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

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

• Lill Trogstad^{a, ,} ,
• Inger Johanne Bakken^a, ,
• Nina Gunnes^a, ,
• Sara Ghaderi^a, ,
• Camilla Stoltenberg^{a, b,} ,
• Per Magnus^{a, c,} ,
• Siri E. H?berg^a,

Open Access

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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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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--vaccines/questions-remain-about-possible-narcolepsy-risk-for-some-h1n1-vaccines/article/568831/

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

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

STUDY OBJECTIVES:

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

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.
RESULTS:

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.
CONCLUSIONS:

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.


KEYWORDS:

Pandemrix; adult; case-coverage; narcolepsy; vaccination

PMID: 26856903 [PubMed - as supplied by publisher]

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H1N1 influenza virus induces narcolepsy-like sleep disruption and targets sleep?wake regulatory neurons in mice

• Chiara Tesoriero^a,^b,¹,
• Alina Codita^c,¹,
• Ming-Dong Zhang^a,^d,¹,
• Andrij Cherninsky^e,
• H?kan Karlsson^a,
• Gigliola Grassi-Zucconi^b,
• Giuseppe Bertini^b,
• Tibor Harkany^d,^f,
• Karl Ljungberg^g,
• Peter Liljestr?m^g,
• Tomas G. M. H?kfelt^a,²,
• Marina Bentivoglio^b, and
• Krister Kristensson^a,²

• ^aDepartment of Neuroscience, Karolinska Institutet, Stockholm SE-17177, Sweden;
• ^bDepartment of Neurological and Movement Sciences, University of Verona, Verona 37134, Italy;
• ^cSection of Neurogeriatrics, Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet, Huddinge 14157, Sweden;
• ^dDivision of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm SE-17177, Sweden;
• ^eDepartment of Brain Physiology, Institute of Biology of Taras Shevchenko National University, Kiev 01601, Ukraine;
• ^fDepartment of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Vienna A-1090, Austria;
• ^gDepartment of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, Stockholm SE-17177, Sweden

• Contributed by Tomas G. M. H?kfelt, October 31, 2015 (sent for review July 16, 2015; reviewed by Antoine Adamantidis, Daniel Gonzalez-Dunia, Fang Han, and Thomas S. Kilduff)

Significance

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.

Abstract

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

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Pandemrix

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


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

http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000832/human_med_000965.jsp&mid=WC0b01ac058001d124

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Pandemrix? and narcolepsy: A critical appraisal of the observational studies

Full text HTML PDF
Open access

DOI: 10.1080/21645515.2015.1068486 Thomas Verstraeten^a*, Catherine Cohet^b, Ga?l Dos Santos^c, Germano LC Ferreira^ab, Kaatje Bollaerts^a, Vincent Bauchau^b & Vivek Shinde^d


Abstract

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

full article

http://www.tandfonline.com/doi/full/10.1080/21645515.2015.1068486

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53 suspicion cases related with the swine influenza vaccine Pandemrix


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

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

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

http://www.aerztezeitung.de/medizin/krankheiten/infektionskrankheiten/schweinegrippe/article/893168/bundesweit-53-narkolepsie-verdachtsfaelle-schweinegrippe-impfung.html

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Journal of Autoimmunity
Available online 27 July 2015
In Press, Corrected Proof — Note to users



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

• Anna-Helena Saariaho^{a, b, ,} ,
• Arja Vuorela^c, ,
• Tobias L. Freitag^{a, b,} ,
• Fabio Pizza^{d, e,} ,
• Giuseppe Plazzi^{d, e,} ,
• Markku Partinen^{f, g,} ,
• Outi Vaarala^{c, 1,} ,
• Seppo Meri^{a, b, ,}

Highlights


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

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Abstract

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

http://www.sciencedirect.com/science/article/pii/S0896841115300093

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Vaccine
Available online 1 August 2015
In Press, Corrected Proof ? Note to users



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

• Woo Jung Kim^{a, b},
• Sang Don Lee^c,
• Eun Lee^{b, d, e},
• Kee Namkoong^{b, d},
• Kang-Won Choe^f,
• Joon Young Song^g,
• Hee Jin Cheong^g,
• Hye Won Jeong^h,
• Jung Yeon Heo^{h, ,}

Highlights

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

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Abstract

Background

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

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

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

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

http://www.sciencedirect.com/science/article/pii/S0264410X15010166

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J Intern Med. 2015 Jun 30. doi: 10.1111/joim.12391. [Epub ahead of print]
A coordinated cross-disciplinary research initiative to address an increased incidence of narcolepsy following the 2009-2010 Pandemrix vaccination programme in Sweden.

