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Finland - National Health Dept. Suspends A/H1N1 Vaccine Due to Possible Narcolepsy Connection + other countries investigate

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  • #76
    Available online 1 August 2015
    In Press, Corrected ProofNote to users

    Incidence of narcolepsy before and after MF59-adjuvanted influenza A(H1N1)pdm09 vaccination in South Korean soldiers


    • The incidence rate of narcolepsy in Korean soldiers was 0.91 cases per 100,000 person-years in 2007–2013.
    • There was no increase in narcolepsy cases after the vaccination campaign with the MF59-adjuvanted H1N1 vaccine.
    • The MF59-adjuvanted H1N1 vaccine did not contribute to the occurrence of narcolepsy in Korean soldiers.



    Previous reports mostly from Europe suggested an association between an occurrence of narcolepsy and an influenza A(H1N1)pdm09 vaccine adjuvanted with AS03 (Pandemrix®). During the 2009 H1N1 pandemic vaccination campaign, the Korean military performed a vaccination campaign with one type of influenza vaccine containing MF59-adjuvants. This study was conducted to investigate the background incidence rate of narcolepsy in South Korean soldiers and the association of the MF59-adjuvanted vaccine with the occurrence of narcolepsy in a young adult group.

    To assess the incidence of narcolepsy, we retrospectively reviewed medical records of suspicious cases of narcolepsy in 2007–2013 in the whole 20 military hospitals of the Korean military. The screened cases were classified according to the Brighton Collaboration case definition of narcolepsy. After obtaining the number of confirmed cases of narcolepsy per 3 months in 2007–2013, we compared the crude incidence rate of narcolepsy before and after the vaccination campaign.

    We included 218 narcolepsy suspicious cases in the initial review, which were screened by the diagnostic code on the computerized disease registry in 2007–2013. Forty-one cases were finally diagnosed with narcolepsy in 2007–2013 (male sex, 95%; median age, 21 years). The average background incidence rate of narcolepsy in Korean soldiers was 0.91 cases per 100,000 persons per year. During the 9 months before vaccination implementation (April to December 2009), 6 narcolepsy cases occurred, whereas during the next 9 months (January to September 2010) including the 3-month vaccination campaign, 5 cases occurred.

    The incidence of narcolepsy in South Korean soldiers was not increased after the pandemic vaccination campaign using the MF59-adjuvanted vaccine. Our results suggest that the MF59-adjuvanted H1N1 vaccine did not contribute to the occurrence of narcolepsy in this young adult group.


    • #77
      Journal of Autoimmunity
      Available online 27 July 2015
      In Press, Corrected ProofNote to users

      Autoantibodies against ganglioside GM3 are associated with narcolepsy-cataplexy developing after Pandemrix vaccination against 2009 pandemic H1N1 type influenza virus Highlights

      • Pandemrix vaccine induced autoimmunity against gangliosides, particularly against GM3.
      • Anti-GM3 antibodies were associated with Pandemrix-related narcolepsy-cataplexy.
      • Anti-GM3 antibodies associated with HLA-DQB1*0602 in vaccinated patients and controls.
      • Acting as a viral receptor GM3 could make complexes with H1 and lead to immunization.
      • No anti-GM3 antibodies were found in sporadic Pandemrix-unrelated narcolepsy.


      Following the mass vaccinations against pandemic influenza A/H1N1 virus in 2009, a sudden increase in juvenile onset narcolepsy with cataplexy (NC) was detected in several European countries where AS03-adjuvanted Pandemrix vaccine had been used.
      NC is a chronic neurological disorder characterized by excessive daytime sleepiness and cataplexy. In human NC, the hypocretin-producing neurons in the hypothalamus or the hypocretin signaling pathway are destroyed by an autoimmune reaction. Both genetic (e.g. HLA-DQB1*0602) and environmental risk factors (e.g. Pandemrix) contribute to the disease development, but the underlying and the mediating immunological mechanisms are largely unknown.
      Influenza virus hemagglutinin is known to bind gangliosides, which serve as host cell virus receptors. Anti-ganglioside antibodies have previously been linked to various neurological disorders, like the Guillain-Barré syndrome which may develop after infection or vaccination. Because of these links we screened sera of NC patients and controls for IgG anti-ganglioside antibodies against 11 human brain gangliosides (GM1, GM2, GM3, GM4, GD1a, GD1b, GD2, GD3, GT1a, GT1b, GQ1b) and a sulfatide by using a line blot assay. Samples from 173 children and adolescents were analyzed: 48 with Pandemrix-associated NC, 20 with NC without Pandemrix association, 57 Pandemrix-vaccinated and 48 unvaccinated healthy children. We found that patients with Pandemrix-associated NC had more frequently (14.6%) anti-GM3 antibodies than vaccinated healthy controls (3.5%) (P = 0.047). Anti-GM3 antibodies were significantly associated with HLA-DQB1*0602 (P = 0.016) both in vaccinated NC patients and controls. In general, anti-ganglioside antibodies were more frequent in vaccinated (18.1%) than in unvaccinated (7.3%) individuals (P = 0.035). Our data suggest that autoimmunity against GM3 is a feature of Pandemrix-associated NC and that autoantibodies against gangliosides were induced by Pandemrix vaccination.


