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

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  • tetano
    replied

    Nat.Com. Enhanced influenza A H1N1 T cell epitope recognition and cross-reactivity to protein-O-mannosyltransferase 1 in Pandemrix-associated narcolepsy type 1

    Today, 09:34 AMEnhanced influenza A H1N1 T cell epitope recognition and cross-reactivity to protein-O-mannosyltransferase 1 in Pandemrix-associated narcolepsy type 1Nature Communications volume 12, Article number: 2283 (2021) Cite this article
    Subjects


    Abstract

    Narcolepsy type 1 (NT1) is a chronic neurological disorder having a strong association with HLA-DQB1*0602, thereby suggesting an immunological origin. Increased risk of NT1 has been reported among children or adolescents vaccinated with AS03 adjuvant-supplemented pandemic H1N1 influenza A vaccine, Pandemrix. Here we show that pediatric Pandemrix-associated NT1 patients have enhanced T-cell immunity against the viral epitopes, neuraminidase 175?189 (NA175?189) and nucleoprotein 214?228 (NP214?228), but also respond to a NA175?189-mimic, brain self-epitope, protein-O-mannosyltransferase 1 (POMT1675?689). A pathogenic role of influenza virus-specific T-cells and T-cell cross-reactivity in NT1 are supported by the up-regulation of IFN-?, perforin 1 and granzyme B, and by the converging selection of T-cell receptor TRAV10/TRAJ17 and TRAV10/TRAJ24 clonotypes, in response to stimulation either with peptide NA175?189 or POMT1675?689. Moreover, anti-POMT1 serum autoantibodies are increased in Pandemrix-vaccinated children or adolescents. These results thus identify POMT1 as a potential autoantigen recognized by T- and B-cells in NT1.



    https://www.nature.com/articles/s41467-021-22637-8



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  • tetano
    replied
    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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  • tetano
    replied
    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

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  • tetano
    replied
    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


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  • tetano
    replied
    Autoimmunity to hypocretin and molecular mimicry to flu in type 1 narcolepsy

    Guo Luo, Aditya Ambati, Ling Lin, M?lodie 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

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  • tetano
    replied
    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.





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  • tetano
    replied
    Autoimmunity to hypocretin and molecular mimicry to flu in type 1 narcolepsy

    Guo Luo, Aditya Ambati, Ling Lin, M?lodie 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

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  • tetano
    replied
    Incidence rates of narcolepsy diagnoses in Taiwan, Canada, and Europe: The use of statistical simulation to evaluate methods for the rapid assessment of potential safety issues on a population level in the SOMNIA study

    • Caitlin N. Dodd ,
    • Maria de Ridder,
    • Wan-Ting Huang,
    • Daniel Weibel,
    • Maria Giner-Soriano,
    • Silvia Perez-Vilar,
    • Javier Diez-Domingo,
    • Lawrence W. Svenson,
    • Salahddin M. Mahmud,
    • Bruce Carleton,
    • Monika Naus,
    • Jeffrey C. Kwong,
    • Brian J. Murray,
    • [ ... ],
    • Miriam Sturkenboom
    • [ view all ]

    Abstract

    Background & objectives

    Vaccine safety signals require investigation, which may be done rapidly at the population level using ecological studies, before embarking on hypothesis-testing studies. Incidence rates were used to assess a signal of narcolepsy following AS03-adjuvanted monovalent pandemic H1N1 (pH1N1) influenza vaccination among children and adolescents in Sweden and Finland in 2010. We explored the utility of ecological data to assess incidence of narcolepsy following exposure to pandemic H1N1 virus or vaccination in 10 sites that used different vaccines, adjuvants, and had varying vaccine coverage.

    Methods

    We calculated incidence rates of diagnosed narcolepsy for periods defined by influenza virus circulation and vaccination campaign dates, and used Poisson regression to estimate incidence rate ratios (IRRs) comparing the periods during which wild-type virus circulated and after the start of vaccination campaigns vs. the period prior to pH1N1 virus circulation. We used electronic health care data from Sweden, Denmark, the United Kingdom, Canada (3 provinces), Taiwan, Netherlands, and Spain (2 regions) from 2003 to 2013. We investigated interactions between age group and adjuvant in European sites and conducted a simulation study to investigate how vaccine coverage, age, and the interval from onset to diagnosis may impact the ability to detect safety signals.