Feltelius N¹, Persson I¹, Ahlqvist-Rastad J¹, Andersson M¹, Arnheim-Dahlstr?m L², Bergman P³, Granath F⁴, Adori C⁵, H?kfelt T⁵, K?hlmann-Berenzon S⁶, Liljestr?m P⁷, Maeurer M⁸, Olsson T⁹, ?rtqvist ?^10,11, Partinen M^12,13, Salmonson T¹, Zethelius B¹.
Author information

Abstract

In response to the 2009-2010 influenza A(H1N1)pdm09 pandemic, a mass vaccination programme with the AS03-adjuvanted influenza A(H1N1) vaccine Pandemrix was initiated in Sweden. Unexpectedly, there were a number of narcolepsy cases amongst vaccinated children and adolescents reported. In this review, we summarize the results of a joint cross-disciplinary national research effort to investigate the adverse reaction signal from the spontaneous reporting system and to better understand possible causative mechanisms. A three- to fourfold increased risk of narcolepsy in vaccinated children and adolescents was verified by epidemiological studies. Of importance, no risk increase was observed for the other neurological and autoimmune diseases studied. Genetic studies confirmed the association with the allele HLA-DQB1*06:02, which is known to be related to sporadic narcolepsy. Furthermore, a number of studies using cellular and molecular experimental models investigated possible links between influenza vaccination and narcolepsy. Serum analysis, using a peptide microarray platform, showed that individuals who received Pandemrix exhibited a different epitope reactivity pattern to neuraminidase and haemagglutinin, as compared to individuals who were infected with H1N1. Patients with narcolepsy were also found to have increased levels of interferon-gamma production in response to streptococcus-associated antigens. The chain of patient-related events and the study results emerging over time were subjected to intense nationwide media attention. The importance of transparent communication and collaboration with patient representatives to maintain public trust in vaccination programmes is also discussed in the review. Organizational challenges due to this unexpected event delayed the initiation of some of the research projects, still the main objectives of this joint, cross-disciplinary research effort were reached, and important insights were acquired for future, similar situations in which a fast and effective task force may be required to evaluate vaccination-related adverse events.
? 2015 The Association for the Publication of the Journal of Internal Medicine.


KEYWORDS:

Sweden; adverse events; influenza; narcolepsy; vaccination

PMID: 26123389 [PubMed - as supplied by publisher]

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The oiginal article

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Flu Vaccine and Narcolepsy: New Findings May Explain Link

An unusual increase in narcolepsy cases in Europe was linked to a new flu vaccine used there, and now researchers may have figured out why: A protein in the vaccine appears to mimic one in the brain that plays a role in the sleep disorder.
People with narcolepsy experience severe daytime sleepiness and "sleep attacks," in which they suddenly fall asleep for a short time. The vaccine that was linked to the disorder was used in 2009 and 2010 to protect against the H1N1 strain of flu, which is sometimes called the swine flu.
The new findings also suggest that the immune system may play a role in the disorder, and that in rare cases vaccines or infections can trigger narcolepsy in people with a certain genetic mutation.

...

Flu Vaccine and Narcolepsy: New Findings May Explain Link

by Rachael Rettner, Senior Writer | July 01, 2015 02:05pm ET

Credit: Syda Productions/Shutterstock.com View full size image

An unusual increase in narcolepsy cases in Europe was linked to a new flu vaccine used there, and now researchers may have figured out why: A protein in the vaccine appears to mimic one in the brain that plays a role in the sleep disorder.
People with narcolepsy experience severe daytime sleepiness and "sleep attacks," in which they suddenly fall asleep for a short time. The vaccine that was linked to the disorder was used in 2009 and 2010 to protect against the H1N1 strain of flu, which is sometimes called the swine flu.
The new findings also suggest that the immune system may play a role in the disorder, and that in rare cases vaccines or infections can trigger narcolepsy in people with a certain genetic mutation.



