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Enhanced monitoring of vaccine safety for 2009 pandemic vaccines

Updated 15 August 2013 

Mass vaccination campaigns using newly developed monovalent pandemic A(H1N1) vaccines were initiated in a number of countries worldwide starting progressively from late September 2009. See ECDC Pandemic Timeline.  A range of vaccines based on different technologies were purchased by European (EU, EEA and EFTA) countries.

  • Three pandemic vaccines were authorised through the central procedure in the EU under the European Medicines Agency and the European Commission; Pandemrix, Focetria and Celvapan.
  • Two pandemic vaccines were authorised for national use in Hungary (Fluval P) and in Romania (Cantgrip).  
  • Three pandemic vaccines were authorised nationally and through mutual recognition (Panenza, Celtura and  PanvaxH1N1).

Hence the vaccines used differed between European countries. The final recommended target groups for vaccination also differed.  A number of countries had the option of offering  the pandemic vaccines to their entire population on the basis of contracts. Some exercised this option, but others did not. Most recommended vaccination of certain risk groups broadly following the recommendations of WHO and the European Health Security Committee, which was working in the light of ECDC guidance.  Some Member States offered one single vaccine to their risk/target groups or to the wider population, depending on their vaccination approach. Other countries offered several vaccines, resulting in different vaccines offered to different risk/target groups.

Authorisation of new centrally authorised vaccines is regulated in the European Union through the European Medicine Agency (EMA). This takes place following assessment of safety and immunogenicity in clinical trials. Common adverse events (occurring in more than 1/100 vaccinated individuals) can be identified in pre-licensure clinical trials. The EMA is also the primary EU authority for monitoring safety of centrally authorised vaccines. For more rare adverse events (occurring in less than 1/1,000 vaccinated individuals) routine monitoring of adverse events following immunisation (AEFIs) in the post-authorisation period is undertaken.  Very rare events (occurring in less than 1/10,000 vaccinated individuals) may only be identified when vaccines are introduced in larger populations. Routine monitoring of AEFIs are therefore essential and performed in all EU, EEA and EFTA Member States however, under-reporting by professionals has to be accepted as a reality and allowed for.

ECDC supports the vaccine safety monitoring systems organized by EMA and Member States within the limits of its mandate of risk assessment, surveillance and technical guidance.  This is done by sharing best practices of enhanced monitoring and by sometimes investigating reported suspected AEFIs, including identification and assessment of any vaccine safety signals. This work is undertaken in close collaboration with Member State authorities, the EMA, the European Commission and the World Health Organisation. This is reviewed by an EU Vaccines Task Force. In preparation for this ECDC identified Member States with capacity to establish enhanced monitoring of vaccine safety and likely to be able to investigate should a vaccine safety signal arise.  Consequently a network of researchers (VAESCO - Vaccine Adverse Events Surveillance and Communication) in nine Member States was established initially to estimate background incidence rates of medical events that possibly could be associated with administration of pandemic vaccines and then to investigate potential signals.  This enhanced monitoring and investigation of vaccine safety was entirely funded at a European level by ECDC and directed scientifically by the VAESCO consortium and ECDC.

 

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Guillain-Barré syndrome (GBS) and narcolepsy

 

The VAESCO network was asked by ECDC to investigate  a possible association between Guillain-Barré syndrome and the pandemic vaccines used in Europe in the winter season 2009/2010. This was undertaken prospectively because another swine origin influenza A(H1N1) vaccine - subtype A/NJ/76 vaccine – developed and used in the U.S. in 1976 in anticipation of a pandemic – was found to be associated with an increased number of GBS cases. Consequently vaccination was stopped abruptly.  Though subsequent studies have repeatedly found little or no association between the different seasonal influenza vaccines and GBS during later seasons the 2009/2010 study was initiated to exclude a similar association with the 2009 pandemic vaccines. Similar studies were carried out throughout the world; eg the US, Canada, Australia, Japan, Taiwan, Singapore etc.  In addition, following the safety signal of narcolepsy after vaccination with one of the adjuvanted pandemic vaccines (Pandemrix) the network was asked by ECDC  to investigate a possible association.

