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. 2018 Oct 1;36(41):6202-6211.
doi: 10.1016/j.vaccine.2018.08.008. Epub 2018 Aug 16.

Narcolepsy and adjuvanted pandemic influenza A (H1N1) 2009 vaccines - Multi-country assessment

Daniel Weibel  1 , Miriam Sturkenboom  2 , Steven Black  3 , Maria de Ridder  4 , Caitlin Dodd  4 , Jan Bonhoeffer  5 , Ann Vanrolleghem  4 , Nicoline van der Maas  6 , Gert Jan Lammers  7 , Sebastiaan Overeem  8 , Angela Gentile  9 , Norberto Giglio  9 , Vanesa Castellano  9 , Jeffrey C Kwong  10 , Brian J Murray  11 , Karen Cauch-Dudek  10 , Diana Juhasz  10 , Michael Campitelli  10 , Alexandre N Datta  12 , Ulf Kallweit  13 , Wan-Ting Huang  14 , Yu-Shu Huang  15 , Chung-Yao Hsu  16 , Hsi-Chung Chen  17 , Maria Giner-Soriano  18 , Rosa Morros  18 , Carles Gaig  19 , Ester Tió  20 , Silvia Perez-Vilar  21 , Javier Diez-Domingo  22 , Francisco Javier Puertas  23 , Lawrence W Svenson  24 , Salaheddin M Mahmud  25 , Bruce Carleton  26 , Monika Naus  26 , Lisen Arnheim-Dahlström  27 , Lars Pedersen  28 , Frank DeStefano  29 , Tom T Shimabukuro  29
Affiliations

Narcolepsy and adjuvanted pandemic influenza A (H1N1) 2009 vaccines - Multi-country assessment

Daniel Weibel et al. Vaccine. .

Abstract

Background: In 2010, a safety signal was detected for narcolepsy following vaccination with Pandemrix, an AS03-adjuvanted monovalent pandemic H1N1 influenza (pH1N1) vaccine. To further assess a possible association and inform policy on future use of adjuvants, we conducted a multi-country study of narcolepsy and adjuvanted pH1N1 vaccines.

Methods: We used electronic health databases to conduct a dynamic retrospective cohort study to assess narcolepsy incidence rates (IR) before and during pH1N1 virus circulation, and after pH1N1 vaccination campaigns in Canada, Denmark, Spain, Sweden, Taiwan, the Netherlands, and the United Kingdom. Using a case-control study design, we evaluated the risk of narcolepsy following AS03- and MF59-adjuvanted pH1N1 vaccines in Argentina, Canada, Spain, Switzerland, Taiwan, and the Netherlands. In the Netherlands, we also conducted a case-coverage study in children born between 2004 and 2009.

Results: No changes in narcolepsy IRs were observed in any periods in single study sites except Sweden and Taiwan; in Taiwan incidence increased after wild-type pH1N1 virus circulation and in Sweden (a previously identified signaling country), incidence increased after the start of pH1N1 vaccination. No association was observed for Arepanrix-AS03 or Focetria-MF59 adjuvanted pH1N1 vaccines and narcolepsy in children or adults in the case-control study nor for children born between 2004 and 2009 in the Netherlands case-coverage study for Pandemrix-AS03.

Conclusions: Other than elevated narcolepsy IRs in the period after vaccination campaigns in Sweden, we did not find an association between AS03- or MF59-adjuvanted pH1N1 vaccines and narcolepsy in children or adults in the sites studied, although power to evaluate the AS03-adjuvanted Pandemrix brand vaccine was limited in our study.

Keywords: AS03; Adjuvant; MF59; Narcolepsy; Pandemic H1N1 influenza.

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Conflict of interest statement

6. Declaration of interests

Maria de Ridder, Caitlin Dodd, Jan Bonhoeffer, Ann Vanrolleghem, Gert Jan Lammers, Sebastiaan Overeem, Jeffrey C. Kwong, Karen Cauch-Dudek, Diana Juhasz, Michael Campitelli, Wan-Ting Huang, Maria Giner-Soriano, Rosa Morros, Carles Gaig, Ester Tió, Silvia Perez-Vilar, Javier Diez-Domingo, Lawrence W. Svenson, Bruce Carleton, Lisen Arnheim-Dahlström, Lars Pedersen, Frank DeStefano, Tom T. Shimabukuro, Nicoline van der Maas, Brian J. Murray, Alexandre N. Datta, Ulf Kallweit, Yu-Shu Huang, ChungYao Hsu, Hsi-Chung Chen, Francisco Javier Puertas, Monika Naus have no conflicts of interest.

Daniel Weibel, receives consultancy honoraria from GSK for a consultancy related to malaria vaccine implementation in Africa, independent from any flu vaccines, or any work related to this publication.

Angela Gentile, Norberto Giglio, Vanesa Castellano received research contracts from the U.S. Centers for Disease Control and Prevention independent from this study.

Miriam Sturkenboom received honorarium from GSK and post-authorisation safety studies (PASS) research contracts independent from this study.

Salaheddin M. Mahmud received research funding from GSK, Merck, Pfizer, Roche and Sanofi Pasteur and speaking and consulting fees from GSK and Sanofi not related to this study.

Steven Black reports contracts from U.S. Centers for Disease Control, during the conduct of the study; other from GSK Vaccines, outside the submitted work.

Figures

Fig. 1.
Fig. 1.
Two-stage hybrid approach for pooling case-control data from study sites. The two-stage hybrid approach pooled case-control data to estimate an odds ratio from European Union country sites and Argentina (β1). Odds ratios from Taiwan and Ontario (β2 and β3) were analyzed in a subsequent meta-analytic approach including the pooled odds ratio from European Union country sites and Argentina (Wk = weight related to estimate βk, being the reciprocal of its variance, ∑ = summation operator, β = meta-analysis result for the odds ratio).
Fig. 2.
Fig. 2.
Incidence rates of narcolepsy by age group and year from Sweden (left, a signaling country) and other study sites excluding Sweden (right, pooled data). Alberta, Canada (2003–2013); British Columbia, Canada (2003–2013), Manitoba, Canada (2003–2010); Catalonia, Spain (2007–2013), Valencia, Spain (2009–2013), Denmark (2003–2013), the Netherlands (2003–2013); Sweden (2003–2013), Taiwan (2003–2012), United Kingdom (2003–2013).
Fig. 3.
Fig. 3.
Odds ratios (OR) for narcolepsy and 95% confidence intervals (CI) by vaccine brands in the total period analysis for children (≤18 years) and adults (≥19 years). Arepanrix-AS03: case-control study in Ontario, Canada. Focetria-MF59: two-stage random effects meta-analysis of data from Taiwan, Argentina, the Netherlands, and Valencia and Catalonia, Spain. Pandemrix-AS03: case-coverage study in the Netherlands for children and case-control study in Valencia, Spain, for adults.
See this image and copyright information in PMC

References

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