In late March, 2011 ECDC reported that the Swedish Medical Product Agency published preliminary results from an on-going cohort study involving 5.3 million people, where 67% of children and adolescents and 51.0% of adults were vaccinated with Pandemrix. A relative risk of 4.19 (95%CI 1.76-12.1) for vaccinated children and adolescents developing narcolepsy compared to those unvaccinated was reported. No similar risk was reported for vaccinated adults.(1) This followed earlier findings from Finland and Iceland which ECDC summarised at the start of March along with the background of the situation.(2) Further data have become available from France and all the data have been considered by the European Medicines Agency and the WHO Global Advisory Committee on Vaccine Safety. This public health development summarizes the French findings (3), the European Medicines Agency (4,5) and WHO (6) assessments of all available data on reported cases of narcolepsy following immunization with Pandemrix. It should be read along with earlier ECDC publications.(1,2)
Routine reports of narcolepsy following pandemic influenza A H1N1 2009 vaccination in France
On 4 April, 2011 the French regulatory agency AFSSAPS published a press release concluding that 25 cases of narcolepsy following immunization with pandemic influenza A H1N1 2009 vaccines have been reported to AFSSAPS through their routine spontaneous reporting of adverse events. Eleven of the 25 cases occurred in children and adolescents younger than 16 years. 23 narcolepsy cases followed vaccination with the adjuvanted vaccine Pandemrix and 2 cases with the unadjuvanted vaccine Panenza. In total, 4.1 million individuals received the Pandemrix vaccine and 1.6 million received the Panenza vaccine in France. An observed versus expected assessment was reported for the age group 10-15 years where nine cases have been reported compared to on average 2.1 cases years before.(3) The French release points out that their results do not take into account any individual risk factors such as underlying medical conditions and further studies are expected .(3) Also there may be reporting bias with the recent interest in narcolepsy. However these data are compatible with the data of reported increase of narcolepsy cases obtained in Sweden and Finland.(1,2)
EMA/CHMP recommends interim measures for Pandemrix
In April at a routine meeting the European Medicines Agency Committee on Human Medicinal Products (CHMP) reviewed all the available data on the possible link between narcolepsy-cataplexy in children/adolescents and Pandemrix, including the new reported findings from Sweden and France. The CHMP assessment was published on 15 April, 2011 stating: ‘following earlier results of an epidemiological study from Finland, the new evidence strengthen the signal in children and adolescents’.(4,5) The Committee also stressed the lack of a clear increase in reports of narcolepsy following Pandemrix in other EU or non-EU countries and why results from already on-going pharmacoepidemiological studies in Europe (VAESCO) and Canada (GSK) will be essential for the final benefit-risk assessment. Finally, the need for non-clinical studies, especially in the juvenile setting to initiate investigations into a biological plausibility was mentioned.
Following this review the EMA/CHMP recommended that the product information for Pandemrix should be amended to advise prescribers to take into account preliminary results from epidemiological studies on Pandemrix and narcolepsy, and to perform an individual benefit-risk assessment when considering use. The exact wording of this amendment to the product information for Pandemrix is:
Preliminary reports from epidemiological studies in two countries (Sweden and Finland) have indicated a 4-9-fold risk increase of narcolepsy in vaccinated as compared with unvaccinated children/adolescents, corresponding to an absolute risk increase of about 3-4 additional cases in 100,000 vaccinated subjects. This risk increase has not been found in adults (older than 20 years). Similar epidemiological studies have not yet been conducted in other countries. The relationship between Pandemrix and narcolepsy is still under investigation. When considering the use of Pandemrix in children and adolescents, an individual benefit-risk assessment should be performed taking this information into account.
Furthermore, EMA-CHMP is planning for an expert meeting with the participation of international experts, the World Health Organization and ECDC. The next formal review of the data will be at the routine CHMP meeting in July, 2011.
