View source for Chemistry:Pandemrix

{{Short description|Flu vaccine}}
{{Drugbox
| Verifiedfields = changed
| verifiedrevid = 411609781
<!-- Vacine data -->
| type = vaccine
| target = Pandemic H1N1/09 virus
| vaccine_type = inactivated
<!-- Clinical data -->
| tradename =
| licence_EU =
| licence_US =
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S or Unscheduled -->
| legal_CA = <!-- Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_UK = P
| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->
| legal_EU = Rx-only
| legal_EU_comment = <ref>{{cite web | title=Pandemrix EPAR | website=European Medicines Agency | url=https://www.ema.europa.eu/en/medicines/human/EPAR/pandemrix | access-date=14 June 2022}}</ref>
| routes_of_administration = [[Biology:Intramuscular injection|Intramuscular injection]]
<!-- Identifiers -->
| CAS_number = 1385778-30-2
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = none
| ATC_prefix = J07
| ATC_suffix = BB02
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
<!-- Chemical data -->
}}
{{flu}}
'''Pandemrix''' is an [[Medicine:Influenza vaccine|influenza vaccine]] for [[Biology:Influenza pandemic|influenza pandemic]]s, such as the 2009 flu pandemic. The vaccine was developed by [[Company:GlaxoSmithKline|GlaxoSmithKline]] (GSK)<ref>
{{cite press release
 |url         = http://www.gsk.com/media/pressreleases/2009/2009_pressrelease_10089.htm
 |title       = Pandemic (H1N1) 2009 Influenza Update: GSK's H1N1 'Pandemrix' vaccine receives positive opinion from European Regulators
 |publisher   = GlaxoSmithKline
 |date        = 25 September 2009
 |access-date  = 2009-11-07
 |url-status     = dead
 |archive-url  = https://web.archive.org/web/20090929111101/http://www.gsk.com/media/pressreleases/2009/2009_pressrelease_10089.htm
 |archive-date = 29 September 2009
}}</ref> and patented in September 2006.<ref>{{Cite patent|country=WO|number=2006100109|title=Use of an influenza virus an oil-in-water emulsion adjuvant to induce CD4 T-cell and/or improved B-memory cell response|pubdate=2006-09-28|assign=[[Company:GlaxoSmithKline|Glaxosmithkline Biolog SA]]|inventor1-last=Hanon|inventor1-first=Emmanuel Jules|inventor2-last=Stephenne|inventor2-first=Jean}}</ref>

The vaccine was one of the H1N1 vaccines approved for use by the European Commission in September 2009, upon the recommendations of the [[Organization:European Medicines Agency|European Medicines Agency]] (EMEA).<ref name="EPAR-H-C-832">{{cite web|url=http://www.emea.europa.eu/humandocs/Humans/EPAR/pandemrix/pandemrix.htm|title=EMEA Pandemrix page|website=Emea.europa.eu|access-date=8 September 2018|url-status=dead|archive-url=https://web.archive.org/web/20091008131258/http://www.emea.europa.eu/humandocs/Humans/EPAR/pandemrix/pandemrix.htm|archive-date=8 October 2009}}</ref> The vaccine is only approved for use when an H1N1 [[Biology:Influenza pandemic|influenza pandemic]] has been officially declared by the [[Organization:World Health Organization|World Health Organization]] (WHO) or [[Social:European Union|European Union]] (EU).<ref name="EPAR-H-C-832"/> The vaccine was initially developed as a pandemic mock-up vaccine using an H5N1 strain.<ref>{{cite web|url=http://www.emea.europa.eu/humandocs/PDFs/EPAR/pandemrix/H-832-en6.pdf |title=Assessment report for the mock-up H5N1 vaccine |publisher=[[Organization:European Medicines Agency|EMEA]] |access-date=2009-11-07 |url-status=dead |archive-url=https://web.archive.org/web/20090902094324/http://www.emea.europa.eu/humandocs/PDFs/EPAR/pandemrix/H-832-en6.pdf |archive-date=September 2, 2009 }}</ref>

Pandemrix was found to be associated with an increased risk of [[Medicine:Narcolepsy|narcolepsy]]<ref name=":0" /> following investigations by Swedish and Finnish health authorities<ref name="lakemedelsverket.se">{{cite news|date=2010-08-18|title=The MPA investigates reports of narcolepsy in patients vaccinated with Pandemrix|work=The Swedish Medical Products Agency|url=http://www.lakemedelsverket.se/english/All-news/NYHETER-2010/The-MPA-investigates-reports-of-narcolepsy-in-patients-vaccinated-with-Pandemrix/|access-date=2010-08-19|archive-url=https://web.archive.org/web/20110217101203/http://www.lakemedelsverket.se/english/All-news/NYHETER-2010/The-MPA-investigates-reports-of-narcolepsy-in-patients-vaccinated-with-Pandemrix/|archive-date=17 February 2011}}</ref> and had higher rates of [[Medicine:Vaccine adverse event|adverse events]] than other vaccines for H1N1.<ref name=":1" /> This resulted in several legal cases.<ref name=":2" /> [[Organization:Stanford University|Stanford University]] studies suggested that narcolepsy is an autoimmune disease<ref name="Stanford_narcolepsy_autoimmune" /> and that it appears to be triggered by upper airway respiratory infections.<ref name="Stanford_narcolepsy_flu" />

