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

[h=1]H1N1 influenza virus induces narcolepsy-like sleep disruption and targets sleep?wake regulatory neurons in mice[/h]
  • [SUP]a[/SUP]Department of Neuroscience, Karolinska Institutet, Stockholm SE-17177, Sweden;
  • [SUP]b[/SUP]Department of Neurological and Movement Sciences, University of Verona, Verona 37134, Italy;
  • [SUP]c[/SUP]Section of Neurogeriatrics, Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet, Huddinge 14157, Sweden;
  • [SUP]d[/SUP]Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm SE-17177, Sweden;
  • [SUP]e[/SUP]Department of Brain Physiology, Institute of Biology of Taras Shevchenko National University, Kiev 01601, Ukraine;
  • [SUP]f[/SUP]Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Vienna A-1090, Austria;
  • [SUP]g[/SUP]Department of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, Stockholm SE-17177, Sweden
  • Contributed by Tomas G. M. H?kfelt, October 31, 2015 (sent for review July 16, 2015; reviewed by Antoine Adamantidis, Daniel Gonzalez-Dunia, Fang Han, and Thomas S. Kilduff)

[h=2]Significance[/h] 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.

[h=2]Abstract[/h] 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.

http://www.pnas.org/content/early/2015/12/09/1521463112.abstract
 
Sleep. 2016 Feb 1. pii: sp-00484-15. [Epub ahead of print]
[h=1]Risk of Narcolepsy after AS03 Adjuvanted Pandemic A/H1N1 2009 Influenza Vaccine in Adults: A Case-Coverage Study in England.[/h] Stowe J, Miller E, Andrews N, Kosky C, Leschziner G, Shneerson JM, Hall A, Eriksson S, Reading P, Dennis G, Donegan K.
[h=3]Abstract[/h] [h=4]STUDY OBJECTIVES:[/h] 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.
[h=4]METHODS:[/h] 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.
[h=4]RESULTS:[/h] 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.
[h=4]CONCLUSIONS:[/h] 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.


[h=4]KEYWORDS:[/h] Pandemrix; adult; case-coverage; narcolepsy; vaccination

PMID: 26856903 [PubMed - as supplied by publisher]
 
[h=1]Questions Remain About Possible Narcolepsy Risk for Some H1N1 Vaccines[/h] 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--va...y-risk-for-some-h1n1-vaccines/article/568831/
 
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
 
[h=2]The immunogenetics of narcolepsy associated with A(H1N1)pdm09 vaccination (Pandemrix) supports a potent gene-environment interaction[/h] 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 IL[SUP]1,[/SUP][SUP]2[/SUP], Lamb F[SUP]3[/SUP], Fink K[SUP]1,[/SUP][SUP]4[/SUP], Szak?cs A[SUP]5[/SUP], Silveira A[SUP]2,[/SUP][SUP]6[/SUP], Franz?n L[SUP]1,[/SUP][SUP]2[/SUP], Azhary V[SUP]1,[/SUP][SUP]2[/SUP], Maeurer M[SUP]7,[/SUP][SUP]8[/SUP], Feltelius N[SUP]9[/SUP], Darin N[SUP]10[/SUP], Hallb??k T[SUP]10[/SUP], Arnheim-Dahlstr?m L[SUP]3[/SUP], Kockum I[SUP]1,[/SUP][SUP]2[/SUP], Olsson T[SUP]1,[/SUP][SUP]2,[/SUP][SUP]4[/SUP].
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

Tags: None
 
Sleep Medicine
[h=1]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[/h] Doris Oberle
article_notepad.gif
Correspondence 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 |
cm_sbs_018_plain.png





[h=2]Highlights[/h]
  • ?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.


[h=2]Abstract[/h] [h=3]Objective[/h] 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.


[h=3]Methods[/h] 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).


[h=3]Results[/h] 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).