      • #78
        53 suspicion cases related with the swine influenza vaccine Pandemrix

        BERLIN. All over the country 53 suspicion cases with which the pork influenza-vaccine Pandemrix has possibly released Narkolepsie are registered. This arises from the answer of the federal health ministry to a small inquiry of the left faction.

        27 persons under age also count to the affected persons afterwards. With children with secure diagnoses the symptoms have appeared on average about 160 days after the vaccination, with adults these were 194 days.

        Indeed: Also pork influenza itself apparently releases Narkolepsie, suggest like data from China where in 2009 was barely inoculated. As a trigger a virus protein which seems on the Influenzaviren, as well as in the vaccine Pandemrix is supposed


        • #79
          Pandemrix™ and narcolepsy: A critical appraisal of the observational studies

          Full text HTML PDF
          Open access

          DOI: 10.1080/21645515.2015.1068486 Thomas Verstraetena*, Catherine Cohetb, Gaël Dos Santosc, Germano LC Ferreiraab, Kaatje Bollaertsa, Vincent Bauchaub & Vivek Shinded


          A link between Pandemrix™ (AS03-adjuvanted H1N1 pandemic influenza vaccine, GSK Vaccines, Belgium) and narcolepsy was first suspected in 2010 in Sweden and Finland following a number of reports in children and adolescents. Initial scepticism about the reported association faded as additional countries reported similar findings, leading several regulatory authorities to restrict the use of Pandemrix™. The authors acknowledge that currently available data suggest an increased risk of narcolepsy following vaccination with Pandemrix™; however, from an epidemiologist's perspective, significant methodological limitations of the studies have not been fully addressed and raise questions about the reported risk estimates. We review the most important biases and confounders that potentially occurred in 12 European studies of the observed association between Pandemrix™ and narcolepsy, and call for further analyses and debate.

          full article


          • #80

            influenza vaccine (H1N1)v (split virion, inactivated, adjuvanted) A/California/7/2009 (H1N1)v like strain (x-179a)

            The marketing authorisation for Pandemrix has expired following the marketing-authorisation holder’s decision not to apply for a renewal.



            • #81
              H1N1 influenza virus induces narcolepsy-like sleep disruption and targets sleep–wake regulatory neurons in mice

              • aDepartment of Neuroscience, Karolinska Institutet, Stockholm SE-17177, Sweden;
              • bDepartment of Neurological and Movement Sciences, University of Verona, Verona 37134, Italy;
              • cSection of Neurogeriatrics, Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet, Huddinge 14157, Sweden;
              • dDivision of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm SE-17177, Sweden;
              • eDepartment of Brain Physiology, Institute of Biology of Taras Shevchenko National University, Kiev 01601, Ukraine;
              • fDepartment of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Vienna A-1090, Austria;
              • gDepartment of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, Stockholm SE-17177, Sweden
              • Contributed by Tomas G. M. Hökfelt, October 31, 2015 (sent for review July 16, 2015; reviewed by Antoine Adamantidis, Daniel Gonzalez-Dunia, Fang Han, and Thomas S. Kilduff)


              Influenza A virus infections are risk factors for narcolepsy, a disease in which autoimmunity has been implicated. We tested experimentally whether influenza virus infections could be causally related to narcolepsy. We found that mice infected with a H1N1 influenza A virus strain developed over time sleep–wake changes described in murine models of narcolepsy and narcolepsy patients. In the brain, the virus infected orexin/hypocretin-producing neurons, which are destroyed in human narcolepsy, and other cells in the distributed sleep–wake-regulating neuronal network. The findings, obtained in mice lacking an adaptive autoimmune response, thus provide new avenues for research on infection-related mechanisms in narcolepsy.


