the association between autoimmune diseases and natural infections. It concludes by assimilating the historical observations and recent clinical studies to formulate a feasible hypothesis on why vaccine-associated narcolepsy may not be solely linked to the AS03 adjuvant but more likely be linked to how the specific influenza antigen component of the European AS03-adjuvanted pandemic vaccine was prepared. Careful and long-term epidemiological studies of subjects who developed narcolepsy in association with AS03-adjuvanted A(H1N1) pandemic vaccine prepared with the European inactivation/purification protocol are needed.
authors.affiliation: Global Clinical Sciences, Vaccines Research, Novartis Vaccines Srl, via, Fiorentina 1, Siena 53100, Italy. Electronic address: sohail.ahmed@novartis.com.
authors.forename: S Sohail
authors.initials: SS
authors.lastname: Ahmed
authors.affiliation: Harvard Medical School, Division of Rheumatology, Brigham and Women's, Hospital, 45 Francis Street, Boston, MA 02115, USA. Electronic address: pschur@partners.org.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Schur
authors.affiliation: Dalhousie University, Division Pediatric Infectious Diseases, IWK Health Center, 5850/5980 University Avenue, PO Box 9700, Halifax, Nova Scotia B3K 6R8, Canada. Electronic address: noni.macdonald@dal.ca.
authors.forename: Noni E
authors.initials: NE
authors.lastname: MacDonald
authors.affiliation: Beckman Center for Molecular Medicine, B002, 279 Campus Drive, Stanford University, Stanford, CA 94305, USA. Electronic address: steinman@stanford.edu.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Steinman
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000737:chemistry; D000914:Antibodies, Viral / Q000097:blood; D000956:Antigens, Viral / Q000737:chemistry* / Q000276:immunology; D015551:Autoimmunity; D002170:Canada / Q000453:epidemiology; D004338:Drug Combinations; D005060:Europe / Q000453:epidemiology; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology* / Q000472:pathogenicity; D007252:Influenza Vaccines / Q000009:adverse effects* / Q000096:biosynthesis / Q000276:immunology; D007251:Influenza, Human / Q000453:epidemiology / Q000276:immunology / Q000517:prevention & control*; D009290:Narcolepsy / Q000139:chemically induced* / Q000503:physiopathology; D058873:Pandemics / Q000517:prevention & control*; D011136:Polysorbates / Q000008:administration & dosage / Q000737:chemistry; D013185:Squalene / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology; D014611:Vaccination / Q000009:adverse effects; D024502:alpha-Tocopherol / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral; D000956:Antigens, Viral; D004338:Drug Combinations; D007252:Influenza Vaccines; C089950:MF59 oil emulsion; D011136:Polysorbates; D013185:Squalene; C550253:AS03 adjuvant; D024502:alpha-Tocopherol
keywords: Adjuvants; Autoimmune disease; H1N1 infection; Molecular mimicry; Narcolepsy; Vaccines