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

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  • #91
    Autoimmunity to hypocretin and molecular mimicry to flu in type 1 narcolepsy

    Guo Luo, Aditya Ambati, Ling Lin, Mélodie Bonvalet, Markku Partinen, Xuhuai Ji, Holden Terry Maecker, and Emmanuel Jean-Marie Mignot
    PNAS published ahead of print December 12, 2018 https://doi.org/10.1073/pnas.1818150116
    • Contributed by Emmanuel Jean-Marie Mignot, November 17, 2018 (sent for review October 25, 2018; reviewed by Roland S. Liblau and Joseph S. Takahashi)




    Significance

    This work shows that the amidated terminal ends of the secreted hypocretin (HCRT) peptides (HCRTNH2) are autoantigens in type 1 narcolepsy, an autoimmune disorder targeting HCRT neurons. The autoimmune process is usually initiated by influenza A flu infections, and a particular piece of the hemagglutinin (HA) flu protein of the pandemic 2009 H1N1 strain was identified as a likely trigger. This HA epitope has homology with HCRTNH2 and T cells cross-reactive to both epitopes are involved in the autoimmune process by molecular mimicry. Genes associated with narcolepsy mark the particular HLA heterodimer (DQ0602) involved in presentation of these antigens and modulate expression of the specific T cell receptor segments (TRAJ24 and TRBV4-2) involved in T cell receptor recognition of these antigens, suggesting causality.

    Abstract

    Type 1 narcolepsy (T1N) is caused by hypocretin/orexin (HCRT) neuronal loss. Association with the HLA DQB1*06:02/DQA1*01:02 (98% vs. 25%) heterodimer (DQ0602), T cell receptors (TCR) and other immune loci suggest autoimmunity but autoantigens are unknown. Onset is seasonal and associated with influenza A, notably pandemic 2009 H1N1 (pH1N1) infection and vaccination (Pandemrix). Peptides derived from HCRT and influenza A, including pH1N1, were screened for DQ0602 binding and presence of cognate DQ0602 tetramer-peptide–specific CD4+ T cells tested in 35 T1N cases and 22 DQ0602 controls. Higher reactivity to influenza pHA273–287 (pH1N1 specific), PR8 (H1N1 pre-2009 and H2N2)-specific NP17–31 and C-amidated but not native version of HCRT54–66 and HCRT86–97 (HCRTNH2) were observed in T1N. Single-cell TCR sequencing revealed sharing of CDR3β TRBV4-2-CASSQETQGRNYGYTF in HCRTNH2 and pHA273–287-tetramers, suggesting molecular mimicry. This public CDR3β uses TRBV4-2, a segment modulated by T1N-associated SNP rs1008599, suggesting causality. TCR-α/β CDR3 motifs of HCRT54–66-NH2 and HCRT86–97-NH2 tetramers were extensively shared: notably public CDR3α, TRAV2-CAVETDSWGKLQF-TRAJ24, that uses TRAJ24, a chain modulated by T1N-associated SNPs rs1154155 and rs1483979. TCR-α/β CDR3 sequences found in pHA273–287, NP17–31, and HCRTNH2 tetramer-positive CD4+ cells were also retrieved in single INF-γ–secreting CD4+ sorted cells stimulated with Pandemrix, independently confirming these results. Our results provide evidence for autoimmunity and molecular mimicry with flu antigens modulated by genetic components in the pathophysiology of T1N.

    https://www.pnas.org/content/early/2.../11/1818150116

    Comment


    • #92
      Narcolepsy and 2009 H1N1 pandemic vaccination in Taiwan

      Author links open overlay panelWan-TingHuanga



      Yu-ShuHuangbChung-YaoHsucHsi-ChungChendHsin-ChunLeeaHui-ChenLinaCheng-FangHsiehcMeng-NiWucChin-HuiYanga


      https://doi.org/10.1016/j.sleep.2018.10.036Get rights and content

      Highlights

      • During H1N1 virus circulation, narcolepsy increased in children and young adults.
      • No association between H1N1 vaccination and narcolepsy was identified.
      • Epilepsy, depression, migraine, and recent ILI/URI were risk factors for narcolepsy.



      Abstract

      Background

      Several European countries have observed an association between narcolepsy and H1N1 vaccines containing AS03® adjuvant in children/adolescents. In Taiwan, a nationwide campaign starting November 2009 administered H1N1 vaccines without adjuvant or with MF59® adjuvant to 67% of children and 12% of adults.

