AS03 Adjuvanted AH1N1 Vaccine Associated with an Abrupt Increase in the Incidence of Childhood Narcolepsy in Finland

Abstract

BackgroundNarcolepsy is a chronic sleep disorder with strong genetic predisposition causing excessive daytime sleepiness and cataplexy. A sudden increase in childhood narcolepsy was observed in Finland soon after pandemic influenza epidemic and vaccination with ASO3-adjuvanted Pandemrix. No increase was observed in other age groups.MethodsRetrospective cohort study. From January 1, 2009 to December 31, 2010 we retrospectively followed the cohort of all children living in Finland and born from January 1991 through December 2005. Vaccination data of the whole population was obtained from primary health care databases. All new cases with assigned ICD-10 code of narcolepsy were identified and the medical records reviewed by two experts to classify the diagnosis of narcolepsy according to the Brighton collaboration criteria. Onset of narcolepsy was defined as the first documented contact to health care because of excessive daytime sleepiness. The primary follow-up period was restricted to August 15, 2010, the day before media attention on post-vaccination narcolepsy started.FindingsVaccination coverage in the cohort was 75%. Of the 67 confirmed cases of narcolepsy, 46 vaccinated and 7 unvaccinated were included in the primary analysis. The incidence of narcolepsy was 9.0 in the vaccinated as compared to 0.7/100,000 person years in the unvaccinated individuals, the rate ratio being 12.7 (95% confidence interval 6.1–30.8). The vaccine-attributable risk of developing narcolepsy was 1∶16,000 vaccinated 4 to 19-year-olds (95% confidence interval 1∶13,000–1∶21,000).ConclusionsPandemrix vaccine contributed to the onset of narcolepsy among those 4 to 19 years old during the pandemic influenza in 2009–2010 in Finland. Further studies are needed to determine whether this observation exists in other populations and to elucidate potential underlying immunological mechanism. The role of the adjuvant in particular warrants further research before drawing conclusions about the use of adjuvanted pandemic vaccines in the future.

Rapid changes in serum cytokines and chemokines in response to inactivated influenza vaccination

“…Ongoing efforts to develop more effective influenza vaccines have had limited success. In addition, the unexpected association of an adjuvanted 2009 H1N1 vaccine in Europe with increased risk of narcolepsy in children25, 26, 27 highlights the need to better understand the biologic mechanisms mediating vaccine responses.…”

Molecular and clinical relationship between live‐attenuated Japanese encephalitis vaccination and childhood onset myasthenia gravis

“…However, problems generated by immunization, such as vaccination‐related Guillain–Barré syndrome, narcolepsy, acute disseminating encephalomyelitis, and multiple sclerosis, are becoming a public concern 23, 47, 54, 55, 56, 57, 58, 59, 60, 61. Whether the cellular and humoral autoimmunity related to LA‐JEV vaccination is involved in other immune‐mediated neurological diseases also remains unclear.…”

Preclinical evaluation of Vaxfectin®-adjuvanted Vero cell-derived seasonal split and pandemic whole virus influenza vaccines

“…While a variety of different adjuvant formulations have been clinically tested with H5N1, predominantly squalene-based oil-in-water adjuvants including MF-59, AS03 and AF01, [40][41][42] additional adjuvant formulations such as Vaxfectin ® should be developed because it is conceivable that even adjuvant supplies may be limited during a pandemic. In addition, potential safety issues observed for some adjuvant formulations in pandemic settings, most recently with the reported association of AS03-adjuvanted H1N1 vaccine and narcolepsy in children, 43 could restrict their annual usage with seasonal vaccines in normal healthy subjects. In addition to squalene-based adjuvants, other cationic liposome-based adjuvants with a variety of different cationic and neutral lipid components have been explored with seasonal and pandemic strains and have demonstrated enhanced immunogenicity, [44][45][46] supporting consideration of cationic liposomes as a discrete adjuvant class.…”