Narcolepsy in association with pandemic influenza vaccination – a multi-country European epidemiological investigation
This report summarises the results from two epidemiological studies conducted by the Vaccine Adverse Event Surveillance and Communication (VAESCO) Consortium undertaken in eight European Union (EU)/European Economic Area (EEA) countries in order to investigate a possible association between an unexpected increase in narcolepsy cases following the use of influenza A(H1N1)pdm09 vaccines. Narcolepsy is an underdiagnosed disease of widely unknown etiology. The VAESCO studies on narcolepsy include Sweden and Finland, which originally reported the safety signal (the signalling countries). Apart from Sweden and Finland, the studies include the following six EU/EEA Member States: Denmark, Italy, France, the Netherlands, Norway and the United Kingdom (UK). These six countries are hereafter referred to as non-signalling countries when they are being referred to collectively.
ECDC technical report “Narcolepsy in association with pandemic influenza vaccination – a multi-country European epidemiological investigation” summarises results from two studies undertaken by ECDC and the Vaccine Adverse Event Surveillance and Communication (VAESCO) Consortium. It covers a study on narcolepsy background incidence rates and a case–control study to determine risk factors. Both studies concern the association between narcolepsy and specific influenza A(H1N1)pdm09 vaccines while at the same time considering other likely causes. These studies include Denmark, Finland, France, Italy, the Netherlands, Norway, Sweden and the United Kingdom.
A summary of the report is available as a separate document.
The case–control study confirms an association between vaccination with Pandemrix® and an increased risk of narcolepsy in children and adolescents (5 to 19 years of age) in Sweden and Finland that originally reported on this issue (signalling countries). No such association was found in adults in these two countries.
According to the strictest primary analysis, the kind of assessment designed to avoid most biases like media and diagnostic awareness biases, no significant risk was found in children and adolescents in other countries included in the study – Denmark, Italy, France, the Netherlands, Norway and the United Kingdom (non-signalling countries).
However, sensitivity analyses that assess the robustness of the results from the primary analysis, have highlighted the importance of several time-related factors that affect the strength of association between influenza pandemic vaccines and narcolepsy. An example of a time-related factor shown to influence results is the length of the chosen study period, that is, the inclusion of cases occurring before and after the period of media attention would give a different outcome.
One such sensitivity analysis was based on the date of onset of excessive day-time sleepiness before media attention. This identified an increased risk for narcolepsy for children and adolescents following influenza A(H1N1)pdm09 vaccination in both signalling and non-signalling countries.
A similar sensitivity analysis also addressed date of onset of excessive daytime sleepiness and showed an association in adults in non-signalling countries before awareness increased.
To further inform the regulatory actions and the public, the report recommends increasing the statistical power by ensuring completeness of the case–control study through an exhaustive case inclusion in all age groups in the primary study period before increased awareness.
VAESCO is a European research network funded by ECDC and coordinated for ECDC by the Brighton Collaboration. It includes researchers from public health institutes, regulatory agencies and universities. The long term aim of the work is to create an independent infrastructure and epidemiological resource in support of vaccine safety monitoring and investigation in Europe.