AS03 adjuvanted AH1N1 vaccine associated with an abrupt increase in the incidence of childhood narcolepsy in Finland

Abstract

Background: Narcolepsy 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.

Methods: Retrospective 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.

Findings: Vaccination 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).

Conclusions: Pandemrix 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.

Figure 1. The temporal associations of pandemic vaccination, onset of narcolepsy (with four different definitions), and August 16, 2010, i.e. the date when the Swedish Medical Agency published the press release on the observation on the association between narcolepsy and Pandemrix vaccination (vertical dotted line).

Panel top left is Recall = Parental/Patient recall when excessive daytime sleepiness (EDS) started; Panel top right is First contact = first contact to health care because of EDS; Panel bottom left is Referral = referral to specialist (paediatrician, neurologist); and Panel bottom right is Diagnosis = when diagnosis of narcolepsy was set.

Figure 2. The different time intervals from the vaccination to the onset of narcolepsy depending on the definition of the onset time point, i.e. a) estimated onset time based on the extensive review of the patient records by a sleep and/or narcolepsy specialist, and closest to the parental/patient recall; b) first recorded contact to health care because of excessive sleepiness; c) date of referral to paediatrician or pediatric neurologist; and d) date of setting the diagnosis of narcolepsy, ICD-10 G47.4.

Figure 3. The age distribution of the new narcoleptic cases among the Pandemrix vaccinated and unvaccinated children and adolescents.

Age presented in years.

Figure 4. Sensitivity analyses of the risk ratio of Pandemrix vaccination and narcolepsy using different definitions of the onset dates of narcolepsy and follow-up time periods.

The two intervals in the top left panel are missing because of infinite estimates (i.e. no cases among unvaccinated).