      Methods

      For those registered in the 2000–2012 National Health Insurance (NHI) databases, we compared age-stratified (0–4, 5–18, 19–59, and ≥60 years) incidence of first referral for a diagnostic MSLT for the pre-pandemic, pandemic/pre-vaccination, and vaccination/post-pandemic period. We also compared the odds of H1N1 vaccination in each chart-ascertained narcolepsy patient, whoever had an onset of excessive daytime sleepiness between April 2009 and December 2012, with 10 population-based controls from the NHI databases on year of birth, sex, and index date, using conditional logistic regressions.

      Results

      Incidence of MSLT referral for narcolepsy was highest and significantly increased in the pandemic/pre-vaccination period in the age group 5–18 (IRR 3.40, 95% confidence intervals (CI) 2.12–5.45) and 19–59 (IRR 2.90, 95% CI 1.62–5.02) years. Among 137 confirmed narcolepsy cases (86 adults and 51 children), the odds ratios (ORs) were 1.67 (95% CI 0.81–3.45) (adults) and 1.22 (95% CI 0.62–2.39) (children) for H1N1 vaccination without adjuvant, and 1.39 (95% CI 0.17–11.48) (adults) and 3.66 (95% CI 0.37–36.02) (children) with MF59® adjuvant.

      Conclusion

      No substantial association between the use of H1N1 vaccines and narcolepsy was identified in Taiwan. Instead, the H1N1 infection itself could have played a role in triggering narcolepsy in children and young adults.





      Comment


      • #93
        Autoimmunity to hypocretin and molecular mimicry to flu in type 1 narcolepsy

        Guo Luo, Aditya Ambati, Ling Lin, Mélodie Bonvalet, Markku Partinen, Xuhuai Ji, Holden Terry Maecker, and Emmanuel Jean-Marie Mignot
        PNAS December 26, 2018 115 (52) E12323-E12332; published ahead of print December 12, 2018 https://doi.org/10.1073/pnas.1818150116
        • Contributed by Emmanuel Jean-Marie Mignot, November 17, 2018 (sent for review October 25, 2018; reviewed by Roland S. Liblau and Joseph S. Takahashi)










        Significance

        This work shows that the amidated terminal ends of the secreted hypocretin (HCRT) peptides (HCRTNH2) are autoantigens in type 1 narcolepsy, an autoimmune disorder targeting HCRT neurons. The autoimmune process is usually initiated by influenza A flu infections, and a particular piece of the hemagglutinin (HA) flu protein of the pandemic 2009 H1N1 strain was identified as a likely trigger. This HA epitope has homology with HCRTNH2 and T cells cross-reactive to both epitopes are involved in the autoimmune process by molecular mimicry. Genes associated with narcolepsy mark the particular HLA heterodimer (DQ0602) involved in presentation of these antigens and modulate expression of the specific T cell receptor segments (TRAJ24 and TRBV4-2) involved in T cell receptor recognition of these antigens, suggesting causality.

        Abstract

        Type 1 narcolepsy (T1N) is caused by hypocretin/orexin (HCRT) neuronal loss. Association with the HLA DQB1*06:02/DQA1*01:02 (98% vs. 25%) heterodimer (DQ0602), T cell receptors (TCR) and other immune loci suggest autoimmunity but autoantigens are unknown. Onset is seasonal and associated with influenza A, notably pandemic 2009 H1N1 (pH1N1) infection and vaccination (Pandemrix). Peptides derived from HCRT and influenza A, including pH1N1, were screened for DQ0602 binding and presence of cognate DQ0602 tetramer-peptide–specific CD4+ T cells tested in 35 T1N cases and 22 DQ0602 controls. Higher reactivity to influenza pHA273–287 (pH1N1 specific), PR8 (H1N1 pre-2009 and H2N2)-specific NP17–31 and C-amidated but not native version of HCRT54–66 and HCRT86–97 (HCRTNH2) were observed in T1N. Single-cell TCR sequencing revealed sharing of CDR3β TRBV4-2-CASSQETQGRNYGYTF in HCRTNH2 and pHA273–287-tetramers, suggesting molecular mimicry. This public CDR3β uses TRBV4-2, a segment modulated by T1N-associated SNP rs1008599, suggesting causality. TCR-α/β CDR3 motifs of HCRT54–66-NH2 and HCRT86–97-NH2 tetramers were extensively shared: notably public CDR3α, TRAV2-CAVETDSWGKLQF-TRAJ24, that uses TRAJ24, a chain modulated by T1N-associated SNPs rs1154155 and rs1483979. TCR-α/β CDR3 sequences found in pHA273–287, NP17–31, and HCRTNH2 tetramer-positive CD4+ cells were also retrieved in single INF-γ–secreting CD4+ sorted cells stimulated with Pandemrix, independently confirming these results. Our results provide evidence for autoimmunity and molecular mimicry with flu antigens modulated by genetic components in the pathophysiology of T1N.

        https://www.pnas.org/content/115/52/E12323

        Comment


        • #94
          Ireland: more than 80 cases now before High Court over swine flu vaccine