Guillain-Barré syndrome (GBS)

For GBS a multi-country case control study was undertaken in 2009/2010. Centres in Denmark, France, the Netherlands, Sweden and the UK participated in this study.  The study found that the risk of occurrence of GBS was not increased after administration of adjuvanted pandemic influenza vaccines (Pandemrix and Focetria) and the results were published in July 2011. The pattern was consistent across the five countries.

 

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Narcolepsy

Following the first vaccine safety signal of narcolepsy (reported in August 2010), VAESCO is undertaking a similar multi-country case control study to test whether a true association between the used 2009 pandemic vaccine Pandemrix and narcolepsy is being seen in Europe. Centres in Denmark, Finland, France, Italy, the Netherlands, Norway, Sweden and the UK are participating in the study.

The GSK H1N1 AS03-adjuvanted vaccine Pandemrix (produced in Germany) was used in more than 47 countries starting October 2009; high coverage was obtained in some countries (eg Finland, Sweden, Norway, and Ireland). Another GSK H1N1 AS03-adjuvanted vaccine Arepanrix (produced in Canada) was used in Canada and several other countries starting October 2009; high coverage was obtained in Canada and as of now no similar safety signal has been reported following vaccination with this vaccine.

An estimated 30.8 million doses of Pandemrix were administered in the EU during the 2009/2010 pandemic influenza season. An estimated 12 million doses of Arepanrix were administered in Canada during the same winter season.

 

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Timeline

Timeline for ECDC 2009 Pandemic Vaccine Safety Assessment in Europe – background-incidence rates of specified medical events of interest, Guillain-Barré syndrome and narcolepsy*  

Date Source Item (with link)
8 August 2013 National Institute for Health and Welfare (Finland)

 

PLoS ONE publishes No Serological Evidence of Influenza A H1N1pdm09 Virus Infection as a Contributing Factor in Childhood Narcolepsy after Pandemrix Vaccination Campaign in Finland

 

August 2013 National Reference Network for Narcolepsy in France

 

Brain journal publishes Increased risk of narcolepsy in children and adults after pandemic H1N1 vaccination in France

 

14 June 2013 Norwegian Resource Center for ADHD, Tourette Syndrome and Narcolepsy, Oslo University Hospital, Norway

 

Sleep Medicine publishes Incidence of narcolepsy in Norwegian children and adolescents after vaccination against H1N1 influenza A

 

March 2013 US Centers for Disease Control and Prevention

 

CDC sponsors an international study on the associations between adjuvanted monovalent 2009 H1N1 influenza vaccines and narcolepsy. The study is expected to be completed in 2014.

 

March 2013 Läkemedelsverket, The Swedish Medical Product Agency

 

Registerstudie med fokus på neurologiska och immunrelaterade sjukdomar och eftervaccination med Pandemrix (in Swedish)

 

ECDC publishes Scientific Advance: New Swedish Registry study confirms increased risk of narcolepsy in children and adolescents after vaccination with Pandemrix

 

March 2013

 

Department of Children, County Hospital, Halmstad, Sweden and The Queen Silvia Children’s Hospital, Gothenburg, Sweden

 

Neurology journal publishes Increased childhood incidence of narcolepsy in western Sweden after H1N1 influenza vaccination.
26 February 2013 UK Health Protection Agency (HPA)

 

British medical journal publishes Risk of narcolepsy in children and young people receiving AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine: retrospective analysis.

 

7-8 February 2013 First Nordic Narcolepsy Symposium in Finland

 

First Nordic Symposium on Narcolepsy (Event organisers: The NarpaNord Consortium, Helsinki Sleep Clinic, University of Helsinki)

 

February 2013 ECDC/VAESCO network

 

Vaccine publishes The incidence of narcolepsy in Europe: Before, during, and after the influenza A(H1N1)pdm09 pandemic and vaccination campaigns.

