Current information on narcolepsy in the temporal context of A/H1N1 influenza vaccination

Current state of knowledge in brief

With the information from the Swedish Medicines Agency Läkemedelsverket on 18 August 2010 about cases of narcolepsy in children and adolescents after Pandemrix vaccination, attention was drawn for the first time to a possible link between this vaccine and the first development of narcolepsy.

In addition to the results from Sweden, the results of further retrospective epidemiological studies in Finland, Ireland, France and England indicate a risk of narcolepsy in children and adolescents as well as young adults due to Pandemrix. In France, a signal was also detected in adults, which must be confirmed by further investigations.

The human vaccine Pandemrix was approved in the EU in September 2009 to protect against influenza caused by the H1N1A/v influenza strain. During the 2009/2010 influenza pandemic, around 30.8 million people in the EU were vaccinated with Pandemrix. Currently the vaccine is no longer used in the EU. A recommendation of the European Medicines Agency (EMA) of July 2011 to restrict the use of the vaccine to persons under 20 years of age is not relevant for Germany, as the Standing Vaccination Commission STIKO does not recommend Pandemrix but a trivalent vaccine to protect against the (seasonal) viral flu (see 'Regulatory measures').

Reports of suspected cases of narcolepsy at the Paul Ehrlich Institute (as of October 2016)

By the end of October 2016, the Paul Ehrlich Institute (PEI) from Germany had received 86 reports of suspected narcolepsy cases (44 female and 42 male patients) after the Pandemrix vaccination within the framework of spontaneous registration in accordance with the Infection Protection Act (IfSG). Affected are 37 children and adolescents aged between seven and 17 years (19 female, 18 male patients) and 48 adults (24 women, 24 men). When reporting, it is unclear whether the 18th year of age was completed.

Against the background of the signal observed in Sweden and Finland, these reports were the reason for further pharmaco-epidemiological studies in Germany.

European Studies

In the meantime, the results of several European epidemiological studies on the potential association between Pandemrix and narcolepsy are available [1-18].

In summary, they indicate a significantly increased risk of narcolepsy after Pandemrix vaccination in children, adolescents and adults compared to non-vaccinated children of the same age.

Based on the results of the epidemiological studies, 2-6 additional cases of narcolepsy per 100,000 vaccinated doses of Pandemrix in children and adolescents and 0.6-1 additional cases per 100,000 vaccinated doses of Pandemrix in adults must be assumed.

Disease

Narcolepsy is a rare sleep-wake disorder characterized by the core symptoms of daytime sleepiness and cataplexy (sudden loss of muscle tone due to strong emotions). Usually the disease affects 26 to 50 out of 100,000 people. A prospective multicentre study conducted in 2002 by the Paediatrics Working Group of the German Society for Sleep Research and Sleep Medicine (DGSM) and the Survey Unit for Rare Paediatric Diseases in Germany (ESPED) [19][20], found an incidence of narcolepsy in Germany of 0.12 per 100,000 children and adolescents under 18 years of age per year, although not all cases may have been recorded, as the survey only covered paediatric hospitals.

The cause of the disease is unknown. In a few cases narcolepsy occurs after damage to certain regions of the brain (brain stem and diencephalon). Multifactorial causes with disturbances in the cholinergic and noradrenergic system and a reduction of hypocretin-containing neurons in the dorsolateral hypothalamus are assumed. 98 percent of Caucasian narcolepsy patients have the HLA-DRB1*1501-DQB1*0602 type. In the normal population, this HLA type accounts for 25 to 35 percent [21]. This HLA type thus has a high sensitivity but low specificity. A genome-wide association study suggests further genetic polymorphisms [22]. More recently, autoimmune processes have been increasingly discussed as causes, among other factors [23] [24] [25]. Regulatory measures (limitation of the scope of application) were taken in response to the findings of epidemiological studies on pandemic matrix vaccination and narcolepsy.

Pathomechanism

Activation of the transcription of the gene of the transcription factor Nrf2 after α-tocopherol addition

In their own research, scientists from the Paul Ehrlich Institute have discovered an activation of the transcription of the gene of the transcription factor Nrf2 after α-tocopherol addition to human neuronal cells in vitro. α-tocopherol or vitamin E, a component of AS03, the immune booster (adjuvant) present in the vaccine Pandemrix [26]. Nrf2 activation was associated with an increase in the formation of hypocretin and a subunit of the proteasome in these cells. Furthermore, the sensitivity of α-tocopherol-treated neuronal cells to the stimuli causing cell death (apoptosis) was increased. This is consistent with the assumption, currently discussed as the cause of narcolepsy, that certain neuronal cells in the brain of affected individuals die. However, it is unknown whether cell death sensitization of neuronal cells relevant for the development of narcolepsy by α-tocopherol in the brain takes place in vivo after vaccination. In vivo results are necessary for further conclusions.

