Reassessment of the risk of narcolepsy in children in England 8 years after receipt of the AS03-adjuvanted H1N1 pandemic vaccine: A case-coverage study.

Julia Stowe,Elizabeth Miller,Nick Andrews,Paul Gringras,Timothy Quinnell,John Shneerson,Zenobia Zaiwalla,Jonathan Duffy

doi:10.1371/journal.pmed.1003225

Abstract

BackgroundEarly studies of narcolepsy after AS03-adjuvanted pandemic A/H1N12009 vaccine (Pandemrix) could not define the duration of elevated risk post-vaccination nor the risk in children aged under 5 years who may not present until much older.Methods/FindingsClinical information and sleep test results, extracted from hospital notes at 3 large pediatric sleep centers in England between September 2017 and June 2018 for narcolepsy cases aged 4–19 years with symptom onset since January 2009, were reviewed by an expert panel to confirm the diagnosis. Vaccination histories were independently obtained from general practitioners (GPs). The odds of vaccination in narcolepsy cases compared with the age-matched English population was calculated after adjustment for clinical conditions that were indications for vaccination.GP questionnaires were returned for 242 of the 244 children with confirmed narcolepsy. Of these 5 were under 5 years, 118 were 5–11 years, and 119 were 12–19 years old at diagnosis; 39 were vaccinated with Pandemrix before onset. The odds ratio (OR) for onset at any time after vaccination was 1.94 (95% confidence interval [CI] 1.30–2.89), The elevated risk period was restricted to onsets within 12 months of vaccination (OR 6.65 [3.44–12.85]) and was highest within the first 6 months. After one year, ORs were not significantly different from 1 up to 8 years after vaccination. The ORs were similar in under five-year-olds and older ages. The estimated attributable risk was 1 in 34,500 doses. Our study is limited by including cases from only 3 sleep centers, who may differ from cases diagnosed in nonparticipating centers, and by imprecision in defining the centers’ catchment population. The potential for biased recall of onset shortly after vaccination in cases aware of the association cannot be excluded.ConclusionsIn this study, we found that vaccine-attributable cases have onset of narcolepsy within 12 months of Pandemrix vaccination. The attributable risk is higher than previously estimated in England because of identification of vaccine-attributable cases with late diagnoses. Absence of a compensatory drop in risk 1–8 years after vaccination suggests that Pandemrix does not trigger onsets in those in whom narcolepsy would have occurred later.

Highlights

In August 2010, concerns were raised in Finland and Sweden about a possible association between narcolepsy and the AS03-adjuvanted H1N1 pandemic vaccine Pandemrix following reports of an excess of cases in recently vaccinated children [1,2]
We found that vaccine-attributable cases have onset of narcolepsy within 12 months of Pandemrix vaccination
The attributable risk is higher than previously estimated in England because of identification of vaccine-attributable cases with late diagnoses

Summary

Introduction

In August 2010, concerns were raised in Finland and Sweden about a possible association between narcolepsy and the AS03-adjuvanted H1N1 pandemic vaccine Pandemrix following reports of an excess of cases in recently vaccinated children [1,2]. A subsequent cohort study in Finland reported a 13-fold increased risk of narcolepsy following Pandemrix in children aged 4 to 19 years, almost of whom had onset within 6 months [3]. In the UK, Pandemrix was used from October 2009 for individuals considered at high risk followed by children under 5 years of age from December onwards. It was used again in the UK in the 2010/11 season because of a shortage of seasonal influenza vaccine. Studies of narcolepsy after AS03-adjuvanted pandemic A/H1N12009 vaccine (Pandemrix) could not define the duration of elevated risk post-vaccination nor the risk in children aged under 5 years who may not present until much older

Methods

Results

Conclusion