In the new study, the researchers compared components of the Pandemrix vaccine with those of another H1N1 vaccine, called Focetria, which was manufactured by Novartis.
They found that part of a viral protein in the Pandemrix vaccine mimicked the structure of a brain receptor that binds to a hormone called hypocretin. This hormone is involved in keeping people awake, and people with narcolepsy have lower levels of hypocretin, which led the researchers to hypothesize that problems with hypocretin or its receptor could play a role in the sleep disorder.
In contrast to the Pandemrix vaccine, the Focetria vaccine contained much lower levels of the viral protein that mimicked the hypocretin receptor.
Next, the researchers analyzed blood samples from 20 people in Finland who developed narcolepsy after Pandemrix vaccination, and found that these people had antibodies in their blood that bound to the H1N1 virus and also to the hypocretin receptor. But people who received the Focetria vaccines did not have these antibodies.
The researchers speculate that, in people who are already predisposed to narcolepsy because of a genetic mutation, receiving the Pandemrix vaccination triggered an autoimmune response ? these patients developed antibodies that not only attacked the virus, but also attacked the hypocretin receptor in the brain.

http://www.livescience.com/51411-flu-vaccine-narcolepsy-immune-response.html

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J Intern Med. 2015 Feb 14. doi: 10.1111/joim.12355. [Epub ahead of print]
Increased β-haemolytic group A streptococcal M6 serotype and streptodornase B-specific cellular immune responses in Swedish narcolepsy cases.

Ambati A¹, Poiret T, Svahn BM, Valentini D, Khademi M, Kockum I, Lima I, Arnheim-Dahlstr?m L, Lamb F, Fink K, Meng Q, Kumar A, Rane L, Olsson T, Maeurer M.
Author information

Abstract

BACKGROUND:

Type 1 narcolepsy is a neurological disorder characterized by excessive daytime sleepiness and cataplexy associated with the HLA allele DQB1*06:02. Genetic predisposition along with external triggering factors may drive autoimmune responses, ultimately leading to the selective loss of hypocretin-positive neurons.
OBJECTIVE:

The aim of this study was to investigate potential aetiological factors in Swedish cases of post-vaccination (Pandemrix) narcolepsy defined by interferon-gamma (IFNγ) production from immune cells in response to molecularly defined targets.
METHODS:

Cellular reactivity defined by IFNγ production was examined in blood from 38 (HLA-DQB1*06:02⁺ ) Pandemrix-vaccinated narcolepsy cases and 76 (23 HLA-DQB1*06:02⁺ and 53 HLA-DQB1*06:02^- ) control subjects, matched for age, sex and exposure, using a variety of different antigens: β-haemolytic group A streptococcal (GAS) antigens (M5, M6 and streptodornase B), influenza (the pandemic A/H1N1/California/7/09 NYMC X-179A and A/H1N1/California/7/09 NYMC X-181 vaccine antigens, previous Flu-A and -B vaccine targets, A/H1N1/Brisbane/59/2007, A/H1N1/Solomon Islands/3/2006, A/H3N2/Uruguay/716/2007, A/H3N2/Wisconsin/67/2005, A/H5N1/Vietnam/1203/2004 and B/Malaysia/2506/2004), non-influenza viral targets (CMVpp65, EBNA-1 and EBNA-3) and auto-antigens (hypocretin peptide, Tribbles homolog 2 peptide cocktail and extract from rat hypothalamus tissue).
RESULTS:

IFNγ production was significantly increased in whole blood from narcolepsy cases in response to streptococcus serotype M6 (P = 0.0065) and streptodornase B protein (P = 0.0050). T cell recognition of M6 and streptodornase B was confirmed at the single-cell level by intracellular cytokine (IL-2, IFNγ, tumour necrosis factor-alpha and IL-17) production after stimulation with synthetic M6 or streptodornase B peptides. Significantly higher (P = 0.02) titres of serum anti-streptolysin O were observed in narcolepsy cases, compared to vaccinated controls.
CONCLUSION:

β-haemolytic GAS may be involved in triggering autoimmune responses in patients who developed narcolepsy symptoms after vaccination with Pandemrix in Sweden, characterized by a Streptococcus pyogenes M-type-specific IFNγ cellular immune response. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.


