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. 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.



Background and subsequent incidence rates of narcolepsy by age and time
• The pooled background incidence rate of diagnosed narcolepsy was low and stable at around 1 per 100 000 PY between 2000 and 2010 (0.85/100 000 PY prior to the vaccination campaigns).
• Lower background rates of diagnoses were observed among children: <5 years and 5–19 years (0.12/100 000 PY and 0.56/100 000 PY, respectively
• No increased incidence rate of narcolepsy was observed in temporal association with the 2009 pandemic itself.
• The overall incidence rates of narcolepsy differed substantially between the signalling and non-signalling countries after the start of the vaccination campaigns: 1.67/100 000 PY vs. 0.95/100 000 PY, respectively.
• In the signalling countries the following incidence rate patterns were identified:
− In Finland, an increase in the incidence rate of narcolepsy diagnoses after September 2009 was observed in children and adolescents 5–19 years of age with a relative risk of 6.4 (95%CI 4.2-9.7).
− In Sweden, a similar increase was also observed after September 2009 in the 5–19  year age group with a relative risk of 7.5 (95%CI 5.2–10.7). The pattern was different in the other non-signalling five study countries during the period for which data could be
analysed. While in Denmark a small increase in the incidence rate of narcolepsy was also observed, the upward trend started earlier, prior to the start of the vaccination campaign (focusing on risk groups only) and in a different age group. In the Netherlands, the UK and Italy no increase in incidence was seen, however vaccination coverage was low in all the non-signalling countries. Associations of narcolepsy with risk factors including influenza, other infections, influenza A(H1N1)pdm09 vaccination and other vaccinations
• The primary analysis focusing on the primary study period before professional/regulatory and media attention in the signalling countries Finland and Sweden showed an association between pandemic influenza immunisation and narcolepsy in children and adolescents (5-19 years) but not in adults. This confirmed
observations made with different methodologies in those countries in national studies.
• A similar association in the primary analysis was not found in the non-signalling countries.
• Sensitivity analyses highlight the importance of time-related factors for the strength of association. It should be noted that sensitivity analyses of different study periods and different index dates may contain a mixture of potential vaccine and/or regulatory and media attention effects.
• All epidemiologic studies investigating the association between the influenza A(H1N1)pdm09 vaccine and narcolepsy have the challenge to address a multitude of time-related biases, and results obtained beyond the primary study period should be interpreted cautiously.
• To increase statistical power for further association analyses on these observations, especially for cases diagnosed prior to regulatory/media attention the following possibilities should be considered:
− pooling all data available across Europe (including data from studies when completed from the
Swedish Medical Products Agency, Finnish National Institute for Health and Welfare, Irish Health Service Executive and Health Protection Surveillance Centre, and the UK Health Protection Agency)
− finalising VAESCO study case inclusion especially in Finland, France, and Sweden  where many cases could not be included at the time of completion of the contract and which is particularly important for this investigation
− including further European countries with significant vaccine coverage such as Ireland
− extending the investigations beyond Europe in countries where narcolepsy cases could be diagnosed and where media attention was less pronounced but where Pandemrix and other pandemic vaccines (including the adjuvanted Arepanrix) were offered for children.
• The observations are sufficiently strong and consistent for children in the signalling countries using different methodologies to warrant further investigations as to a possible mechanism. While it is the case that the vaccine concerned is one with a novel adjuvant there is a confounding factor in Europe in that this was the only vaccine offered for children in any volume in Europe. Hence it cannot be concluded that the adjuvant is
the cause of the observation. Equally there is also the possibility that it is the combination of vaccination TECHNICAL REPORT Narcolepsy in association with pandemic influenza vaccination and influenza transmission or another unrecognised infection or environmental factor in individuals with developing nervous systems. There will be a role also for animal models and mechanistic studies. As of August 2012 more than 600 narcolepsy cases (including more than 100 in adults) have been reported spontaneously to the EMA EudraVigilance database following the influenza A(H1N1)pdm09 vaccination. Cases are still being reported in 2012 but in lower numbers compared to 2010–2011. Surprisingly, more than 500 of the cases originate from Member States being part of the current VAESCO project. Continued investigations are needed in the VAESCO countries as well as in other countries where influenza A(H1N1)pdm09 vaccines were used.

