Update on narcolepsy cases associated with Pandemrix vaccination in 2009 in the Netherlands

ECDC comment

​In November 2014, the Pharmacovigilance Centre of Netherlands (Lareb) provided an updated overview of Dutch cases of narcolepsy reported to have a link to Pandemrix.

In November 2014, the Pharmacovigilance Centre of Netherlands (Lareb) provided an updated overview of Dutch cases of narcolepsy reported to have a link to Pandemrix, one of the vaccines used in the vaccination campaign against the 2009 influenza A(H1N1) pandemic. The Netherlands offered Pandemrix to children 6 months to 5 years old as part of large national vaccination campaigns, while older children were offered Focetria. In total 588,750 children received one dose of Pandemrix, while 490,584  (83%) received two doses as recommended by the Dutch authorities.
 
This update provides information on 20 cases of narcolepsy (1) reported to Lareb that were closely linked in time to the pandemic influenza vaccination. Of those, 3 cases were reported in 2011, another 4 cases in May 2014 and finally 13  cases have been reported since May 2014, although the onset of disease was significantly earlier.
 
All of the reported cases, with one exception, are children that received the vaccine before 5 years of age. For three of the cases onset of symptoms started before vaccination while for the other seventeen the onset varied from a few days to three years post vaccination. In its conclusions, Lareb makes a note of the unexpected young age of these cases, as it is usually only in adolescence when narcolepsy starts to occur, or is first diagnosed.
 
A causative mechanism between vaccination with Pandemrix  and an increased risk of narcolepsy has not been established, although a T-cell-mediated autoimmune reaction is suspected. The respective roles of the AS03 adjuvant, the vaccine antigens, the circulating 2009 pandemic influenza A(H1N1) viruses, or possibly even other environmental factors in this process is currently unclear.
 
The report notes that background incidence data on narcolepsy among young children in the Netherlands are largely missing, and recommends further research into the causal association between Pandemrix and narcolepsy.

ECDC comment

The Netherlands Pharmacovigilance Centre Lareb collects and analyses reports of adverse reactions of medicines and vaccines. Healthcare professionals, patients and also manufacturers can report an adverse reaction. Lareb also sends anonymised copies of the reports to the European Medicines Agency and the World Health Organization.
 
The recent Lareb report is interesting from several aspects; the affected age group is younger than reported elsewhere where the use of Pandemrix was associated with cases of narcolepsy, for example, in Finland, Norway and Sweden (2-10), and significant delay in reporting is observed. These observations could possibly be explained by the significant uptake overall of the recommended Pandemrix vaccination,  the use in a two-dose schedule (83%) rather than a one-dose schedule as in most other countries, and the difficulty in diagnosing narcolepsy in the very young. Further investigations are needed to establish the potential respective contributions of these factors.
 
It is also of great interest that there are no reported cases in the older age group (> 5 years) that received another adjuvanted pandemic vaccine Focetria. Both the adjuvant and the antigen preparation differ between the Pandemrix and Focetria vaccines. In Pandemrix the adjuvant is squalene combined with α-tocopherol and in Focetria the adjuvant is squalene only. Further, Pandemrix is a split-influenza vaccine while Focetria is a subunit vaccine resulting in different antigen compositions, except for the hemagglutinin content that is standardized to 15 μg/dose. It has been pointed out that the role of the adjuvant and the antigens should be carefully investigated (11).
 
ECDC established enhanced monitoring of vaccine safety for the 2009 pandemic vaccines through the VAESCO network of researchers in nine EU/EEA Member States. In this project the background rates of narcolepsy were investigated for all age groups including children <5 years covering also data from the Netherlands. In the Dutch IPCI general practitioners database covering ~1 million individuals, a very small peak of narcolepsy cases was observed in 2009 among the age groups 5-19 and 20-59 years of age, with a return to baseline in 2010. No similar peak was observed among children under 5 years of age, however, although it should be noted that a larger sample size and extended monitoring over a longer time period would have been advantageous for such a rare disease as narcolepsy.