    Results

    Incidence rates of narcolepsy varied by age, continent, and period. Only in Taiwan and Sweden were significant time-period-by-age-group interactions observed. Associations were found for children in Taiwan (following pH1N1 virus circulation) and Sweden (following vaccination). Simulations showed that the individual-level relative risk of narcolepsy was underestimated using ecological methods comparing post- vs. pre-vaccination periods; this effect was attenuated with higher vaccine coverage and a shorter interval from disease onset to diagnosis.

    Conclusions

    Ecological methods can be useful for vaccine safety assessment but the results are influenced by diagnostic delay and vaccine coverage. Because ecological methods assess risk at the population level, these methods should be treated as signal-generating methods and drawing conclusions regarding individual-level risk should be avoided.


    https://journals.plos.org/plosone/ar...l.pone.0204799




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  • tetano
    replied
    Narcolepsy and adjuvanted pandemic influenza A (H1N1) 2009 vaccines ? Multi-country assessment

    Author links open overlay panelDanielWeibela

    MiriamSturkenboombStevenBlackcMariade RidderaCaitlinDoddaJanBonhoefferdeAnnVanrolleghemaNicolinevan der MaasfGert JanLammersghSebastiaanOvereemiAngelaGentilejNorbertoGigliojVanesaCastellanojJeffrey C.KwongkBrian J.MurraylKarenCauch-DudekkDianaJuhaszkMichaelCampitellik?Tom T.Shimabukuroad



    https://doi.org/10.1016/j.vaccine.2018.08.008Get rights and content
    Open Access funded by VSNU
    Under a Creative Commons license
    open access


    Abstract

    Background

    In 2010, a safety signal was detected for narcolepsy following vaccination with Pandemrix, an AS03-adjuvanted monovalent pandemic H1N1 influenza (pH1N1) vaccine. To further assess a possible association and inform policy on future use of adjuvants, we conducted a multi-country study of narcolepsy and adjuvanted pH1N1 vaccines.

    Methods

    We used electronic health databases to conduct a dynamic retrospective cohort study to assess narcolepsy incidence rates (IR) before and during pH1N1 virus circulation, and after pH1N1 vaccination campaigns in Canada, Denmark, Spain, Sweden, Taiwan, the Netherlands, and the United Kingdom. Using a case-control study design, we evaluated the risk of narcolepsy following AS03- and MF59-adjuvanted pH1N1 vaccines in Argentina, Canada, Spain, Switzerland, Taiwan, and the Netherlands. In the Netherlands, we also conducted a case-coverage study in children born between 2004 and 2009.

    Results

    No changes in narcolepsy IRs were observed in any periods in single study sites except Sweden and Taiwan; in Taiwan incidence increased after wild-type pH1N1 virus circulation and in Sweden (a previously identified signaling country), incidence increased after the start of pH1N1 vaccination. No association was observed for Arepanrix-AS03 or Focetria-MF59 adjuvanted pH1N1 vaccines and narcolepsy in children or adults in the case-control study nor for children born between 2004 and 2009 in the Netherlands case-coverage study for Pandemrix-AS03.

    Conclusions

    Other than elevated narcolepsy IRs in the period after vaccination campaigns in Sweden, we did not find an association between AS03- or MF59-adjuvanted pH1N1 vaccines and narcolepsy in children or adults in the sites studied, although power to evaluate the AS03-adjuvanted Pandemrix brand vaccine was limited in our study.

    https://www.sciencedirect.com/scienc...64410X18311150



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  • tetano
    replied
    Sleepmedicine Review

    Incidence of narcolepsy after H1N1 influenza and vaccinations: Systematic review and meta-analysis


    Tomi O. SarkanenCorrespondence information about the author Tomi O. SarkanenEmail the author Tomi O. Sarkanen
    , Anniina P.E. Alakuijala
    , Yves A. Dauvilliers
    , Markku M. Partinen

    Incidence of narcolepsy after H1N1 influenza and vaccinations: Systematic review and meta-analysis
    DOI: http://dx.doi.org/10.1016/j.smrv.2017.06.006



