A coordinated cross‐disciplinary research initiative to address an increased incidence of narcolepsy following the 2009–2010 Pandemrix vaccination programme in Sweden

Abstract

In response to the 2009-2010 influenza A(H1N1) pdm09 pandemic, a mass vaccination programme with the AS03-adjuvanted influenza A(H1N1) vaccine Pandemrix was initiated in Sweden. Unexpectedly, there were a number of narcolepsy cases amongst vaccinated children and adolescents reported. In this review, we summarize the results of a joint cross-disciplinary national research effort to investigate the adverse reaction signal from the spontaneous reporting system and to better understand possible causative mechanisms. A three-to fourfold increased risk of narcolepsy in vaccinated children and adolescents was verified by epidemiological studies. Of importance, no risk increase was observed for the other neurological and autoimmune diseases studied. Genetic studies confirmed the association with the allele HLA-DQB1*06:02, which is known to be related to sporadic narcolepsy. Furthermore, a number of studies using cellular and molecular experimental models investigated possible links between influenza vaccination and narcolepsy. Serum analysis, using a peptide microarray platform, showed that individuals who received Pandemrix exhibited a different epitope reactivity pattern to neuraminidase and haemagglutinin, as compared to individuals who were infected with H1N1. Patients with narcolepsy were also found to have increased levels of interferongamma production in response to streptococcusassociated antigens. The chain of patient-related events and the study results emerging over time were subjected to intense nationwide media attention. The importance of transparent communication and collaboration with patient representatives to maintain public trust in vaccination programmes is also discussed in the review. Organizational challenges due to this unexpected event delayed the initiation of some of the research projects, still the main objectives of this joint, cross-disciplinary research effort were reached, and important insights were acquired for future, similar situations in which a fast and effective task force may be required to evaluate vaccination-related adverse events.

Autoimmunity to hypocretin and molecular mimicry to flu antigens in Type 1 narcolepsy

“…Whereas genetic 1-6 epidemiological 7-11 and pathophysiological [12][13][14] studies implicate autoimmunity in response to flu infection in type 1 narcolepsy (T1N), a disease caused by hypocretin (HCRT) neuronal loss [15][16][17] the identity of the autoantigen is unknown.…”

Change in risk for narcolepsy over time and impact of definition of onset date following vaccination with AS03 adjuvanted pandemic A/H1N1 influenza vaccine (Pandemrix) during the 2009 H1N1 influenza pandemic

“…Unfortunately, no firm conclusions could be drawn because of a perceived underreporting of Norwegian influenza cases. A substudy within the MPA narcolepsy research program had the objective to elucidate the same questions, but incomplete information of influenza incidence also in Sweden rendered this unsuccessful …”

“…A substudy within the MPA narcolepsy research program had the objective to elucidate the same questions, but incomplete information of influenza incidence also in Sweden rendered this unsuccessful. 8 For most outcomes, a delay between disease onset and a registry- represents another approach to strengthen diagnoses from administrative data. 18 The date for the health care contact or hospital admission is usually considered to represent the date for occurrence of the event.…”

“…[4][5][6][7] An important research objective identified early after the signal of a suspected association was how incidence of narcolepsy and the association with vaccination would develop over time. 8 In order to investigate that, consideration must be given to the time course from exposure to the vaccine, to development of first symptoms, how rapidly progression of disease then leads to clinical contact, and how long the delay caused by referral for diagnostic procedures and specialist contact is, before a diagnosis is established in a registry.…”

Screening for autoantibody targets in post‐vaccination narcolepsy using proteome arrays

“…1 Increased incidence was observed in Finland, Norway and Sweden following Pandemrix®vaccination (A/California/7/2009 NYMC X-179A, AS03-Adjuvanted H1N1 Influenza A Vaccine) in conjunction with the 2009 influenza pandemic. [2][3][4][5][6][7] While the aetiology of NT1 is unknown, indirect evidences support an autoimmune origin, including a strong association with HLA-DQB1*06:02 and with other genes with immune regulatory functions. [8][9][10][11] Pandemrix®-vaccination as a unique and unpredictable environmental trigger, and possibly the virus itself, would be compatible with an autoimmune genesis.…”