 

February 2013 US VAERS spontaneous reporting system

 

Pediatric Infectious Disease Journal publishes Clinical Assessment of Serious Adverse Events in Children Receiving 2009 H1N1 Vaccination

 

30 January 2013 Brighton collaboration working with external experts

 

Vaccine publishes Narcolepsy as an adverse event following immunization: Case definition and guidelines for data collection, analysis and presentation.

 

December 2012 Karolinska Institute, Sweden

 

BMJ publishes Risk of presentation to hospital with epileptic seizures after vaccination with monovalent AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine (Pandemrix): self controlled case series study.

 

20 September 2012 VAESCO & ECDC Consortium

 

ECDC issues a major report from the VAESCO Consortium: Narcolepsy in association with pandemic influenza vaccination – a multi-country European epidemiological investigation. It is accompanied with a Technical Report In Brief.

 

20 September 2012 L’Agence nationale de sécurité du médicament et des produits de santé (ANSM) France

 

Etude NarcoFlu-VF (NarcoFlu VAESCO-France): Grippe, vaccination antigrippale et narcolepsie : contribution française à l’étude cas-témoins européenne. Août 2012 (in French) – Detects narcolepsy & Pandemrix association in children & adults.

 

ECDC commentary on this and the VAESCO study.

 

May 2012 Statens Serum Institute

 

BMJ publishes Vaccination against pandemic A/H1N1 2009 influenza in pregnancy and risk of fetal death: cohort study in Denmark.

 

20 April 2012 European Centre for Disease Prevention and Control

 

ECDC issues sixth piece of scientific advice on Irish investigation of an increase in the incidence of narcolepsy in children and adolescents in 2009 and 2010 – final report of national narcolepsy study steering committee

 

19 April 2012 Department of Health (Ireland)

 

Report from an epidemiological study in Ireland regarding vaccination with Pandemrix and narcolepsy

 

30 March 2012 European Centre for Disease Prevention and Control

 

ECDC issues fifth piece of scientific advice on association of childhood narcolepsy and cataplexy and receipt of a pandemic influenza vaccine in Finland in 2009-10 – First papers in a peer review journal

 

March 2012 Helsinki Sleep Clinic, Finnish Narcolepsy Research Centre, Vitalmed Research Centre, Helsinki, Finland et al

 

First scientific publication addressing narcolepsy following Pandemrix vaccination: Increased incidence and clinical picture of childhood narcolepsy following the 2009 H1N1 pandemic vaccination campaign in Finland

 

March 2012 Department of Vaccines and Immune Protection, National Institute for Health and Welfare, et al (Finland)

 

Second scientific publication addressing narcolepsy following Pandemrix vaccination: AS03 Adjuvanted AH1N1 Vaccine Associated with an Abrupt Increase in the Incidence of Childhood Narcolepsy in Finland

 

28 October 2011 National Institute for Health and Welfare (Finland)

 

News item: Nästan 1 000 biverkningsanmälningar om pandemivaccinet (in Swedish).

101 cases of narcolepsy reported in Finland.

 

October 2011  

 

Study in Stockholm, Sweden of neurological and auto-immune disorders as recorded in health-care databases following use of Pandemrix - no association with well coded disorders

Bardage et al, Neurological and autoimmune disorders after vaccination against pandemic influenza A (H1N1) with a monovalent adjuvanted vaccine: population based cohort study in Stockholm, Sweden

 

1 September 2011 National Institute for Health and Welfare (Finland)

 

THL issues final report from the National Narcolepsy Task Force (in Finnish)

 

Press release on the final report available in English.

 

27 July 2011 World Health Organization

 

WHO statement on narcolepsy and Pandemrix.

 

21 July 2011 European Medicines Agency

 

EMA issues a press release about CHMP decision recommending restrictive use of Pandemrix.

 

21 July 2011 World Health Organization

 

WHO publishes a statement on the EMA recommendation: Pandemrix safety profile updated due to narcolepsy reports.