    Summary

    An increased incidence of narcolepsy was seen in many countries after the pandemic H1N1 influenza vaccination campaign in 2009?2010. The H1N1 vaccine ? narcolepsy connection is based on observational studies that are prone to various biases, e.g., confounding by H1N1 infection, and ascertainment, recall and selection biases. A direct pathogenic link has, however, remained elusive. We conducted a systematic review and meta-analysis to analyze the magnitude of H1N1 vaccination related risk and to examine if there was any association with H1N1 infection itself. We searched all articles from PubMed, Web of Science and Scopus, and other relevant sources reporting the incidence and risk of post-vaccine narcolepsy. In our paper, we show that the risk appears to be limited to only one vaccine (Pandemrix?). During the first year after vaccination, the relative risk of narcolepsy was increased 5 to 14-fold in children and adolescents and 2 to 7-fold in adults. The vaccine attributable risk in children and adolescents was around 1 per 18,400 vaccine doses. Studies from Finland and Sweden also appear to demonstrate an extended risk of narcolepsy into the second year following vaccination, but such conclusions should be interpreted with a word of caution due to possible biases. Benefits of immunization outweigh the risk of vaccination-associated narcolepsy, which remains a rare disease.



    http://www.smrv-journal.com/article/S1087-0792(17)30001-1/fulltext

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  • tetano
    replied
    Antibody Affinity Against 2009 A/H1N1 Influenza and Pandemrix Vaccine Nucleoproteins Differs Between Childhood Narcolepsy Patients and Controls

    To cite this article:
    Lind Alexander, Freyhult Eva, Ramelius Anita, Olsson Tomas, Arnheim-Dahlstr?m Lisen, Lamb Favelle, Khademi Mohsen, Ambati Aditya, Maeurer Markus, Lima Bomfim Izaura, Fink Katharina, Fex Malin, T?rn Carina, Elding Larsson Helena, and Lernmark ?ke. Viral Immunology. August 2017, ahead of print. https://doi.org/10.1089/vim.2017.0066
    Online Ahead of Print: August 10, 2017
    Author information

    Alexander Lind,1 Eva Freyhult,2 Anita Ramelius,1 Tomas Olsson,3 Lisen Arnheim-Dahlstr?m,4 Favelle Lamb,4 Mohsen Khademi,3 Aditya Ambati,5 Markus Maeurer,6 Izaura Lima Bomfim,3 Katharina Fink,3,7 Malin Fex,1 Carina T?rn,1 Helena Elding Larsson,1 and ?ke Lernmark1
    1Department of Clinical Sciences, Lund University/Clinical Research Center (CRC), Sk?ne University Hospital SUS, Malm?, Sweden.
    2Department of Medical Sciences, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    3Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    4Department of Medical Epidemiology and Biostatistics
    5Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
    6TIM, LabMed, Karolinska Institutet and CAST, Karolinska University Hospital, Stockholm, Sweden.
    7Department of Neurology, Karolinska University Hospital, Stockholm, Sweden.
    Address correspondence to:
    Alexander Lind, MSc
    Department of Clinical Sciences
    Lund University/Clinical Research Center (CRC)
    Sk?ne University Hospital SUS Malm? Jan Waldenstr?ms gata 35
    SE-205 02 Malm?
    Sweden
    E-mail: alexander.lind@med.lu.se


    ABSTRACT

    Increased narcolepsy incidence was observed in Sweden following the 2009 influenza vaccination with Pandemrix?. A substitution of the 2009 nucleoprotein for the 1934 variant has been implicated in narcolepsy development. The aims were to determine (a) antibody levels toward wild-type A/H1N1-2009[A/California/04/2009(H1N1)] (NP-CA2009) and Pandemrix-[A/Puerto Rico/8/1934(H1N1)] (NP-PR1934) nucleoproteins in 43 patients and 64 age-matched controls; (b) antibody affinity in reciprocal competitive assays in 11 childhood narcolepsy patients compared with 21 age-matched controls; and (c) antibody levels toward wild-type A/H1N1-2009[A/California/04/2009(H1N1)] (H1N1 NS1), not a component of the Pandemrix vaccine. In vitro transcribed and translated 35S-methionine-labeled H1N1 influenza A virus proteins were used in radiobinding reciprocal competition assays to estimate antibody levels and affinity (Kd). Childhood patients had higher NP-CA2009 (p = 0.0339) and NP-PR1934 (p = 0.0246) antibody levels compared with age-matched controls. These childhood controls had lower NP-CA2009 (p = 0.0221) and NP-PR1934 (p = 0.00619) antibodies compared with controls 13 years or older. In contrast, in patients 13 years or older, the levels of NP-PR1934 (p = 0.279) and NP-CA2009 (p = 0.0644) antibodies did not differ from the older controls. Childhood antibody affinity (Kd) against NP-CA2009 was comparable between controls (68 ng/mL) and patients (74 ng/mL; p = 0.21) with NP-CA2009 and NP-PR1934 displacement (controls: 165 ng/mL; patients: 199 ng/mL; p = 0.48). In contrast, antibody affinity against NP-PR1934 was higher in controls with either NP-PR1934 (controls: 9 ng/mL; patients: 20 ng/mL; p = 0.0031) or NP-CA2009 (controls: 14 ng/mL; patients: 23 ng/mL; p = 0.0048). A/H1N1-NS1 antibodies were detected in 0/43 of the narcolepsy patients compared with 3/64 (4.7%) controls (p = 0.272). Similarly, none (0/11) of the childhood patients and 1/21 (4.8%) of the childhood controls had A/H1N1-NS1 antibodies. The higher antibody affinities against NP-PR1934 in controls suggest better protection against wild-type virus. In contrast, the reduced NP-PR1934 antibody affinities among childhood narcolepsy patients suggest poor protection from the wild-type A/H1N1 virus and possibly increased risk for viral damage.