          THE SOLICITOR HANDLING many of the cases involving people who allegedly developed narcolepsy after receiving the swine flu vaccine has said more than 80 cases have now been lodged before the courts in relation to Pandemrix.
          In 2009, the World Health Organisation (WHO) declared a swine flu pandemic. The Irish government and the HSE purchased over eight million Pandemrix vaccines, which were made by Glaxosmithkline (GSK).
          Many people received the vaccine before its use was suspended in Ireland in 2011 after concerns were raised about negative side effects including a link with narcolepsy and other sleep disorders.


          https://pressfrom.info/uk/news/world...u-vaccine.html


          Comment


          • #95
            The Pediatric Infectious Disease Journal. 38(8):873–876, AUG 2019
            DOI: 10.1097/INF.0000000000002398
            ,
            Issn Print: 0891-3668
            Publication Date: 2019/08/01
            Narcolepsy and Pandemic Influenza Vaccination: What We Need to Know to be Ready for the Next Pandemic

            After the initial identification of the H1N1 pandemic influenza strain in Mexico in April 2009 and its subsequent global spread, several monovalent influenza vaccines were developed as part of the pandemic response. Three of these vaccines, Pandemrix, Arepanrix and Focetria were adjuvanted. One of these, the AS03-adjuvanted Pandemrix vaccine, was primarily used in Europe. Following widespread Pandemrix vaccine administration in Scandinavia, an increased risk of narcolepsy was noted in observational studies. Subsequently, this increased risk was also reported in other European countries as well. In contrast, studies from Canada of a similar AS03-adjuvanted vaccine, Arepanrix, did not demonstrate a similar increased risk of narcolepsy. No studies have identified an increased risk of narcolepsy following the MF59-adjuvanted Focetria vaccine. For many potential pandemic influenza strains, adjuvants might be required to solicit a protective immune response. Thus, it is critical that we understand the nature of the association between adjuvanted vaccine receipt and narcolepsy. Here, we present a potential hypothesis for narcolepsy seen during the 2009 H1N1 pandemic in AS03-adjuvanted influenza vaccine recipients.

            full article

            https://journals.lww.com/pidj/fullte...ation_.23.aspx

            Comment


            • #96
              Reassessment of the risk of narcolepsy in children in England 8 years after receipt of the AS03-adjuvanted H1N1 pandemic vaccine: A case-coverage study
              • Julia Stowe ,
              • Nick Andrews,
              • Paul Gringras,
              • Timothy Quinnell,
              • Zenobia Zaiwalla,
              • John Shneerson,
              • Elizabeth Miller




              Abstract


              Background

              Early studies of narcolepsy after AS03-adjuvanted pandemic A/H1N12009 vaccine (Pandemrix) could not define the duration of elevated risk post-vaccination nor the risk in children aged under 5 years who may not present until much older.


              Methods/Findings

              Clinical information and sleep test results, extracted from hospital notes at 3 large pediatric sleep centers in England between September 2017 and June 2018 for narcolepsy cases aged 4–19 years with symptom onset since January 2009, were reviewed by an expert panel to confirm the diagnosis. Vaccination histories were independently obtained from general practitioners (GPs). The odds of vaccination in narcolepsy cases compared with the age-matched English population was calculated after adjustment for clinical conditions that were indications for vaccination.
              GP questionnaires were returned for 242 of the 244 children with confirmed narcolepsy. Of these 5 were under 5 years, 118 were 5–11 years, and 119 were 12–19 years old at diagnosis; 39 were vaccinated with Pandemrix before onset. The odds ratio (OR) for onset at any time after vaccination was 1.94 (95% confidence interval [CI] 1.30–2.89), The elevated risk period was restricted to onsets within 12 months of vaccination (OR 6.65 [3.44–12.85]) and was highest within the first 6 months. After one year, ORs were not significantly different from 1 up to 8 years after vaccination. The ORs were similar in under five-year-olds and older ages. The estimated attributable risk was 1 in 34,500 doses. Our study is limited by including cases from only 3 sleep centers, who may differ from cases diagnosed in nonparticipating centers, and by imprecision in defining the centers’ catchment population. The potential for biased recall of onset shortly after vaccination in cases aware of the association cannot be excluded.


              Conclusions

              In this study, we found that vaccine-attributable cases have onset of narcolepsy within 12 months of Pandemrix vaccination. The attributable risk is higher than previously estimated in England because of identification of vaccine-attributable cases with late diagnoses. Absence of a compensatory drop in risk 1–8 years after vaccination suggests that Pandemrix does not trigger onsets in those in whom narcolepsy would have occurred later.

              https://journals.plos.org/plosmedici...l.pmed.1003225

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