In 2018, a study team including Centers for Disease Control and Prevention (CDC) scientists analyzed and published vaccine safety data on adjuvanted pH1N1 vaccines (arenaprix-AS03, Focetria-MF59, and Pandemrix-AS03) from 10 global study sites. Researchers did not detect any associations between the vaccines and narcolepsy.<ref>{{Cite web |date=2020-08-20 |title=Narcolepsy Following 2009 Pandemrix Influenza Vaccination in Europe {{!}} Vaccine Safety {{!}} CDC |url=https://www.cdc.gov/vaccinesafety/concerns/history/narcolepsy-flu.html |access-date=2023-01-16 |website=www.cdc.gov |language=en-us}}</ref>

== Constituents ==
As well as the active antigen derived from A/California/7/2009 (H1N1), the vaccine contains an [[Biology:Immunologic adjuvant|immunologic adjuvant]] AS03 which consists of DL-α-tocopherol (vitamin E), [[Chemistry:Squalene|squalene]] and [[Chemistry:Polysorbate 80|polysorbate 80]].{{cn|date=August 2022}}

[[Chemistry:Thiomersal|Thiomersal]] (thimerosal) is added as a preservative. Being manufactured in chicken eggs, it contains trace amounts of egg proteins. Additional important non-medicinal ingredients are [[Physics:Formaldehyde|formaldehyde]], sodium deoxycholate, and [[Chemistry:Sucrose|sucrose]].<ref name=pmid18301743/>

===Use of adjuvant===
While other 2009 H1N1 vaccines have been developed, the use of a proprietary [[Biology:Immunologic adjuvant|immunologic adjuvant]] is claimed to boost the potency of the body's immune response, meaning that only a quarter of the inactivated virus is needed.<ref name=pmid18301743>{{cite journal | vauthors = Leroux-Roels I, Bernhard R, Gérard P, Dramé M, Hanon E, Leroux-Roels G | title = Broad Clade 2 cross-reactive immunity induced by an adjuvanted clade 1 rH5N1 pandemic influenza vaccine | journal = PLOS ONE | volume = 3 | issue = 2 | pages = e1665 | date = February 2008 | pmid = 18301743 | pmc = 2253495 | doi = 10.1371/journal.pone.0001665 | doi-access = free | bibcode = 2008PLoSO...3.1665L }}</ref>

Professor David Salisbury, Head of Immunisation at the UK Department of Health said the vaccines with adjuvants offer good protection even if the virus changes over time; "One of the advantages with adjuvanted vaccines is their ability to protect against drifted (mutated) strains. It opens the door for a whole new strategy in dealing with flu."<ref name="Smith">{{cite news| url=https://www.telegraph.co.uk/health/swine-flu/6719861/Change-in-swine-flu-virus-is-my-biggest-fear-Liam-Donaldson.html | archive-url=https://web.archive.org/web/20091206031729/http://www.telegraph.co.uk/health/swine-flu/6719861/Change-in-swine-flu-virus-is-my-biggest-fear-Liam-Donaldson.html | url-status=dead | archive-date=2009-12-06 | work=The Daily Telegraph | location=London | title=Change in swine flu virus is my biggest fear: Liam Donaldson | first=Rebecca | last=Smith | date=2009-12-03 | access-date=2010-05-21}}</ref>

==Dosage==
The vaccine is supplied in separate vials, one containing the adjuvant, and the other the inactivated virus,<ref>
{{cite web
| url=https://www.ema.europa.eu/en/documents/other/pandemrix-package-leaflet_en.pdf
| title=Pandemrix packaging information
| publisher=[[Organization:European Medicines Agency|EMEA]]
| access-date=2009-11-07
}}</ref> which require mixing before [[Biology:Intramuscular injection|intramuscular injection]]. Originally it was thought that two doses given 21 days apart would be required for full efficacy.<ref>{{cite web |url=https://www.ema.europa.eu/en/documents/product-information/pandemrix-epar-product-information_en.pdf |title=Pandemrix, INN-Influenza vaccine (H1N1)v (split virion, inactivated, adjuvanted) |author=<!--Not stated--> |website=European Medicines Agency |access-date=3 August 2020 }}</ref> Subsequent testing has allowed the UK programme to consist of just a single dose for most people, with a two-dose schedule for children under the age of 10 years and immunocompromised adults.<ref>{{cite web |author=Department of Health (UK) |title=Information sheet on the swine flu vaccination |url=http://www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/@dh/@en/documents/digitalasset/dh_107346.pdf |archive-url=http://webarchive.nationalarchives.gov.uk/20120106094537/http://www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/@dh/@en/documents/digitalasset/dh_107346.pdf |url-status=dead |archive-date=6 January 2012 |date=19 October 2009 |page=8 |access-date=2009-11-10 }}</ref>