[h=3]Conclusions[/h] 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/S1389-9457(17)30126-0/fulltext
 
[h=2]Antibody Affinity Against 2009 A/H1N1 Influenza and Pandemrix Vaccine Nucleoproteins Differs Between Childhood Narcolepsy Patients and Controls[/h] 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
[h=3]Author information[/h]
Alexander Lind,[SUP]1[/SUP] Eva Freyhult,[SUP]2[/SUP] Anita Ramelius,[SUP]1[/SUP] Tomas Olsson,[SUP]3[/SUP] Lisen Arnheim-Dahlstr?m,[SUP]4[/SUP] Favelle Lamb,[SUP]4[/SUP] Mohsen Khademi,[SUP]3[/SUP] Aditya Ambati,[SUP]5[/SUP] Markus Maeurer,[SUP]6[/SUP] Izaura Lima Bomfim,[SUP]3[/SUP] Katharina Fink,[SUP]3,[/SUP][SUP]7[/SUP] Malin Fex,[SUP]1[/SUP] Carina T?rn,[SUP]1[/SUP] Helena Elding Larsson,[SUP]1[/SUP] and ?ke Lernmark[SUP]1[/SUP]
[SUP]1[/SUP]Department of Clinical Sciences, Lund University/Clinical Research Center (CRC), Sk?ne University Hospital SUS, Malm?, Sweden.
[SUP]2[/SUP]Department of Medical Sciences, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
[SUP]3[/SUP]Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
[SUP]4[/SUP]Department of Medical Epidemiology and Biostatistics
[SUP]5[/SUP]Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
[SUP]6[/SUP]TIM, LabMed, Karolinska Institutet and CAST, Karolinska University Hospital, Stockholm, Sweden.
[SUP]7[/SUP]Department 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


[h=3]ABSTRACT[/h]
Increased narcolepsy incidence was observed in Sweden following the 2009 influenza vaccination with Pandemrix[SUP]?[/SUP]. 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 [SUP]35[/SUP]S-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
 
[h=1]Sleepmedicine Review

Incidence of narcolepsy after H1N1 influenza and vaccinations: Systematic review and meta-analysis[/h] [h=1][/h] Tomi O. Sarkanen
article_notepad.gif
Correspondence 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



[h=2]Summary[/h] 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[SUP]?[/SUP]). 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.



[h=4]http://www.smrv-journal.com/article/S1087-0792(17)30001-1/fulltext[/h]
 
[h=1]Narcolepsy and adjuvanted pandemic influenza A (H1N1) 2009 vaccines ? Multi-country assessment[/h] Author links open overlay panelDanielWeibel[SUP]a[/SUP]

MiriamSturkenboom[SUP]b[/SUP]StevenBlack[SUP]c[/SUP]Mariade Ridder[SUP]a[/SUP]CaitlinDodd[SUP]a[/SUP]JanBonhoeffer[SUP]d[/SUP][SUP]e[/SUP]AnnVanrolleghem[SUP]a[/SUP]Nicolinevan der Maas[SUP]f[/SUP]Gert JanLammers[SUP]g[/SUP][SUP]h[/SUP]SebastiaanOvereem[SUP]i[/SUP]AngelaGentile[SUP]j[/SUP]NorbertoGiglio[SUP]j[/SUP]VanesaCastellano[SUP]j[/SUP]Jeffrey C.Kwong[SUP]k[/SUP]Brian J.Murray[SUP]l[/SUP]KarenCauch-Dudek[SUP]k[/SUP]DianaJuhasz[SUP]k[/SUP]MichaelCampitelli[SUP]k[/SUP]?Tom T.Shimabukuro[SUP]ad[/SUP]



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


[h=2]Abstract[/h] [h=3]Background[/h] 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.

[h=3]Methods[/h] 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.

[h=3]Results[/h] 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.

[h=3]Conclusions[/h] 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/science/article/pii/S0264410X18311150
 
[h=1]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[/h]
  • 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 ]
[h=1][/h] [h=2]Abstract[/h] [h=3]Background & objectives[/h] 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.

[h=3]Methods[/h] 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.

[h=3]Results[/h] 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.