The cause of narcolepsy was shown in 2000 to be hypocretin deficiency (12-13). Hypocretin is a neurotransmitter produced by 70,000 – 90,000 neurons located in the hypothalamus. However, the mechanism by which Pandemrix® vaccination could have triggered narcolepsy remains unclear. The main hypothesis is that it was through T-cell mediated autoimmunity, as mentioned above. The first scientific publication that suggested that T-cells in affected individuals recognize the protein hypocretin by molecular mimicry between hypocretin and the hemagglutinin molecule was published in 2013 (15). However, this first publication was formally withdrawn since data could not be reproduced. Further studies of possible mechanisms are on-going (16).

The Pandemrix vaccine is no longer used in the EU.

References

  1. Poli F, Overeem S, Lammers GJ, Plazzi G, Lecendreux M, Bassetti CL, Dauvilliers Y, Keene D, Khatami R, Li Y, Mayer G, Nohynek H, Pahud B, Paiva T, Partinen M, Scammell TE, Shimabukuro T, Sturkenboom M, van Dinther K, Wiznitzer M, Bonhoeffer J Narcolepsy as an adverse event following immunization: case definition and guidelines for data collection, analysis and presentation. Vaccine. 2013 Jan 30;31(6):994-1007.
  2. Dauvilliers Y, Arnulf I, Lecendreux M, Monaca Charley C, Franco P, Drouot X, d'Ortho MP, Launois S, Lignot S, Bourgin P, Nogues B, Rey M, Bayard S, Scholz S, Lavault S, Tubert-Bitter P, Saussier C, Pariente A; Narcoflu-VF study group. Increased risk of narcolepsy in children and adults after pandemic H1N1 vaccination in France. Brain. 2013 Aug;136(Pt 8):2486-96.
  3. Heier MS, Gautvik KM, Wannag E, Bronder KH, Midtlyng E, Kamaleri Y, Storsaeter J. Incidence of narcolepsy in Norwegian children and adolescents after vaccination against H1N1 influenza A. Sleep Med. 2013 Sep;14(9):867-71.
  4. Miller E, Andrews N, Stellitano L, Stowe J, Winstone AM, Shneerson J, Verity C. Risk of narcolepsy in children and young people receiving AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine: retrospective analysis. BMJ. 2013 Feb 26;346
  5. Winstone AM, Stellitano L, Verity C, Andrews N, Miller E, Stowe J, Shneerson J. Clinical features of narcolepsy in children vaccinated with AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine in England. Dev Med Child Neurol. 2014 Nov;56(11):1117-23
  6. Nohynek H, Jokinen J, Partinen M, Vaarala O, Kirjavainen T, Sundman J, Himanen SL, Hublin C, Julkunen I, Olsén P, Saarenpää-Heikkilä O, Kilpi T.
  7. AS03 adjuvanted AH1N1 vaccine associated with an abrupt increase in the incidence of childhood narcolepsy in Finland. PLoS One. 2012;7(3):
  8. Pizza F, Peltola H, Sarkanen T, Moghadam KK, Plazzi G, Partinen M. Childhood narcolepsy with cataplexy: comparison between post-H1N1 vaccination and sporadic cases. Sleep Med. 2014 Feb;15(2):262-5.
  9. O'Flanagan D1, Barret AS, Foley M, Cotter S, Bonner C, Crowe C, Lynch B, Sweeney B, Johnson H, McCoy B, Purcell E.
  10. Investigation of an association between onset of narcolepsy and vaccination with pandemic influenza vaccine, Ireland April 2009-December 2010. Euro Surveill. 2014 May 1;19(17):15-25.
  11. Persson I, Granath F, Askling J, Ludvigsson JF, Olsson T, Feltelius N. Risks of neurological and immune-related diseases, including narcolepsy, after vaccination with Pandemrix: a population- and registry-based cohort study with over 2 years of follow-up. J Intern Med. 2014 Feb;275(2):172-90.
  12. Johansen K. The roles of influenza virus antigens and the AS03 adjuvant in the 2009 pandemic vaccine associated with narcolepsy needs further investigation. Dev Med Child Neurol. 2014 Nov;56(11):1041-2.
  13. Peyron C, Faraco J, Rogers W, Ripley B, Overeem S, Charnay Y, Nevsimalova S, Aldrich M, Reynolds D, Albin R, Li R, Hungs M, Pedrazzoli M, Padigaru M, Kucherlapati M, Fan J, Maki R, Lammers GJ, Bouras C, Kucherlapati R, Nishino S, Mignot E. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med. 2000 Sep;6(9):991-7
  14. Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E. Hypocretin (orexin) deficiency in human narcolepsy. Lancet. 2000 Jan 1;355(9197):39-40
  15. Partinen M, Kornum BR, Plazzi G, Jennum P, Julkunen I, Vaarala O. Narcolepsy as an autoimmune disease: the role of H1N1 infection and vaccination. Lancet Neurol. 2014 Jun;13(6):600-13.
  16. De la Herrán-Arita AK, Kornum BR, Mahlios J, Jiang W, Lin L, Hou T, Macaubas C, Einen M, Plazzi G, Crowe C, Newell EW, Davis MM, Mellins ED, Mignot E.
  17. CD4+ T cell autoimmunity to hypocretin/orexin and cross-reactivity to a 2009 H1N1 influenza A epitope in narcolepsy. Sci Transl Med. 2013 Dec 18;5(216):216ra176
  18. De la Herrán-Arita AK, Kornum BR, Mahlios J, Jiang W, Lin L, Hou T, Macaubas C, Einen M, Plazzi G, Crowe C, Newell EW, Davis MM, Mellins ED, Mignot E.
  19. Retraction of the research article: "CD4⁺ T cell autoimmunity to hypocretin/orexin and cross-reactivity to a 2009 H1N1 influenza A epitope in narcolepsy". Sci Transl Med. 2014 Jul 30;6(247):247

