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Guillain-Barré syndrome and adjuvanted pandemic influenza A (H1N1) 2009 vaccine: multinational case-control study in Europe

BMJ 2011; 343 doi: https://doi.org/10.1136/bmj.d3908 (Published 12 July 2011) Cite this as: BMJ 2011;343:d3908
  1. Jeanne Dieleman, senior pharmacoepidemiologist1,
  2. Silvana Romio, senior medical statistician1,
  3. Kari Johansen, senior infectious diseases scientist2,
  4. Daniel Weibel, senior epidemiologist3,
  5. Jan Bonhoeffer, consultant in infectious diseases and vaccines3,
  6. Miriam Sturkenboom, professor of pharmacoepidemiology and medical informatics1
  7. and the VAESCO-GBS Case-Control Study Group
  1. 1Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, Netherlands
  2. 2European Centre for Disease Prevention and Control, ECDC, Stockholm, Sweden
  3. 3Brighton Collaboration, Basel, Switzerland
  1. Correspondence to: M Sturkenboom m.sturkenboom{at}erasmusmc.nl
  • Accepted 9 May 2011

Abstract

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.

Footnotes

  • The coordinating partner for the VAESCO consortium is the Brighton Collaboration. We thank all the VAESCO members and the Brighton Collaboration coordinating staff for their supportive contributions. This study is based in part on data from the Full Feature General Practice Research Database obtained under licence from the UK Medicines and Healthcare products Regulatory Agency. The interpretation and conclusions contained in this report are those of the authors alone. We acknowledge the use of the UK National Grid Service in carrying out this work.

  • Members of the VAESCO-GBS case-control study group

  • Jeanne P Dieleman (Erasmus University Medical Center, Netherlands), Silvana Romio (Erasmus University Medical Center, Netherlands), Corinne S de Vries (Bath University), Cormac Sammon (Bath University), Nick Andrews (Health Protection Agency), Anders Hviid (Statens Serum Institut, Denmark), Henrik Svanström (Statens Serum Institut, Denmark), Ditte Mølgaard-Nielsen (Statens Serum Institut, Denmark), Maryse Lapeyre-Mestre (University of Toulouse, France), Agnès Sommet (University of Toulouse, France), Christel Saussier (French Medicines Agency, France), Anne Castot (French Medicines Agency, France), Harald Heijbel (Swedish Institute for Infectious Disease Control, Sweden), Lisen Arnheim Dahlström (Karolinska Institutet, Sweden), Jonas Hallgren (Karolinska Institutet, Sweden), Par Sparen (Karolinska Institutet, Sweden), Mees Mosseveld (Erasmus University Medical Center, Netherlands), Martijn Schuemie (Erasmus University Medical Center, Netherlands), Nicoline van der Maas (RIVM, Netherlands), Bart C Jacobs (Erasmus University Medical Center, Netherlands), Kari Johansen (ECDC, Sweden), Piotr Kramarz (ECDC, Sweden), Daniel Weibel (Brighton Collaboration, Switzerland), Jan Bonhoeffer (Brighton Collaboration, Switzerland), and Miriam CJM Sturkenboom (Erasmus University Medical Center, Netherlands).

  • Contributors: JD, JB, and MS drafted the manuscript; SR, Henrik Svanström, DW, Nick Andrews, JD, and MS discussed and performed the statistical analysis. Martijn Schuemie and Mees Mosseveld developed software to collect and process data for the study. DW and JB coordinated the VAESCO studies and took care of communication and distribution of study materials to group members. Data management was done by JPD, SR and MS. All members of the VAESCO-GBS case-control study group contributed to the collection of data for the study and discussions on the design, conduct and interpretation of the local and pooled findings. They had full access to the data and reviewed and approved the drafts of the manuscript. Piotr Kramarz and KJ contributed to the discussion of the study design and interpretation of results and reviewed and commented on the manuscript. MS is guarantor.

  • Funding: This study was funded by the European Centre for Disease Prevention and Control. The VAESCO consortium was funded by the European Centre for Disease Prevention and Control (Specific agreement No 1 to Framework Partnership Agreement No GRANT/2009/003 on a grant for an action, addendum no 1 “Pan Flu Supplement” to specific agreement no 1) for the conduct of safety studies on the new pandemic influenza A (H1N1) vaccine. The GBS case-control study was conducted with part of the funding in work package 4. The project has received funding from the European Centre for Disease Prevention and Control (ECDC, www.ecdc.europa.eu) through the call for proposal. ECDC uses only public money in funding its projects. Piotr Kramarz and KJ collaborated with the VAESCO Consortium in study design, interpretation of results, and in reviewing and commenting on the manuscript. The European Centre for Disease Prevention and Control also provided support on background information regarding the H1N1-pandemic and vaccination policies.

  • Competing interests: All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and claim no conflict of interest related to the submitted work. The following authors make available additional information, which may be deemed relevant to the submitted work: Piotr Kramarz was employed by Pfizer during 2001-7. KJ received research grants from GSK and SPMSD until 2008. JB has provided scientific advice to GSK and Wyeth/Pfizer. Pär Sparén and Lisen Arnheim Dahlström were involved in studies with unconditional grants from GSK and SPMSD. Jonas Hällgren has been involved in studies with unconditional grants from GSK. Corinne de Vries and Cormac Sammon hold research and consultancy contracts with GSK and with other pharmaceutical companies. MS, JD, Martijn Schuemie, Mees Mosseveld, and SR conduct occasionally unconditional research for pharmaceutical companies including Pfizer, Boehringer, Lilly, and AstraZeneca. Bart Jacobs has been involved in studies with unconditional grants from Baxter.

  • Ethical approval: In France, the case-control study was approved by the ethics committee of Toulouse (Comité de Protection des Personnes Sud Ouest et Outre Mer I et II) and participants (cases and controls) gave informed consent. In the Netherlands, the study was provided with a declaration of no objection from the medical ethics committee of the Erasmus University Medical Center in Rotterdam (MEC-2009-404). Subsequent amendments to collect data entirely anonymously through the GP allowed the inclusion of study subjects without requiring informed consent. In Denmark ethics approval was not required, though the National Board of Health approved chart review. In Sweden the study was approved by the regional ethics committee, Karolinska Institute, Stockholm, and participants gave written informed consent. In the UK, the GPRD Group has obtained ethical approval from a multicentre research ethics committee (MREC) for all purely observational research using GPRD data. Individual studies must be granted approval by an Independent Scientific Advisory Committee (ISAC). This study received ISAC approval (protocol No 10_058).

  • Data sharing: No additional data available.

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