Immune response against influenza nucleoprotein

In a multinational experimental study on the pathomechanism [27][28] a group around Soheil Ahmed investigated the following:

The sleep disorder narcolepsy is associated with the HLA-DQB1*0602 haplotype, vaccination with Pandemrix (an AS03-adjuvanted pandemic influenza vaccine) and possibly with infection by the influenza virus strain A/H1N1pmd, which was responsible for the last influenza pandemic in autumn/winter 2009/2010. In contrast, very few cases have been reported after vaccination with Focetria (a pandemic influenza vaccine produced and adjuvanted differently). Differences between these two vaccines could therefore explain the association between Pandemrix vaccination and narcolepsy. The scientists were able to identify an influenza nucleoprotein A peptide that resembles a fragment of the first extracellular domain of hypocretin receptor 2.

A significantly higher percentage of sera from Finnish HLA-DQB1*0602 haplotype-positive patients with narcolepsy after Pandemrix vaccination contained antibodies against hypocretin receptor 2 compared to control sera from persons who did not develop narcolepsy after infection with Influenza A (H1N1) or vaccination with Focetria. Antibodies of patients with narcolepsy after vaccination with Pandemrix reacted with both influenza nucleoprotein and hypocretin receptor 2, and mass spectrometry showed that Focetria contains 72.7% less influenza nucleoprotein compared to Pandemrix. This is consistent with the observation that no sustained immune response against influenza nucleoprotein could be detected in sera of control persons who did not develop narcolepsy after vaccination with Focetria. The differences in nucleoprotein content and immune response could explain the association with Pandemrix.

Further research needed

Despite the considerable progress made so far in deciphering the pathomechanism, further research is needed to elucidate the molecular processes involved in the development of narcolepsy after vaccination with Pandemrix.

 Regulatory measures

As early as July 2011, the European Medicines Agency EMA [29] announced, against the background of the study results from Finland and Sweden determined at that time, that it recommends using the pandemic vaccine Pandemrix in persons under 20 years of age only if a trivalent seasonal vaccine is not available. For Germany, this recommendation is currently of no relevance, since - as in the previous season - trivalent seasonal influenza vaccines are available and recommended by the Standing Commission on Vaccination (STIKO).

Note

The Paul-Ehrlich-Institut has published a review article on the topic of "Narcolepsy after vaccination against pandemic influenza A/H1N1/v" in issue III/2013 of the journal "Schlaf" [30].

