The AS03-adjuvanted 2009 pandemic H1N1 influenza vaccine (trade name: PandemrixTM) was associated with an increased risk of narcolepsy in several northern European countries. In other countries where there is a lower prevalence of genetic factors associated with narcolepsy, studies did not find an increase in risk with this vaccine or other influenza vaccines. The vaccine in question (PandemrixTM) was not licensed in the United States, and vaccines in routine use in the United States* have not been shown to cause narcolepsy.
A sharp increase in the number of narcolepsy diagnoses in children was noticed shortly after immunization campaigns for the pandemic 2009 H1N1 vaccines in Finland and Sweden. Subsequent analysis confirmed an association between the European AS03-adjuvanted pandemic 2009 H1N1 vaccine (PandemrixTM) and narcolepsy onset in several northern European countries. Immunization with this vaccine is thus no longer recommended in children [1-3]. This vaccine was not used in the United States, and no increase in narcolepsy has been found with any vaccine routinely used in the United States.
Multiple studies have consistently documented an increased risk of narcolepsy associated with AS03-adjuvanted influenza vaccines, primarily in the childhood populations of northern European countries [1-12]. The estimated rate was 1 case per 16,000 persons vaccinated between 4 and 19 years of age in Finland . The strength of this association varied depending on the country studied, with an intermediate association in the rest of Europe and a possible association in Canada [8, 13]. This could be explained by differences in population genetics . Studies have not shown any association between narcolepsy and other influenza vaccines, either MF59-adjuvanted or without an adjuvant [15-18]. A cohort study of almost one million adolescent girls in Denmark and Sweden found no association between quadrivalent HPV vaccine and narcolepsy .
The 1918 pandemic of influenza infection was associated with an illness consistent with narcolepsy. The 2009-10 pandemic influenza may have been associated with an increase in narcolepsy in China, but no increase was observed in many other countries . Almost all patients with narcolepsy have HLA DQB1*0602, a genetic marker for predisposition to the disorder [21, 22]. Recent studies have provided further evidence that infections may serve as a potential trigger for the pathogenesis of narcolepsy . A number of mechanisms have been postulated to explain the association with the ASO3-adjuvanted vaccine in several European countries, but many of these hypotheses have been found to be lacking. One recent hypothesis includes the possibility that a combination of infection with the 2009 pandemic H1N1 influenza virus followed by the ASO3-adjuvanted vaccine could have resulted in narcolepsy in genetically predisposed individuals .
1. Nohynek H, Jokinen J, Partinen M, et al. AS03 adjuvanted AH1N1 vaccine associated with an abrupt increase in the incidence of childhood narcolepsy in Finland. PloS one 2012;7:e33536.
2. Partinen M, Saarenpaa-Heikkila O, Ilveskoski I, et al. Increased incidence and clinical picture of childhood narcolepsy following the 2009 H1N1 pandemic vaccination campaign in Finland. PloS one 2012;7:e33723.
3. Szakacs A, Darin N, Hallbook T. Increased childhood incidence of narcolepsy in western Sweden after H1N1 influenza vaccination. Neurology 2013;80:1315-21.
4. Persson I, Granath F, Askling J, Ludvigsson JF, Olsson T, Feltelius N. Risks of neurological and immune-related diseases, including narcolepsy, after vaccination with Pandemrix: a population- and registry-based cohort study with over 2 years of follow-up. Journal of internal medicine 2014;275:172-90.
5. Johansen K. The roles of influenza virus antigens and the AS03 adjuvant in the 2009 pandemic vaccine associated with narcolepsy needs further investigation. Dev Med Child Neurol 2014;56:1041-2.
6. Dauvilliers Y, Arnulf I, Lecendreux M, et al. Increased risk of narcolepsy in children and adults after pandemic H1N1 vaccination in France. Brain : a journal of neurology 2013;136:2486-96.
7. Wijnans L, Lecomte C, de Vries C, et al. The incidence of narcolepsy in Europe: before, during, and after the influenza A(H1N1)pdm09 pandemic and vaccination campaigns. Vaccine 2013;31:1246-54.
8. European Centre for Disease Prevention and Control. Narcolepsy in association with pandemic influenza vaccination (a multi-country European epidemiological investigation). Stockholm: ECDC; September 2012.
9. Miller E, Andrews N, Stellitano L, et al. Risk of narcolepsy in children and young people receiving AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine: retrospective analysis. BMJ (Clinical research ed) 2013;346:f794.
10. O'Flanagan D, Barret AS, Foley M, et al. Investigation of an association between onset of narcolepsy and vaccination with pandemic influenza vaccine, Ireland April 2009-December 2010. Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin 2014;19:15-25.
11. Stowe J, Andrews N, Kosky C, et al. Risk of Narcolepsy after AS03 Adjuvanted Pandemic A/H1N1 2009 Influenza Vaccine in Adults: A Case-Coverage Study in England. Sleep 2016;39:1051-7.
12. Heier MS, Gautvik KM, Wannag E, et al. Incidence of narcolepsy in Norwegian children and adolescents after vaccination against H1N1 influenza A. Sleep medicine 2013;14:867-71.
13. Montplaisir J, Petit D, Quinn MJ, et al. Risk of narcolepsy associated with inactivated adjuvanted (AS03) A/H1N1 (2009) pandemic influenza vaccine in Quebec. PloS one 2014;9:e108489.
14. Partinen M, Kornum BR, Plazzi G, Jennum P, Julkunen I, Vaarala O. Narcolepsy as an autoimmune disease: the role of H1N1 infection and vaccination. Lancet Neurol 2014;13:600-13.
15. Tsai TF, Crucitti A, Nacci P, et al. Explorations of clinical trials and pharmacovigilance databases of MF59(R)-adjuvanted influenza vaccines for associated cases of narcolepsy. Scand J Infect Dis 2011;43:702-6.
16. Ahmed SS, Schur PH, MacDonald NE, Steinman L. 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. J Autoimmun 2014;50:1-11.
17. McCarthy NL, Gee J, Lin ND, et al. Evaluating the safety of influenza vaccine using a claims-based health system. Vaccine 2013;31:5975-82.
18. Duffy J, Weintraub E, Vellozzi C, DeStefano F. Narcolepsy and influenza A(H1N1) pandemic 2009 vaccination in the United States. Neurology 2014;83:1823-30.
19. Arnheim-Dahlström L, Pasternak B, Svanström H, Sparén P, Hviid A. Autoimmune, neurological, and venous thromboembolic adverse events after immunisation of adolescent girls with quadrivalent human papillomavirus vaccine in Denmark and Sweden: cohort study. BMJ : British Medical Journal 2013;347.
20. Han F, Lin L, Warby SC, et al. Narcolepsy onset is seasonal and increased following the 2009 H1N1 pandemic in China. Ann Neurol 2011;70:410-7.
21. Matsuki K, Grumet FC, Lin X, et al. DQ (rather than DR) gene marks susceptibility to narcolepsy. Lancet 1992;339:1052.
22. Kadotani H, Faraco J, Mignot E. Genetic studies in the sleep disorder narcolepsy. Genome research 1998;8:427-34.
23. Dye TJ, Gurbani N, Simakajornboon N. Epidemiology and Pathophysiology of Childhood Narcolepsy. Paediatric respiratory reviews 2016.
24. Johansen K, Brasseur D, MacDonald N, et al. Where are we in our understanding of the association between narcolepsy and one of the 2009 adjuvanted influenza A (H1N1) vaccines? Biologicals : journal of the International Association of Biological Standardization 2016;44:276-80.