    http://online.liebertpub.com/doi/10.1089/vim.2017.0066

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  • tetano
    replied
    Sleep Medicine
    Retrospective multicenter matched case?control study on the risk factors for narcolepsy with special focus on vaccinations (including pandemic influenza vaccination) and infections in Germany

    Doris OberleCorrespondence information about the author Doris OberleEmail the author Doris Oberle
    , Jutta Pavel
    , Geert Mayer
    , Peter Geisler
    , Brigitte Keller-Stanislawski
    for the German Narcolepsy Study Group

    DOI: http://dx.doi.org/10.1016/j.sleep.2017.02.026 |




    Highlights

    • ?In Germany, pandemic influenza vaccination coverage was low.
    • ?An increased risk for narcolepsy after pandemic H1N1 vaccination is supported.
    • ?This risk applies to children and adolescents as well as adults.
    • ?Exposed cases had a more severe clinical picture as compared to nonexposed cases.
    • ?No other risk factors for narcolepsy were identified.



    Abstract

    Objective

    Studies associate pandemic influenza vaccination with narcolepsy. In Germany, a retrospective, multicenter, matched case?control study was performed to identify risk factors for narcolepsy, particularly regarding vaccinations (seasonal and pandemic influenza vaccination) and infections (seasonal and pandemic influenza) and to quantify the detected risks.


    Methods

    Patients with excessive daytime sleepiness who had been referred to a sleep center between April 2009 and December 2012 for multiple sleep latency test (MSLT) were eligible. Case report forms were validated according to the criteria for narcolepsy defined by the Brighton Collaboration (BC). Confirmed cases of narcolepsy (BC level of diagnostic certainty 1−4a) were matched with population-based controls by year of birth, gender, and place of residence. A second control group was established including patients in whom narcolepsy was definitely excluded (test-negative controls).


    Results

    A total of 103 validated cases of narcolepsy were matched with 264 population-based controls. The second control group included 29 test-negative controls. A significantly increased odd ratio (OR) to develop narcolepsy (crude OR [cOR] = 3.9, 95% confidence interval [CI] = 1.8?8.5; adjusted OR [aOR] = 4.5, 95% CI = 2.0?9.9) was detected in individuals immunized with pandemic influenza A/H1N1/v vaccine prior to symptoms onset as compared to nonvaccinated individuals. Using test-negative controls, in individuals immunized with pandemic influenza A/H1N1/v vaccine prior to symptoms onset, a nonsignificantly increased OR of narcolepsy was detected when compared to nonvaccinated individuals (whole study population, BC levels 1−4a: cOR = 1.9, 95% CI = 0.5?6.9; aOR = 1.8, 95% CI = 0.3?10.1).


    Conclusions

    The findings of this study support an increased risk for narcolepsy after immunization with pandemic influenza A/H1N1/v vaccine.

    http://www.sleep-journal.com/article...126-0/fulltext



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

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    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, Szak?cs A5, Silveira A2,6, Franz?n L1,2, Azhary V1,2, Maeurer M7,8, Feltelius N9, Darin N10, Hallb??k T10, Arnheim-Dahlstr?m L3, Kockum I1,2, Olsson T1,2,4.
    Author information

    Abstract

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


    Open Access

    Abstract

    Background

    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.
    Methods

    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.
    Results

    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).
    Conclusions

    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.

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

    http://www.sciencedirect.com/science...64410X17302669

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  • tetano
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    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).


    http://www.empr.com/idweek-2016--vac...rticle/568831/

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