Incidence of narcolepsy diagnosis in the NL-IPCI database by age and year  per 100 000 PY. Population covered in this database ~1 million.
The cause of narcolepsy was shown in 2000 to be hypocretin deficiency (12-13). Hypocretin is a neurotransmitter produced by 70,000 – 90,000 neurons located in the hypothalamus. However, the mechanism by which Pandemrix® vaccination could have triggered narcolepsy remains unclear. The main hypothesis is that it was through T-cell mediated autoimmunity, as mentioned above. The first scientific publication that suggested that T-cells in affected individuals recognize the protein hypocretin by molecular mimicry between hypocretin and the hemagglutinin molecule was published in 2013 (15). However, this first publication was formally withdrawn since data could not be reproduced. Further studies of possible mechanisms are on-going (16).
 
The Pandemrix vaccine is no longer used in the EU.
 Read more:VAESCO report in briefEnhanced monitoring of vaccine safety for 2009 pandemic vaccinesReferences:
1. Poli F, Overeem S, Lammers GJ, Plazzi G, Lecendreux M, Bassetti CL, Dauvilliers Y, Keene D, Khatami R, Li Y, Mayer G, Nohynek H, Pahud B, Paiva T, Partinen M, Scammell TE, Shimabukuro T, Sturkenboom M, van Dinther K, Wiznitzer M, Bonhoeffer J Narcolepsy as an adverse event following immunization: case definition and guidelines for data collection, analysis and presentation. Vaccine. 2013 Jan 30;31(6):994-1007.2. Dauvilliers Y, Arnulf I, Lecendreux M, Monaca Charley C, Franco P, Drouot X, d'Ortho MP, Launois S, Lignot S, Bourgin P, Nogues B, Rey M, Bayard S, Scholz S, Lavault S, Tubert-Bitter P, Saussier C, Pariente A; Narcoflu-VF study group. Increased risk of narcolepsy in children and adults after pandemic H1N1 vaccination in France. Brain. 2013 Aug;136(Pt 8):2486-96.3. Heier MS, Gautvik KM, Wannag E, Bronder KH, Midtlyng E, Kamaleri Y, Storsaeter J. Incidence of narcolepsy in Norwegian children and adolescents after vaccination against H1N1 influenza A. Sleep Med. 2013 Sep;14(9):867-71.4. Miller E, Andrews N, Stellitano L, Stowe J, Winstone AM, Shneerson J, Verity C. Risk of narcolepsy in children and young people receiving AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine: retrospective analysis. BMJ. 2013 Feb 26;3465. Winstone AM, Stellitano L, Verity C, Andrews N, Miller E, Stowe J, Shneerson J. Clinical features of narcolepsy in children vaccinated with AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine in England. Dev Med Child Neurol. 