              An increased incidence in the sleep-disorder narcolepsy has been associated with the 2009–2010 pandemic of H1N1 influenza virus in China and with mass vaccination campaigns against influenza during the pandemic in Finland and Sweden. Pathogenetic mechanisms of narcolepsy have so far mainly focused on autoimmunity. We here tested an alternative working hypothesis involving a direct role of influenza virus infection in the pathogenesis of narcolepsy in susceptible subjects. We show that infection with H1N1 influenza virus in mice that lack B and T cells (Recombinant activating gene 1-deficient mice) can lead to narcoleptic-like sleep–wake fragmentation and sleep structure alterations. Interestingly, the infection targeted brainstem and hypothalamic neurons, including orexin/hypocretin-producing neurons that regulate sleep–wake stability and are affected in narcolepsy. Because changes occurred in the absence of adaptive autoimmune responses, the findings show that brain infections with H1N1 virus have the potential to cause per se narcoleptic-like sleep disruption.



              • #82
                Sleep. 2016 Feb 1. pii: sp-00484-15. [Epub ahead of print]
                Risk of Narcolepsy after AS03 Adjuvanted Pandemic A/H1N1 2009 Influenza Vaccine in Adults: A Case-Coverage Study in England.

                Stowe J, Miller E, Andrews N, Kosky C, Leschziner G, Shneerson JM, Hall A, Eriksson S, Reading P, Dennis G, Donegan K.

                STUDY OBJECTIVES:

                An increased risk of narcolepsy has been observed in children following ASO3-adjuvanted pandemic A/H1N1 2009 (Pandemrix) vaccine. We investigated whether this risk extends to adults in England.

                Six adult sleep centers in England were visited between November 2012 and February 2014 and vaccination/clinical histories obtained from general practitioners. Suspected narcolepsy cases aged older than 17 y were selected. The risk of narcolepsy following Pandemrix was calculated using cases diagnosed by the time of the center visits and those with a diagnosis by November 30, 2011 after which there was increased awareness of the risk in children. The odds of vaccination in cases and in matched population data were compared using a case-coverage design.

                Of 1,446 possible cases identified, most had onset before 2009 or were clearly not narcolepsy. Of the 60 remaining cases, 20 were excluded after expert review, leaving 40 cases with narcolepsy; 5 had received Pandemrix between 3 and 18 mo before onset. All the vaccinated cases had cataplexy, two received a diagnosis by November 2011 and two were aged 40 y or older. The odds ratio for vaccination in cases compared to the population was 4.24 (95% confidence interval 1.45-12.38) using all cases and 9.06 (1.90-43.17) using cases with a diagnosis by November 2011, giving an attributable risk of 0.59 cases per 100,000 doses.

                We found a significantly increased risk of narcolepsy in adults following Pandemrix vaccination in England. The risk was lower than that seen in children using a similar study design.
                Copyright © 2016 Associated Professional Sleep Societies, LLC. All rights reserved.


                Pandemrix; adult; case-coverage; narcolepsy; vaccination

                PMID: 26856903 [PubMed - as supplied by publisher]


                • #83
                  Questions Remain About Possible Narcolepsy Risk for Some H1N1 Vaccines

                  NEW ORLEANS, LA—A multinational retrospective analysis failed to confirm a possible association between pediatric narcolepsy and the AS03- and MF-59-adjuvanted monovalent pandemic H1N1 vaccines, according to authors of a poster presentation at IDWeek 2016.
                  However, geographic variation might have complicated efforts to assess such an association, and the study's statistical power for assessing risk after MF-59 vaccine was “limited,” they cautioned.
                  “Overall, our results do not support an association between receipt of AS03-adjuvanted 2009 H1N1 vaccine and narcolepsy although our results are based almost exclusively on Arepanrix® use in Ontario,” Steven Black, MD, of the Center for Global Health, Cincinnati Children's Hospital, in Cincinnati, OH, and coauthors, reported in a poster presentation.
                  In Europe, an increased risk of narcolepsy was reported among children administered the AS03-adjuvanted 2009 pandemic H1N1 influenza vaccine but that effect might have been influenced by news “media attention bias,” the study authors noted.
                  The international SOMNIA study was undertaken to evaluate the potential narcolepsy association with the AS03- and MF-59-adjuvanted monovalent pandemic H1N1 vaccines during 2003–2013. Narcolepsy incidence rates were assessed for the periods before, during, and after the pandemic influenza (A)H1N1 vaccination campaigns and a case-control analysis was undertaken to assess relative risks of narcolepsy among children and adults receiving the MF-59 and AS03 vaccines.
                  “No changes in incidence rates of narcolepsy diagnoses were observed between the period after the start of AS03- or MF-59-containing H1N1 vaccination programs and the period before H1N1 circulation, in any of the age groups or countries except for Sweden, where a steep increase was observed in children 5–19 years in 2010,” the authors noted. “In the primary case control analysis, no association was observed for AS03-containing vaccines in children or adults. Based on three exposed cases, an association with MF-59 vaccine was observed in Argentina in the primary analysis in children, but no association was found when cases from Europe were included.”
                  The study is funded by the U.S. Centers for Disease Control and Prevention (CDC).