 

21 July 2011 European Centre for Disease Prevention and Control

 

ECDC issues further communication highlighting the recommendation by the European Medicines Agency concerning Pandemrix vaccination and reports of narcolepsy in children and adolescents.

 

15 July 2011 European Centre for Disease Prevention and Control/ Vaccine Adverse Event Surveillance & Communication

 

Interim VAESCO results from narcolepsy background incidence data and case control study on narcolepsy/cataplexy presented to CHMP (not public).

 

12 July 2011 ECDC/VAESCO Consortium

 

Publication of case control study in BMJ finding no evidence of an association of adjuvanted vaccines in Europe and development of Guillain-Barré syndrome.

 

12 July 2011 Norwegian Medicines Agency (Norway)

 

Narkolepsi og Pandemrix - nye norske tall (Narcolepsy and Pandemrix – new cases in Norway).

 

1 Jul 2011 European Centre for Disease Prevention and Control

 

ECDC issues fourth piece of scientific advice on case inventory study from Sweden concerning association of Pandemrix vaccination and reports of narcolepsy with cataplexy in children and adolescents.

 

30 June 2011 Medical Products Agency (Sweden)

 

Report from an epidemiological study in Sweden on vaccination with Pandemrix and narcolepsy.

 

21 June 2011 Norwegian Medicines Agency (Norway)

 

Norwegian authorities release data regarding narcolepsy cases associated with vaccination with Pandemrix.

 

21 April 2011 World Health Organization

 

WHO statement on narcolepsy and vaccination.

 

15 April 11 European Medicines Agency

 

EMA issues press release recommending interim measures for Pandemrix.

 

04 April 2011 l’Agence Française de Sécurité Sanitaire des Produits de Santé (AFSSAPS), France

 

French authorities publish a pharmacovigilance update regarding the reported cases of narcolepsy in people vaccinated with Pandemrix and another pandemic vaccine (Panenza).

 

30 March 2011 European Centre for Disease Prevention and Control

 

ECDC comments on the Swedish MPA interim results of a cohort study assessing the risk of narcolepsy after vaccination with  Pandemrix.

 

29 March 2011 Medical Products Agency (Sweden)

 

Swedish registry-based cohort study provides strengthened evidence of an association between vaccination with Pandemrix and narcolepsy in children and adolescents.

 

2 March 2011 European Centre for Disease Prevention and Control

 

ECDC publishes second scientific advice on the initial findings on this topic and describes relevant developments for Europe.

 

21 February 2011 Norwegian Medicines Agency (Statens legemiddelverk), Norway

 

Norwegian Medicines Agency issues statement Pandemrix og narkolepsi – flere studier nødvendig (Pandemrix and narcolepsy – more studies needed).

 

18 February 2011 European Medicines Agency

 

EMA publishes review of further data on narcolepsy and possible association with Pandemrix.

 

10 February 2011 World Health Organization

 

Statement of Global Advisory Committee on Vaccine Safety (GACVS) on Pandemrix vaccine and narcolepsy.

 

2 February 2011 European Centre for Disease Prevention and Control

 

ECDC publishes its first commentary, as a scientific advice, on the development, explaining the background.

 

31 January/1 February 2011 National Institute for Health and Welfare (Finland)

 

Publication of the Finnish National Narcolepsy Task Force's Interim Report.

 

Press release: Increased risk of narcolepsy observed among children and adolescents vaccinated with Pandemrix.

 

25 January 2011 European Centre for Disease Prevention and Control

 

ECDC issues its risk assessment for the 2010-11 season reminding Member States on the importance of the use of the triple seasonal vaccine.

 

January 2011 European Medicines Agency/ European Centre for Disease Prevention and Control / Vaccine Adverse Event Surveillance & Communication network

 

EMA publishes first data in the scientific literature on adverse event monitoring and pandemic vaccines in the Eudravigilance database using crude ECDC/VAESCO background incidence medical event rates;  Safety monitoring of Influenza A/H1N1 pandemic vaccines in EudraVigilance.