Background Rates of Events of Special Interest (ESI) 2010

Up to 260 million person years were available for calculation of background rates. Most of the here reported rates are based on unvalidated coded events and therefore these initial rates will be overestimated. Further work to validate the diagnoses is ongoing.

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Pandemic Influenza Vaccine (H1N1) 2010 and Guillain-Barre Syndrome

The possible association of Pandemic Influenza Vaccine (H1N1) 2010 and Guillain-Barre Syndrome was investigated in 2 multinational European studies: a case control study and self controlled case series (SCCS) study.

The abstract of the aricle published in BMJ, July 2011:

Objective: To assess the association between pandemic influenza A (H1N1) 2009 vaccine and Guillain-Barré syndrome. Design: Case-control study. Setting: Five European countries. Participants: 104 patients with Guillain-Barré syndrome and its variant Miller-Fisher syndrome matched to one or more controls. Case status was classified according to the Brighton Collaboration definition. Controls were matched to cases on age, sex, index date, and country. Main outcome measures: Relative risk estimate for Guillain-Barré syndrome after pandemic influenza vaccine. Results: Case recruitment and vaccine coverage varied considerably between countries; the most common vaccines used were adjuvanted (Pandemrix and Focetria). The unadjusted pooled risk estimate for all countries was 2.8 (95% confidence interval 1.3 to 6.0). After adjustment for influenza-like illness/upper respiratory tract infection and seasonal influenza vaccination, receipt of pandemic influenza vaccine was not associated with an increased risk of Guillain-Barré syndrome (adjusted odds ratio 1.0, 0.3 to 2.7). The 95% confidence interval shows that the absolute effect of vaccination could range from one avoided case of Guillain-Barré syndrome up to three excess cases within six weeks after vaccination in one million people. Conclusions: The risk of occurrence of Guillain-Barré syndrome is not increased after pandemic influenza vaccine, although the upper limit does not exclude a potential increase in risk up to 2.7-fold or three excess cases per one million vaccinated people. When assessing the association between pandemic influenza vaccines and Guillain-Barré syndrome it is important to account for the effects of influenza-like illness/upper respiratory tract infection, seasonal influenza vaccination, and calendar time.

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Pandemic influenza vaccine (H1N1) 2010 and Narcolpesy

We investigated the possible association of pandemic influenza vaccine (H1N1) 2010 and narcolpesy in a multinational European case control study.

Thrombocytopenic purpura after measles-mumps-rubella vaccination in England and Denmark

The abstract of the aricle in press in VACCINE:

The assessment of rare adverse events following vaccination may not be possible within a single country due to an insufficiently large denominator population. In 2008 a European consortium (VAESCO) was funded to perform collaborative vaccine safety studies. To help assess the feasibility of multi-country  collaboration England and Denmark, who have established vaccine safety research infrastructures, undertook to work to a common protocol and share results and data to estimate the risk of thrombocytopenic purpura (TP) following measles-mumps-rubella (MMR) vaccination. TP is a known rare reaction to MMR and therefore provided an opportunity to assess whether two countries would produce similar results when working collaboratively. Despite some initial problems with ensuring data were comparable the two countries gave very similar estimates of the relative incidence in the 6 weeks after vaccination and a pooled relative incidence estimate of 2.13 (95% confidence interval 1.55-2.94) and attributable risk of 1 in 50,000 doses. Both countries used hospital admissions for TP and the analysis was performed using the self controlled case series method which is particularly suited to collaborative studies because of its implicit control for individual level confounding. The study therefore shows the potential for vaccine safety collaborations across Europe to detect true associations through use of common protocols and sharing of results or data.

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