                  • #84
                    Narcolepsy and hypersomnia in Norwegian children and young adults following the influenza A(H1N1) 2009 pandemic

                    Open Access



                    Associations between influenza infection and sleep disorders are poorly studied. We investigated if pandemic influenza infection or vaccination with Pandemrix in 2009/2010 was associated with narcolepsy or hypersomnia in children and young adults.

                    We followed the Norwegian population under age 30 from January 2008 through December 2012 by linking national health registry data. Narcolepsy diagnoses were validated using hospital records. Risks of narcolepsy or hypersomnia were estimated as adjusted hazard ratios (HRs) in Cox regression models with influenza infection and vaccination as time-dependent exposures.

                    Among the 1,638,526 persons under age 30 in Norway in 2009, 3.6% received a physician diagnosis of influenza during the pandemic, while 41.9% were vaccinated against pandemic influenza. Between October 1st 2009 and December 31st 2012, 72 persons had onset of narcolepsy and 305 were diagnosed with hypersomnia. The risk of a sleep disorder was associated with infection during the first six months, adjusted HR 3.31 with 95% confidence interval [CI], 1.01–10.79 for narcolepsy and adjusted HR 3.13 (95% CI, 1.12–8.76) for hypersomnia. The risk of narcolepsy was strongly associated with vaccination during the first six months adjusted HR 17.21 (95% CI, 6.28–47.14), while the adjusted HR for hypersomnia was 1.54 (95% CI, 0.81–2.93).

                    The study confirms an increased HR of narcolepsy following pandemic vaccination. Slightly increased HRs of narcolepsy and hypersomnia are also seen after influenza infection. However, the role of infection should be viewed with caution due to underreporting of influenza.

                    • Influenza A(H1N1)pdm09;
                    • Pandemic vaccination;
                    • Pandemrix;
                    • Narcolepsy, hypersomnia;
                    • Immunisation registry


                    • #85
                      The immunogenetics of narcolepsy associated with A(H1N1)pdm09 vaccination (Pandemrix) supports a potent gene-environment interaction

                      Today, 10:52 AM

                      Genes Immun. 2017 Mar 23. doi: 10.1038/gene.2017.1. [Epub ahead of print]
                      The immunogenetics of narcolepsy associated with A(H1N1)pdm09 vaccination (Pandemrix) supports a potent gene-environment interaction.

                      Bomfim IL1,2, Lamb F3, Fink K1,4, Szakács A5, Silveira A2,6, Franzén L1,2, Azhary V1,2, Maeurer M7,8, Feltelius N9, Darin N10, Hallböök T10, Arnheim-Dahlström L3, Kockum I1,2, Olsson T1,2,4.
                      Author information


                      The influenza A(H1N1)pdm09 vaccination campaign from 2009 to 2010 was associated with a sudden increase in the incidence of narcolepsy in several countries. Narcolepsy with cataplexy is strongly associated with the human leukocyte antigen (HLA) class II DQB1*06:02 allele, and protective associations with the DQB1*06:03 allele have been reported. Several non-HLA gene loci are also associated, such as common variants of the T-cell receptor-α (TRA), the purinergic receptor P2RY11, cathepsin H (CTSH) and TNFSF4/OX40L/CD252. In this retrospective multicenter study, we investigated if these predisposing gene loci were also involved in vaccination-associated narcolepsy. We compared HLA- along with single-nucleotide polymorphism genotypes for non-HLA regions between 42 Pandemrix-vaccinated narcolepsy cases and 1990 population-based controls. The class II gene loci associations supported previous findings. Nominal association (P-value<0.05) with TRA as well as suggestive (P-value<0.1) associations with P2RY11 and CTSH were found. These associations suggest a very strong gene-environment interaction, in which the influenza A(H1N1)pdm09 strain or Pandemrix vaccine can act as potent environmental triggers.Genes and Immunity advance online publication, 23 March 2017; doi:10.1038/gene.2017.1.

                      PMID: 28332559 DOI: 10.1038/gene.2017.1

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