Conclusion
The AS03-adjuvanted 2009 pandemic H1N1 influenza vaccine (trade name: Pandemrix™) 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 (Pandemrix™) was not licensed in the United States, and vaccines in routine use in the United States* have not been shown to cause narcolepsy.
Why This is an Issue
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 (Pandemrix™) 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.
Epidemiological Evidence
Multiple studies have consistently documented an increased risk of narcolepsy associated with AS03-adjuvanted influenza vaccines, primarily in the child populations of northern European countries 1-16. The estimated rate was 1 case per 16,000 persons vaccinated between 4 and 19 years of age in Finland 1. A 2018 meta-analysis found that during the first year after vaccination with Pandemrix™ the relative risk of narcolepsy increased 5 to 14-fold in children and adolescents and 2 to 7-fold in adults, and the vaccine attributable risk in children and adolescents was approximately 1 per 18,400 doses of vaccine 17. 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 8,18. This could be explained by differences in population genetics 19. One case-control study found no association between narcolepsy and Arepanrix™ (an AS03-adjuvanted H1N1 vaccine primarily used in Canada), but had limited power to evaluate Pandemrix™ 20. Studies have not shown any association between narcolepsy and other influenza vaccines, either MF59-adjuvanted or without an adjuvant 15,20-26. A cohort study of almost one million adolescent girls in Denmark and Sweden found no association between quadrivalent HPV vaccine and narcolepsy 27. A 2017 South Korean nationwide cohort study found no associations between HPV vaccination and 33 predefined serious adverse events (including narcolepsy) 28. A 2020 systematic review and meta-analysis found no association between HPV vaccines and many autoimmune or other rare diseases (including narcolepsy) 29.
Proposed Biological Mechanism
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 30. Almost all patients with narcolepsy have HLA DQB1*0602, a genetic marker for predisposition to the disorder 31,32. Studies have provided further evidence that infections may serve as a potential trigger for the pathogenesis of narcolepsy 33.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 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 34. Another hypothesis is the “double-hit hypothesis”, which proposes that in some patients infected with the 2009 pandemic H1N1 influenza virus, it may have migrated through the olfactory pathway to the hypothalamus and infected hypocretin producing neurons causing some neuronal damage which was likely amplified by natural CD8 responses to viral antigens; then the administration of a strongly adjuvanted vaccine concomitantly with or soon after infection may have greatly amplified the CD8 response and its pathogenic effects. This hypothesis would explain the disparate risk data following receipt of ASO3-adjuvanted vaccines; for example, the observed association between AS03-adjuvanted H1N1 vaccine and narcolepsy in Scandinavia, where wild-type virus circulated during vaccination, compared to its absence in Canada, where wild-type virus circulated at a time far from the vaccination program 35.
* These conclusions do not necessarily consider vaccines recommended only for special populations in the United States such as Yellow Fever vaccine (international travelers) or Smallpox vaccine (military personnel), or vaccines no longer recommended to the public such as the Janssen (J&J) COVID-19 vaccine.
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