 

22 December 2010 European Centre for Disease Prevention and Control

 

ECDC Director makes a routine statement on influenza reminding Member States on the importance of use of triple seasonal vaccines.

 

December 2010 European Centre for Disease Prevention and Control

 

Second ECDC/VAESCO vaccine safety study initiated to investigate background rates of narcolepsy in the EU and conduct a multi-country association study (case control methodology) to assess a possible association between pandemic vaccines and development of narcolepsy.

 

November 2010 Narcolepsy experts worldwide

 

Sleep publishes Post-H1N1 narcolepsy-cataplexy

 

23 September 2010 Eurosurveillance

 

European Medicines Agency updates on the review of Pandemrix and reports of narcolepsy.

 

10 September 2010 Medical Products Agency (Sweden)

 

Update on the investigation of narcolepsy cases in Sweden.

 

8 September 2010 European Medicines Agency

 

CHMP meets to discuss Pandemrix.

 

2 September 2010 European Medicines Agency

 

EMA updates on the review of Pandemrix and reports of narcolepsy: CHMP concluded in its initial review of available data that the available evidence did not confirm a link but that more research was needed.

 

September 2010 European Union

 

Member States start immunising against seasonal influenza – mostly following WHO guidance and using non-adjuvanted triple seasonal influenza.

 

27 August 2010 European Medicines Agency

 

EMA starts a review of Pandemrix at the request of the European Commission under Article 20 of Regulation (EC) No 726/2004, following an increased number of reports of narcolepsy in Finland and Sweden.

 

26 August 2010 Medical Products Agency (Läkemedelsverket), Sweden

 

Sweden's Medical Products Agency issues an update on the investigation of cases of narcolepsy after vaccination with Pandemrix.

 

25 August 2010 National Institute for Health and Welfare (Terveyden ja hyvinvoinnin laitos), Finland

 

On the basis of cases of narcolepsy in association with use of a Pandemic Vaccine (Pandemrix ®) in Finland, the Finnish National Institute for Health and Welfare recommends discontinuation of Pandemrix vaccinations.

 

19 August 2010 European Medicines Agency

 

EMA issues its 22nd and last Eudravigilance based update on adverse drug reports. Narcolepsy cases in association with vaccination were not being reported by member states at that time.

 

18 August 2010 Medical Products Agency (Läkemedelsverket), Sweden

 

Swedish Medical Products Agency investigates reports of narcolepsy in patients vaccinated with Pandemrix.

 

10 August 2010 World Health Organization

 

Announcement of end of the pandemic. Following this, the European Commission approved the authorisation of three vaccines for use outside the pandemic.

 

4 June 2010 United States Centers for Disease  Control and Prevention (CDC)

 

Publication in the CDC’s Morbidity and Mortality Weekly Report showing no evidence of an association of non-adjuvanted pandemic vaccines and Guillain-Barré Syndrome in United States.

 

2 June 2010 Medical Products Agency (Läkemedelsverket), Sweden

 

Final summary of adverse drug reports (ADR) in Sweden with Pandemrix October 2009 – mid April 2010.

 

April 2010 European Medicines Agency

 

By April 2010, the information supplied on the safety and effectiveness of three of the centrally authorised pandemic-influenza vaccines (Pandemrix, Focetria and Celvapan) was considered complete enough for the EMA’s Committee for Medicinal Products for Human Use (CHMP) to recommend their use outside a pandemic situation. On the basis of this recommendation, the European Commission approved the authorisation of these vaccines for use outside the pandemic two days after the WHO announced the end of the pandemic on 10 August 2010.

 

February 2010 World Health Organization

 

Recommendation by WHO to switch back to use of triple seasonal influenza vaccines including the new A(H1N1)pdm09 and previous A(H3N2) and B-Victoria like vaccine virus for the Northern Hemisphere 2010-2011. Manufacturers start producing accordingly and decide to generally revert to not using adjuvants as extensively as they did with the pandemic vaccines. 