[h=3]Conclusions[/h] 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/article?id=10.1371/journal.pone.0204799
 
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 (HCRT[SUB]NH2[/SUB]) 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 HCRT[SUB]NH2[/SUB] 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&#150;specific CD4[SUP]+[/SUP] T cells tested in 35 T1N cases and 22 DQ0602 controls. Higher reactivity to influenza pHA[SUB]273&#150;287[/SUB] (pH1N1 specific), PR8 (H1N1 pre-2009 and H2N2)-specific NP[SUB]17&#150;31[/SUB] and C-amidated but not native version of HCRT[SUB]54&#150;66[/SUB] and HCRT[SUB]86&#150;97[/SUB] (HCRT[SUB]NH2[/SUB]) were observed in T1N. Single-cell TCR sequencing revealed sharing of CDR3β TRBV4-2-CASSQETQGRNYGYTF in HCRT[SUB]NH2[/SUB] and pHA[SUB]273&#150;287[/SUB]-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 HCRT[SUB]54&#150;66-NH2[/SUB] and HCRT[SUB]86&#150;97-NH2[/SUB] 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 pHA[SUB]273&#150;287[/SUB], NP[SUB]17&#150;31[/SUB], and HCRT[SUB]NH2[/SUB] tetramer-positive CD4[SUP]+[/SUP] cells were also retrieved in single INF-γ&#150;secreting CD4[SUP]+[/SUP] 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
 
[h=1]Narcolepsy and 2009 H1N1 pandemic vaccination in Taiwan[/h] Author links open overlay panelWan-TingHuang[SUP]a[/SUP]



https://www.sciencedirect.com/science/article/pii/S1389945718305677?via=ihub#! Yu-ShuHuang[SUP]b[/SUP]Chung-YaoHsu[SUP]c[/SUP]Hsi-ChungChen[SUP]d[/SUP]Hsin-ChunLee[SUP]a[/SUP]Hui-ChenLin[SUP]a[/SUP]Cheng-FangHsieh[SUP]c[/SUP]Meng-NiWu[SUP]c[/SUP]Chin-HuiYang[SUP]a[/SUP]


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

[h=2]Highlights[/h]
? 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.



[h=2]Abstract[/h] [h=3]Background[/h] Several European countries have observed an association between narcolepsy and H1N1 vaccines containing AS03[SUP]?[/SUP] adjuvant in children/adolescents. In Taiwan, a nationwide campaign starting November 2009 administered H1N1 vaccines without adjuvant or with MF59[SUP]?[/SUP] adjuvant to 67% of children and 12% of adults.

[h=3]Methods[/h] 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.

[h=3]Results[/h] 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[SUP]?[/SUP] adjuvant.

[h=3]Conclusion[/h] 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.
 
[h=1]Autoimmunity to hypocretin and molecular mimicry to flu in type 1 narcolepsy[/h] 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)









[h=2]Significance[/h] This work shows that the amidated terminal ends of the secreted hypocretin (HCRT) peptides (HCRT[SUB]NH2[/SUB]) 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 HCRT[SUB]NH2[/SUB] 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.

[h=2]Abstract[/h] 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[SUP]+[/SUP] T cells tested in 35 T1N cases and 22 DQ0602 controls. Higher reactivity to influenza pHA[SUB]273?287[/SUB] (pH1N1 specific), PR8 (H1N1 pre-2009 and H2N2)-specific NP[SUB]17?31[/SUB] and C-amidated but not native version of HCRT[SUB]54?66[/SUB] and HCRT[SUB]86?97[/SUB] (HCRT[SUB]NH2[/SUB]) were observed in T1N. Single-cell TCR sequencing revealed sharing of CDR3β TRBV4-2-CASSQETQGRNYGYTF in HCRT[SUB]NH2[/SUB] and pHA[SUB]273?287[/SUB]-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 HCRT[SUB]54?66-NH2[/SUB] and HCRT[SUB]86?97-NH2[/SUB] 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 pHA[SUB]273?287[/SUB], NP[SUB]17?31[/SUB], and HCRT[SUB]NH2[/SUB] tetramer-positive CD4[SUP]+[/SUP] cells were also retrieved in single INF-γ?secreting CD4[SUP]+[/SUP] 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
 
[h=1]Ireland: more than 80 cases now before High Court over swine flu vaccine[/h]

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/worl...before-high-court-over-swine-flu-vaccine.html
 
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
[h=1]Narcolepsy and Pandemic Influenza Vaccination: What We Need to Know to be Ready for the Next Pandemic[/h]
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/fullt...y_and_Pandemic_Influenza_Vaccination_.23.aspx
 
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


logo-plos.png

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/plosmedicine/article?id=10.1371/journal.pmed.1003225
 
