ECDC – VAESCO investigation into narcolepsyArchived

In the second half of 2010 ECDC, has been working with the VAESCO Consortium (Vaccine Adverse Events Monitoring and Communication) to investigate potential risk factors for narcolepsy including infections and vaccinations. This initiative was taken following the indication of a potential association between the 2009 pandemic influenza A(H1N1) monvalent vaccine and the occurrence of narcolepsy following reports, especially in children from Finland and Sweden [1]. Narcolepsy is an uncommon disorder of excessive daytime sleepiness. The incidence has been estimated at around 0.74 - 1.37 per 100 000 person-years depending on the way the condition is defined. However, because narcolepsy is enduring, prevalence rates are much higher [2]. It often presents first with symptoms in adolescents but usually goes unrecognized and undiagnosed until adulthood. It has not been well described in childhood and is normally considered unusual before 16 years of age [2].

In August 2010 the Finnish National Institute for Health and Welfare (THL) recommended that vaccination with Pandemrix® vaccine should be discontinued in Finland until an explanation was found for an observed rise in cases of narcolepsy among children and adolescents vaccinated against 2009 pandemic influenza [3]. This then led to what is called an Article 20 procedure by the European Commission requesting a review by the European Medicines Agency [1]. The available data were reviewed by the Committee for Medicinal Products for Human Use (CHMP) in September which concluded that the available evidence was insufficient to determine whether there was any link between Pandemrix® and reports of narcolepsy, but that further studies were urgently needed to fully understand this issue. The Committee also agreed that the benefit-risk balance for Pandemrix continued to be positive, and that while the review was ongoing there was no need for Europe-wide restrictions on use [4].

To investigate the potential link between narcolepsy and pandemic influenza, pandemic influenza vaccine, and other factors, VAESCO and ECDC have been following a protocol that was reviewed by EMA. From this they have been undertaking several activities, including: 

1. generation of a narcolepsy case definition by European narcolepsy experts according to the Brighton Collaboration process; 
2. calculation of age specific background rates of narcolepsy and analysis of their time trends. The rates will be calculated in several European countries based on national or regional health care data from electronic databases or registries that collectively represent data from a population base of more than 35 million; 
3. a multinational case control study in a number of European countries using a common protocol and standardized data collection tools. This study is investigating any association between the 2009 pandemic influenza vaccine, influenza-like illness, other risk factors and narcolepsy. The results are expected in May 2011.

The VAESCO Consortium is a network of investigators from EU member states and EFTA countries exploring the feasibility and demonstrating the benefits of collaborative post-licensure epidemiological studies that investigate the safety of human vaccines. It has been working in collaboration with ECDC since 2008.  VAESCO investigators come from public health institutes, national regulatory agencies, parmacoepidemiology centres as well as ECDC itself.  The overall aim of the project, coordinated by the Brighton Collaboration is to contribute to enhanced monitoring, epidemiological investigation and communication of adverse events following immunization in the EU / EEA area.  Previous experience in employing analysis of electronic databases for drug safety monitoring proved the potential of the network of performing studies on a population exceeding 120 million subjects.  ECDC has been involved in monitoring and evaluating the situation from the public health perspective and is well placed to investigate this signal through its expertise in planning and designing epidemiological studies through the VAESCO network.

ECDC comment: (February 2nd 2011)

Most recently the Finnish National Institute for Health and Welfare (THL) has announced some preliminary findings of increased risk of falling ill with narcolepsy during the 8 months following vaccination with Pandemrix®-vaccine among those 4-19 years of age [5,6]. Pandemrix was the only pandemic vaccine used in Finland in 2009-10. Smaller increases in the numbers of diagnoses of narcolepsy have also been observed in Iceland and Sweden [5]. Preliminary data from Sweden and Iceland also indicate an increased observed incidence of narcolepsy [5]. However, a very early analysis of a subset of these cases in Sweden does not demonstrate any association with pandemic vaccine. In Europe, drug and vaccine safety monitoring is in the mandate of the European Medicines Agency, which has been leading on investigations related to this signal. In providing information to EMA ECDC and the VAESCO-ECDC case-control study has several scientifc advantages over any single-country studies, especially where only a single vaccine has been employed in any single country including: 

• incorporating regions of Europe which have used different pandemic vaccines (including vaccines with different vaccine adjuvants and no adjuvants) 
• providing results for various subpopulations including different age groups, pregnant women and other subpopulations, 
• including large sample sizes needed for reliable risk estimation of extremely rare events, 
• looking into other possible risk factors in addition to pandemic vaccines.

This places the study in a good position to resolve the uncertainty scientifically. However, it may take more than traditional pharmacoepidemiological studies including e.g.  genetic studies or serological response to infectious agents in affected individuals to answer all of the questions that  the Finnish analysis poses [7]