KEYWORDS:

Streptococcus ; Pandemrix; Streptolysin; T cells; interferon-gamma; narcolepsy

PMID: 25683265 [PubMed - as supplied by publisher]

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H1N1 Viral Proteins Could Be Link Between Pandemrix and Narcolepsy

Though much of the research for a link between Pandemrix and narcolepsy has focused on the flu vaccine?s adjuvant, a new study suggests the focus should actually be on the H1N1 viral proteins.
In their paper, ?Antigenic Differences between AS03 Adjuvanted Influenza A (H1N1) Pandemic Vaccines: Implications for Pandemrix-Associated Narcolepsy Risk? published in PLOS One on December 15, Finnish researchers compare two different versions of the H1N1 flu vaccine-Pandemrix and Arepanrix-and find an interesting difference.
?What is more significant is that given that there were two pandemic vaccines against swine flu?one was Arepanrix, which was used in Canada, and the other was Pandemrix, which was used in Europe?Pandemrix caused narcolepsy,? first author Outi Vaarala told Finnish media outlet Yle. ?The difference was that Pandemrix had one viral protein in a different form and there was more of it.?

...

http://www.sleepreviewmag.com/2014/12/h1n1-viral-proteins-link-pandemrix-narcolepsy/

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

Eurosurveillance, Volume 19, Issue 36, 11 September 2014
Surveillance and outbreak reports
Did narcolepsy occur following administration of AS03-adjuvanted A(H1N1) pandemic vaccine in Ontario, Canada? A review of post-marketing safety surveillance data
T Harris ()1, K Wong1, L Stanford2, J Fediurek1, N Crowcroft1,3,4, S L Deeks1,3

Public Health Ontario, Toronto, Ontario, Canada
Simcoe-Muskoka District Health Unit, Ontario, Canada
Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada

Citation style for this article: Harris T, Wong K, Stanford L, Fediurek J, Crowcroft N, Deeks SL. Did narcolepsy occur following administration of AS03-adjuvanted A(H1N1) pandemic vaccine in Ontario, Canada? A review of post-marketing safety surveillance data . Euro Surveill. 2014;19(36):pii=20900. Available online: http://www.eurosurveillance.org/View...rticleId=20900
Date of submission: 09 October 2013

A vaccine safety signal and association between new onset of narcolepsy and AS03-adjuvanted pandemic influenza A(H1N1) vaccine (Pandemrix, GlaxoSmithKline) in children and young adults has been reported in several European countries. In Ontario, Canada, AS03-adjuvanted pandemic A(H1N1) vaccine (Arepanrix, GlaxoSmithKline) was the primary vaccine administered in 2009/10, with 4.8 million doses distributed. We assessed post-marketing safety surveillance data by extracting adverse events following immunisation (AEFIs) associated with this vaccine from the integrated Public Health Information System. Reports were screened for key terms related to narcolepsy and further limited to children and young adults four to 29 years of age. Of 1,604 AEFIs reported in Ontario, 53 reports met the search criteria. Individual assessment by a nurse consultant for additional context suggestive of narcolepsy yielded five reports for secondary medical review. None of the five reports proved consistent with a possible narcolepsy diagnosis based on the available information. We present the first post-marketing assessment from Canada of narcolepsy reports following receipt of Arepanix. Continued investigation of differences between Arepanrix and Pandemrix and subsequent risk of narcolepsy is indicated. In light of the limitations of passive surveillance to detect a signal in this instance, validation using other data sources is prudent.

http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20900