2014 Nov;56(11):1117-236. Nohynek H, Jokinen J, Partinen M, Vaarala O, Kirjavainen T, Sundman J, Himanen SL, Hublin C, Julkunen I, Olsén P, Saarenpää-Heikkilä O, Kilpi T.AS03 adjuvanted AH1N1 vaccine associated with an abrupt increase in the incidence of childhood narcolepsy in Finland. PLoS One. 2012;7(3):7. Pizza F, Peltola H, Sarkanen T, Moghadam KK, Plazzi G, Partinen M. Childhood narcolepsy with cataplexy: comparison between post-H1N1 vaccination and sporadic cases. Sleep Med. 2014 Feb;15(2):262-5.8. O'Flanagan D1, Barret AS, Foley M, Cotter S, Bonner C, Crowe C, Lynch B, Sweeney B, Johnson H, McCoy B, Purcell E.9. Investigation of an association between onset of narcolepsy and vaccination with pandemic influenza vaccine, Ireland April 2009-December 2010. Euro Surveill. 2014 May 1;19(17):15-25.10. Persson I, Granath F, Askling J, Ludvigsson JF, Olsson T, Feltelius N. Risks of neurological and immune-related diseases, including narcolepsy, after vaccination with Pandemrix: a population- and registry-based cohort study with over 2 years of follow-up. J Intern Med. 2014 Feb;275(2):172-90.11. Johansen K. The roles of influenza virus antigens and the AS03 adjuvant in the 2009 pandemic vaccine associated with narcolepsy needs further investigation. Dev Med Child Neurol. 2014 Nov;56(11):1041-2.12. Peyron C, Faraco J, Rogers W, Ripley B, Overeem S, Charnay Y, Nevsimalova S, Aldrich M, Reynolds D, Albin R, Li R, Hungs M, Pedrazzoli M, Padigaru M, Kucherlapati M, Fan J, Maki R, Lammers GJ, Bouras C, Kucherlapati R, Nishino S, Mignot E. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med. 2000 Sep;6(9):991-713. Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E. Hypocretin (orexin) deficiency in human narcolepsy. Lancet. 2000 Jan 1;355(9197):39-4014. Partinen M, Kornum BR, Plazzi G, Jennum P, Julkunen I, Vaarala O. Narcolepsy as an autoimmune disease: the role of H1N1 infection and vaccination. Lancet Neurol. 2014 Jun;13(6):600-13.15. De la Herrán-Arita AK, Kornum BR, Mahlios J, Jiang W, Lin L, Hou T, Macaubas C, Einen M, Plazzi G, Crowe C, Newell EW, Davis MM, Mellins ED, Mignot E.CD4+ T cell autoimmunity to hypocretin/orexin and cross-reactivity to a 2009 H1N1 influenza A epitope in narcolepsy. Sci Transl Med. 2013 Dec 18;5(216):216ra17616. De la Herrán-Arita AK, Kornum BR, Mahlios J, Jiang W, Lin L, Hou T, Macaubas C, Einen M, Plazzi G, Crowe C, Newell EW, Davis MM, Mellins ED, Mignot E.Retraction of the research article: "CD4⁺ T cell autoimmunity to hypocretin/orexin and cross-reactivity to a 2009 H1N1 influenza A epitope in narcolepsy". Sci Transl Med. 2014 Jul 30;6(247):247rt1
 This Public Health Development was prepared by Kari Johansen and Pasi Penttinen. Comments on the content are welcome and should be sent to IRV@ecdc.europa.eu