References

• [1] Occurrence of narcolepsy with cataplexy among children and adolescents in relation to the H1N1 pandemic and Pandemrix vaccinations. Results of a case inventory study by the MPA in Sweden during 2009-2010.
• [2] Svenska Läkemedelsverket. 26-Mar-2013.
• [3] Szakacs A, Darin N, Hallbook T. Increased childhood incidence of narcolepsy in western Sweden after H1N1 influenza vaccination. Neurology 2013 Apr 2;80(14):1315-21.
• [4] Kansallisen narkolepsia - työryhmän loppuraportti. 31-Aug-2011.
• [5] Association between Pandemrix and narcolepsy confirmed among Finnish children and adolescents. National Institute for Health and Welfare, Finland. 1-Sep-2011.
• [6] National Narcolepsy Task force Interim Report. National Institute for Health and Welfare, Finland. 31-Jan-2011.
• [7] Nohynek H, Jokinen J, Partinen M, Vaarala O, Kirjavainen T et al. AS03 adjuvanted AH1N1 vaccine associated with an abrupt increase in the incidence of childhood narcolepsy in Finland. PLOS one 2012; 7(3); e33536. doi:10.1371/journal.phone.0033536
• [8] THL: Press release 23-May-2013.
• [9] THL: Press release 18-June-2014
• [10] National Narcolepsy Study Steering Committee. Investigation of an increase in the incidence of narcolepsy in children and adolescents in 2009 and 2010.
• [11] Pressemitteilung zum Final Report of the National Narcolepsy Study Steering Committee
• [12] European Centre for Disease Control and Prevention
• [13] Wijnans L1, Lecomte C, de Vries C, Weibel D, Sammon C, Hviid A, Svanström H, Mølgaard-Nielsen D, Heijbel H, Dahlström LA, Hallgren J, Sparen P, Jennum P, Mosseveld M, Schuemie M, van der Maas N, Partinen M, Romio S, Trotta F, Santuccio C, Menna A, Plazzi G, Moghadam KK, Ferro S, Lammers GJ, Overeem S, Johansen K, Kramarz P, Bonhoeffer J, Sturkenboom MC. The incidence of narcolepsy in Europe: before, during, and after the influenza A(H1N1)pdm09 pandemic and vaccination campaigns. Vaccine. 2013 Feb 6;31(8):1246-54. doi: 10.1016/j.vaccine.2012.12.015. Epub 2012 Dec 16.
• [14] Etude NarcoFlu-VF (NarcoFlu VAESCO-France): Grippe, vaccination antigrippale et narcolepsie : contribution française à l’étude cas-témoins européenne. Août 2012. (20/09/2012), Service de pharmacologie (INSERM CIC-P 0005 Pharmaco-Epidémiologie), Université Bordeaux Segalen – CHU de Bordeaux
• [15] Dauvilliers Y ; 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. doi: 10.1093/brain/awt187
• [16] Miller E, Andrews N, Stellitano L, Stowe J, Winstone AM, Shneerson J, Verity C. Risk of narcolepsy in children receiving an AS03 adjuvanted AH1N1 (2009) influenza vaccine : Retrospective analysis of cases diagnosed by sleep centres in England. BMJ 2013 Feb 26; 346: f794. doi: 10.1136/bmj.f794.
• [17] Stowe J, Andrews N, Kosky C, Dennis G, Eriksson S, Hall A, Leschziner G, Reading P, Shneerson JM, Donegan K, Miller E. Risk of Narcolepsy after AS03 Adjuvanted Pandemic A/H1N1 2009 Influenza Vaccine in Adults: A Case-Coverage Study in England. Sleep. 2016 May 1;39(5):1051-7. DOI: 10.5665/sleep.5752
• [18] Heier MS, Gautvik KM, Wannag E, Bronder KH, Midtlyng E, Kamaleri Y, et al. Incidence of narcolepsy in Norwegian children and adolescents after vaccination against H1N1 influenza A. Sleep Med 2013 Jun 14.
• [19] Berner R et al.: Erhebungseinheit für seltene pädiatrische Erkrankungen in Deutschland (ESPED). Monatsschr Kinderheilk. 2004;152:7779
• [20] Handwerker G: Narkolepsie im Kindes- und Jugendalter. Monatsschr Kinderheilk. 2005; 2:153
• [21] Leitlinien der Deutschen Gesellschaft für Neurologie; AWMF-Leitlinien-Register Nr. 030/056: "Narkolepsie"
• [22] Kawashima M et al.: Genomewide Association Analysis of Human Narcolepsy and a New Resistance Gene. Am J Hum Genet. 2006 August; 79(2): 252–263
• [23] Smith AJ et al.: A functional autoantibody in narcolepsy. Lancet. 2004;364(9451): 2122-2124
• [24] Fontana A: Narcolepsy: autoimmunity, effector T cell activation due to infection, or T cell independent, major histocompatibility complex class II induced neuronal loss? Brain. 2010;133(Pt 5):1300-1311
• [25] Longstreth WT et al.: The Epidemiology of Narcolepsy. Sleep. 2007;30:13-26
• [26] Masoudi S et al.: The adjuvant component α tocopherol triggers via modulation of Nrf2 the expression and turnover of hypocretin in vitro and its implication to the development of narcolepsy. Vaccine. 2014 May 23;32(25):2980-8. doi: 10.1016/j.vaccine.2014.03.085. Epub 2014 Apr 14.
• [27] Ahmed SS, Volkmuth W, Duca J, Corti L, Pallaoro M, Pezzicoli A, Karle A, Rigat F, Rappuoli R, Narasimhan V, Julkunen I, Vuorela A, Vaarala O, Nohynek H, Pasini FL, Montomoli E, Trombetta C, Adams CM, Rothbard J, Steinman L. Antibodies to influenza nucleoprotein cross-react with human hypocretin receptor 2. Sci Transl Med. 2015 Jul 1;7(294):294ra105. DOI: 10.1126/scitranslmed.aab2354.
• [28] Ahmed SS, Steinman L (2016): Mechanistic insights into influenza vaccine-associated narcolepsy, Human Vaccines & Immunotherapeutics, DOI: 10.1080/21645515.2016.1171439
• [29] Empfehlung der Europäischen Arzneimittelagentur EMA, die Anwendung des pandemischen Impfstoffs Pandemrix bei Personen unter 20 Jahren einzuschränken.
• [30] Oberle D, Mayer G, Keller-Stanislawski B: Narkolepsie nach Impfung gegen die pandemische Influenza A/H1N1/v?. Schlaf 2013; 2 3:154-160

Translated Version - Original here