 

January 2010 European Centre for Disease Prevention and Control / Vaccine Adverse Event Surveillance & Communication network (VAESCO network)

 

Crude background incidence rates of specified medical events of interest selected by EMA and FDA to allow for timely estimations of observed versus expected number of cases, should a vaccine safety signal arise shared with EMA (not in the public domain).

 

3 December 2009 European Medicines Agency

 

EMA starts publishing regular reports of adverse events following immunisations (AEFIs) as reported to the Agency through the Eudravigilance system. A total of 22 updates were published between December 2009 and 19 August 2010.

 

First publication of reported adverse events following immunization with AS03-adjuvanted pandemic vaccine: Fever in young children.

 

December 2009 European Medicines Agency

 

Between December 2009 and August 2010, the EMA published regular updates on safety monitoring of vaccines and medicines used during the pandemic.

 

November 2009 European Centre for Disease Prevention and Control / Vaccine Adverse Event Surveillance & Communication network (VAESCO network)

 

ECDC/VAESCO initiates first retrospective vaccine safety study to develop background incidence rates of specified medical events of interest selected by EMA and the US Food and Drug Administration (FDA)  to allow for timely estimations of observed versus expected number of cases, should a vaccine safety signal arise. The following medical events were included: Neuritis, convulsion, anaphylaxis, encephalitis, vasculitis, Guillain-Barré syndrome, demyelinization, Bells Palsy, transverse myelitis, autoimmune, hepatitis, thrombocytopenia and sudden death.

 

1 November 2009 European Centre for Disease Prevention and Control / Vaccine Adverse Event Surveillance & Communication network (VAESCO network)

 

ECDC/VAESCO initiates the first prospective vaccine safety studies to exclude an association with current vaccines between swine-influenza based vaccines and development of Guillain-Barré syndrome due to an earlier association identified in 1976 when a swine-influenza based vaccine was used:

 

October 2009 (updated 18 Dec 2009) European Centre for Disease Prevention and Control

 

ECDC publishes Q&A for the general public on vaccines and vaccination in relation to the 2009 influenza A(H1N1) pandemic.

 

October 2009 (updated 18 Dec 2009) European Centre for Disease Prevention and Control

 

ECDC publishes Q&A for health professionals on vaccines and vaccination in relation to the 2009 influenza A(H1N1) pandemic.

 

September 2009 European Medicines Agency (EMA) and National Regulatory Agencies*

 

From September 2009 five pandemic vaccines authorised through the central procedure in the EU; Pandemrix, Focetria, Celvapan. Humenza and Arepanrix. In addition, two unadjuvanted pandemic vaccines were authorised for national use in Hungary (Fluval P) and in Romania (Cantgrip). Finally, another three unadjuvanted pandemic vaccines were authorised nationally and through mutual recognition (Panenza, Celtura and PanvaxH1N1).

 

September 2009 World Health Organization

 

Recommendation following expert advice by WHO to switch back to use of triple seasonal influenza vaccines including the new A(H1N1)pdm09 and previous A(H3N2) and B-Victoria like vaccine virus for the southern hemisphere Season 2010.  Manufacturers start producing accordingly and decide to generally revert to not using adjuvants.

 

August 2009 European Centre for Disease Prevention and Control (ECDC)

 

ECDC issues guidance for use of 2009 pandemic vaccines and Adoption of Recommendations for risk and target groups through the Health Security Committee.

 

July 2009 World Health Organization (WHO)

 

WHO issues recommendations for use of 2009 pandemic vaccines.

 

 * Since new technologies were involved in the production of some pandemic vaccines, which had not yet been extensively evaluated for their safety in certain population groups, it was very important to implement post-marketing surveillance of the highest possible quality. In addition, rapid sharing of the results of immunogenicity and post-marketing safety and effectiveness studies among the international community was viewed as essential for allowing countries to make necessary adjustments to their vaccination policies.

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