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 AM
Enhanced influenza A H1N1 T cell epitope recognition and cross-reactivity to protein-O-mannosyltransferase 1 in Pandemrix-associated narcolepsy type 1
Nature 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 (NA[SUB]175?189[/SUB]) and nucleoprotein 214?228 (NP[SUB]214?228[/SUB]), but also respond to a NA[SUB]175?189[/SUB]-mimic, brain self-epitope, protein-O-mannosyltransferase 1 (POMT1[SUB]675?689[/SUB]). 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 NA[SUB]175?189[/SUB] or POMT1[SUB]675?689[/SUB]. 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
 
Sleep


. 2022 Jun 13;zsac137.
doi: 10.1093/sleep/zsac137. Online ahead of print.
Increased Incidence of Pediatric Narcolepsy Following the 2009 H1N1 Pandemic: A Report from the Pediatric Working Group of the Sleep Research Network


Narong Simakajornboon[SUP] 1 2 [/SUP], Emmanuel Mignot[SUP] 3 [/SUP], Kiran Maski[SUP] 4 [/SUP], Judith Owens[SUP] 4 [/SUP], Carol Rosen[SUP] 5 [/SUP], Sally Ibrahim[SUP] 5 [/SUP], Fauziya Hassan[SUP] 6 [/SUP], Ronald D Chervin[SUP] 6 [/SUP], Gayln Perry[SUP] 7 [/SUP], Lee Brooks[SUP] 8 [/SUP], Leila Kheirandish-Gozal[SUP] 9 [/SUP], David Gozal[SUP] 9 [/SUP], Thornton Mason[SUP] 8 [/SUP], Althea Robinson[SUP] 10 [/SUP], Beth Malow[SUP] 10 [/SUP], Kamal Naqvi[SUP] 11 [/SUP], Maida L Chen[SUP] 12 [/SUP], Supriya Jambhekar[SUP] 13 [/SUP], Ann Halbower[SUP] 14 [/SUP], Katharina Graw-Panzer[SUP] 15 [/SUP], Ehab Dayyat[SUP] 16 [/SUP], Jenny Lew[SUP] 17 [/SUP], Cecilia Melendres[SUP] 18 [/SUP], Suresh Kotagal[SUP] 19 [/SUP], Sejal Jain[SUP] 20 [/SUP], Elizabeth Super[SUP] 21 [/SUP], Thomas Dye[SUP] 1 2 [/SUP], Md Monir Hossain[SUP] 22 [/SUP], Dawit Tadesse[SUP] 22 [/SUP]



Affiliations

Abstract

This study was aimed to evaluate yearly incidence of pediatric narcolepsy prior to and following the 2009 H1N1 pandemic and to evaluate seasonal patterns of narcolepsy onset and associations with H1N1 influenza infection in the United States. This was a multi-center retrospective study with prospective follow-up. Participants were recruited from members of the Pediatric Working Group of the Sleep Research Network including 22 sites across the United States. The main outcomes were monthly and yearly incident cases of childhood narcolepsy in the United States, and relationship to historical H1N1 influenza data. 950 subjects were included in the analysis; 487 subjects were male (51.3%). The mean age at onset of excessive daytime sleepiness (EDS) was 9.6±3.9 years. Significant trend changes in pediatric narcolepsy incidence based on EDS onset (P<0.0001) occurred over the 1998-2016 period, peaking in 2010, reflecting a 1.6-fold increase in narcolepsy incidence. In addition, there was significant seasonal variation in narcolepsy incident cases, with increased cases in spring (P<0.05). Cross correlation analysis demonstrated significant correlation between monthly H1N1 infection and monthly narcolepsy incident cases (ρ=0.397, P<0.0001) with a lag time of 8 months. We conclude that there is a significant increase in pediatric narcolepsy incidence after the 2009 H1N1 pandemic in the United States. However, the magnitude of increase is lower than reported in European countries and in China. The temporal correlation between monthly H1N1 infection and monthly narcolepsy incidence, suggests that H1N1 infection may be a contributing factor to the increased pediatric narcolepsy incidence after the 2009 H1N1 pandemics.

Keywords: 2009 H1N1 pandemics; Pediatric Narcolepsy; narcolepsy incidence; risk factors for narcolepsy; seasonal variation of narcolepsy incidence.
 
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