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. 2014 Jan 3;9(1):e82222.
doi: 10.1371/journal.pone.0082222. eCollection 2014.

Guillain-Barré syndrome and adjuvanted pandemic influenza A (H1N1) 2009 vaccines: a multinational self-controlled case series in Europe

Silvana Romio  1 , Daniel Weibel  2 , Jeanne P Dieleman  1 , Henning K Olberg  3 , Corinne S de Vries  4 , Cormac Sammon  4 , Nick Andrews  5 , Henrik Svanström  6 , Ditte Mølgaard-Nielsen  6 , Anders Hviid  6 , Maryse Lapeyre-Mestre  7 , Agnès Sommet  7 , Christel Saussier  8 , Anne Castot  9 , Harald Heijbel  10 , Lisen Arnheim-Dahlström  11 , Par Sparen  11 , Mees Mosseveld  1 , Martijn Schuemie  1 , Nicoline van der Maas  12 , Bart C Jacobs  13 , Tuija Leino  14 , Terhi Kilpi  14 , Jann Storsaeter  15 , Kari Johansen  16 , Piotr Kramarz  16 , Jan Bonhoeffer  17 , Miriam C J M Sturkenboom  1
Affiliations

Guillain-Barré syndrome and adjuvanted pandemic influenza A (H1N1) 2009 vaccines: a multinational self-controlled case series in Europe

Silvana Romio et al. PLoS One. .

Abstract

Background: The risk of Guillain-Barré syndrome (GBS) following the United States' 1976 swine flu vaccination campaign in the USA led to enhanced active surveillance during the pandemic influenza (A(H1N1)pdm09) immunization campaign. This study aimed to estimate the risk of GBS following influenza A(H1N1)pdm09 vaccination.

Methods: A self-controlled case series (SCCS) analysis was performed in Denmark, Finland, France, Netherlands, Norway, Sweden, and the United Kingdom. Information was collected according to a common protocol and standardised procedures. Cases classified at levels 1-4a of the Brighton Collaboration case definition were included. The risk window was 42 days starting the day after vaccination. Conditional Poisson regression and pooled random effects models estimated adjusted relative incidences (RI). Pseudo likelihood and vaccinated-only methods addressed the potential contraindication for vaccination following GBS.

Results: Three hundred and three (303) GBS and Miller Fisher syndrome cases were included. Ninety-nine (99) were exposed to A(H1N1)pdm09 vaccination, which was most frequently adjuvanted (Pandemrix and Focetria). The unadjusted pooled RI for A(H1N1)pdm09 vaccination and GBS was 3.5 (95% Confidence Interval (CI): 2.2-5.5), based on all countries. This lowered to 2.0 (95% CI: 1.2-3.1) after adjustment for calendartime and to 1.9 (95% CI: 1.1-3.2) when we accounted for contra-indications. In a subset (Netherlands, Norway, and United Kingdom) we further adjusted for other confounders and there the RI decreased from 1.7 (adjusted for calendar month) to 1.4 (95% CI: 0.7-2.8), which is the main finding.

Conclusion: This study illustrates the potential of conducting European collaborative vaccine safety studies. The main, fully adjusted analysis, showed that the RI of GBS was not significantly elevated after influenza A(H1N1)pdm09 vaccination (RI = 1.4 (95% CI: 0.7-2.8). Based on the upper limits of the pooled estimate we can rule out with 95% certainty that the number of excess GBS cases after influenza A(H1N1)pdm09 vaccination would be more than 3 per million vaccinated.

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Conflict of interest statement

Competing Interests: Silvana Romio, Daniel Weibel, Henning K Olberg, Nick Andrews, Henrik Svanström, Ditte Mølgaard-Nielsen, Anders Hviid, Maryse Lapeyre, Agnès Sommet, Christel Saussier, Anne Castot, Harald Heijbel, Lisen Arnheim-Dahlström, Mees Mosseveld, Nicoline van der Maas, Bart C Jacobs, Tuija Leino, Jann Storsaeter, Kari Johansen, and Piotr Kramarz have no conflicts of interest. Jeanne P Dieleman has been involved in studies for pharmaceutical companies (i.e., GSK, Sanofi, Astra-Zeneca, Pfizer). None of these had any conflict with the present study. The affiliation (i.e. University of Bath) of Corinne S de Vries and Cormac Sammon has research and consulting contracts in place with Novartis vaccines and with GSK pharmaceuticals. The authors do not personally benefit from these contracts; all financial compensation is to the University of Bath and not to the authors. Martijn Schuemie was employed at the Erasmus University Medical Center, Rotterdam at the time of the study. Since January 1st 2013 (after completion of the study), he is employed at Janssen R&D. Terhi Kilpi is a principal investigator of a nationwide Finish effectiveness study of the 10-valent pneumococcal conjugate vaccine, a collaborative study, for which her institute has received funding from GSK. Par Sparen received a grant from Glaxo Smith Kline in 2010 to for a retrospective, observational register based cohort study to evaluate the safety of GSK Biological's H1N1 pandemic vaccine administered in Sweden according to local vaccination policy. Miriam CJM Sturkenboom: is head of a research group that occasionally conducts research for pharmaceutical companies including Pfizer, EliLilly, Boehringer, AstraZeneca and Novartis. None was related to this topic.This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1
Figure 1. Flowchart of case inclusion.
Figure 2
Figure 2. Inclusion of GBS cases (DK, FI, FR, NL, NO, SE, UK), influenza A(H1N1)pdm09 immunization period (influenza A(H1N1)vac), and percentage of flu positive cases among all tested per country (Flu pos. DK, …, Flu pos. UK; Source: ECDC 2011) over total study period.
Figure 3
Figure 3. Inclusion of vaccinated cases (% of population) over study period.
See this image and copyright information in PMC

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