WHO Statement on narcolepsy and vaccination by its Global Advisory Committee on Vaccine Safety (GACVS)
Following the statement by EMA, the WHO Global Advisory Committee on Vaccine Safety (GACVS) made a statement on 21 April, 2011.(6) This noted that narcolepsy has not been observed previously in association with the use of any vaccines and at this stage it does not appear that narcolepsy following immunization against pandemic influenza is a general worldwide phenomenon, as no excess of narcolepsy has been reported from several other European states where Pandemrix was used, or from Canada where a pandemic vaccine similar to Pandemrix was used. However GACVS agreed that further investigation is warranted concerning narcolepsy and vaccination with pandemic influenza 2009 vaccines. It noted that interpretation of first preliminary results from Sweden and Finland are complicated and it is possible that some yet unidentified additional factor was operating in Sweden and Finland, a comment also made by the two countries. GACVS concluded that the VAESCO studies and further investigations in Finland and Sweden, may help clarify the determinants of any increased risk of narcolepsy, which currently appears to be restricted to the months following vaccination and by age group and country. WHO will continue to monitor the situation closely.(6)
Narcolepsy reports to EudraVigilance
As of early May 2011, 263 reports suggestive of narcolepsy and mentioning Pandemrix have been recorded in the EU EudraVigilance database of suspected adverse reactions to medicinal products maintained by the European Medicines Agency. Reports are still being received on cases since case ascertainment of cases is still on-going in several countries.
ECDC comment 27 May, 2011:
As pointed out by WHO narcolepsy has never been reported in association with vaccination.(6) Hence the reports of an association with Pandemrix from Sweden, Finland, and now possibly a third country France was unexpected, unlike for example an association with another condition Guillain-Barre Syndrome for which prospective studies were established before the pandemic.(7) At present the newly started, ECDC-funded VAESCO project is the only European resource able to start cross-country investigations of narcolepsy involving larger populations. That is in addition to regional/national studies in the above mentioned countries plus Canada.
Why a possible association is observed in some countries but not in others is unclear. This suggests an effect in conjunction with some other environmental or genetic factor may be inducing narcolepsy. If the on-going epidemiological studies confirm an association after adjustment for possible risk factors for narcolepsy then further studies will be necessary to understand a possible biological mechanism for the adverse effect. Conducting such studies would optimally include the same children/adolescents affected by narcolepsy and their families and needs to be carefully planned to avoid further discomfort to the families. Many of the children/adolescents are currently part of the on-going VAESCO study and it would be natural to continue within the same framework if that is acceptable to the children/adolescents and their families. This would also have the great advantage of including cases and controls from as many as nine EU countries, several of them without a known safety signal. A common study protocol involving countries with and without a signal is optimal, though funding for such studies will have to be identified.
The European Medicines Agency has indicated that an expert meeting will be called to assess the results from the on-going epidemiological studies (final results from the Finnish cohort study, first results from the Swedish registry study, first results from the VAESCO background incidence and case-control studies and the first results from a Canadian case-control study) and hopefully start addressing the further research needs. A close collaboration between narcolepsy experts, Public Health Institutes, the Regulatory Agencies on the national and European levels and European pharmacoepidemiological researchers is needed. In addition, the role of manufacturers in these studies needs to be defined and transparent.
Finally ECDC reiterates its observation that since the autumn of 2010 circulating human influenza has been seasonal in nature with both the new A(H1N1)2009 and B viruses. Seasonal influenza vaccines should be used for prevention of seasonal influenza. Hence the cases where specific pandemic vaccine should be used in preference to seasonal influenza vaccines are few and far between (one example is with immunocompromised patients where the adjuvanted vaccines are especially effective). Hence use of specific pandemic vaccines in Europe should be minimal now and next season.
- ECDC Swedish MPA publishes interim results of a cohort study assessing the risk of narcolepsy after vaccination with Pandemic influenza vaccine Pandemrix® March 30th 2011
- ECDC Reports of cases of narcolepsy and cataplexy in children and adolescents in Finland, Iceland, and Sweden March 2nd 2011
- AFSSAPS Vaccins pandémiques grippe A(H1N1) et narcolepsie - Actualisation des données – Communiqué April 4th 2011. 4. EMA Committee for Medicinal Products for Human Use (CHMP) 11 – 14 April 2011.
- EMA Press Release April 15th 2011.
- WHO Global Advisory Committee on Vaccine Safety Statement on narcolepsy and vaccination April 21 2011.