==Availability==
Pandemrix was given to around 70 million individuals, including 31 million Europeans following the [[Biology:2009 swine flu pandemic|2009 swine flu pandemic]].<ref>{{Cite web|date=2013-09-19|title=Swine flu vaccine can trigger narcolepsy, UK government concedes|url=http://www.theguardian.com/society/2013/sep/19/swine-flu-vaccine-narcolepsy-uk|access-date=2020-11-20|website=the Guardian|language=en}}</ref><ref>{{Cite journal |last=Doshi |first=Peter |date=2018-09-20 |title=Pandemrix vaccine: why was the public not told of early warning signs? |url=https://www.bmj.com/lookup/doi/10.1136/bmj.k3948 |journal=BMJ |volume=362 |language=en |edition= |at=Article Infographic at https://www.bmj.com/content/bmj/suppl/2018/09/20/bmj.k3948.DC1/pandremix1809.ww2.pdf |doi=10.1136/bmj.k3948 |pmid=30237282 |s2cid=52308748 |issn=0959-8138 |quote="the doses of Pandemrix administered went ... to 70 million" |ref=bit.ly/BMJpan}}</ref>

The Marketing Authorisation from the European Medicines Agency expired in August 2015 when GSK Biologicals did not apply for renewal of it citing lack of demand for the vaccine.<ref>European Medicines Agency, Public Statement, EMA/656472/2015 [https://www.ema.europa.eu/en/documents/public-statement/public-statement-pandemrix-expiry-marketing-authorisation-european-union_en.pdf "Pandemrix Expiry of the marketing authorisation in the European Union"] 19 October 2015</ref>

==Clinical trials==
The EMEA reported results from some clinical trials in the CHMP Assessment Report. These relate to vaccination against H5N1 (Bird Flu) and not H1N1 (Swine Flu).<ref>
{{cite web
| url=http://www.emea.europa.eu/humandocs/PDFs/EPAR/pandemrix/Pandemrix-H-832-PU-17-AR.pdf
| title=CHMP Assessment Report for Pandemrix
| publisher=[[Organization:European Medicines Agency|European Medicines Agency]]
| date=24 September 2009
| access-date=2009-11-07
| archive-url=https://web.archive.org/web/20091025133205/http://www.emea.europa.eu/humandocs/PDFs/EPAR/pandemrix/Pandemrix-H-832-PU-17-AR.pdf
| archive-date=2009-10-25
}}</ref>
* H5N1-007 was initiated at a single site in Belgium (Ghent) in March 2006.
* H5N1-008 was initiated at 41 sites in seven countries (6 EU MS plus Russia) in May 2006.
* H5N1-002 was initiated on 24 March 2007 in four SE Asian countries.

GlaxoSmithKline  reported results from the second clinical trial,<ref>{{cite press release|url=http://www.gsk.com/media/pressreleases/2009/2009_pressrelease_10111.htm |title=Pandemic (H1N1) 2009 Influenza Update: Results from second clinical trial of GSK's H1N1 adjuvanted vaccine confirm immune response and tolerability |publisher=GlaxoSmithKline |date=16 October 2009 |access-date=2009-11-07 |url-status=dead |archive-url=https://web.archive.org/web/20091031103005/http://www.gsk.com/media/pressreleases/2009/2009_pressrelease_10111.htm |archive-date=October 31, 2009 }}</ref> from the pediatric clinical trial,<ref>{{cite press release|url=http://www.gsk.com/media/pressreleases/2009/2009_pressrelease_10116.htm |title=Pandemic (H1N1) 2009 Influenza Update: Experience of GSK's H1N1 adjuvanted vaccine, Pandemrix, and preliminary paediatric results |publisher=GlaxoSmithKline |date=23 October 2009 |access-date=2009-11-07 |url-status=dead |archive-url=https://web.archive.org/web/20091029160027/http://www.gsk.com/media/pressreleases/2009/2009_pressrelease_10116.htm |archive-date=October 29, 2009 }}</ref> and the response from the elderly population.<ref>{{cite press release|url=http://www.gsk.com/media/pressreleases/2009/2009_pressrelease_10116.htm |title=Pandemic 2009 Influenza Update: Pandemrix data in an elderly population |date=27 October 2009 |access-date=2009-11-07 |url-status=dead |archive-url=https://web.archive.org/web/20091029160027/http://www.gsk.com/media/pressreleases/2009/2009_pressrelease_10116.htm |archive-date=October 29, 2009 }}</ref>

==Side effects==
According to GlaxoSmithKline's Patient Information Leaflet,<ref>{{cite web|url=https://www.who.int/immunization_standards/vaccine_quality/Pandemrix_Package_Insert.pdf
| title=Pandemrix Package Leaflet|website=Who.int| access-date=2009-11-07}}</ref> the following side effects may occur (sorted by rate of occurrence):{{cn|date=August 2022}}
* '''Very common''' (affects more than 1 in 10 people)
** Headache
** Tiredness
** Pain, redness, swelling or a hard lump at the injection site
** Fever
** [[Medicine:Myalgia|Aching muscles]], [[Medicine:Arthralgia|joint pain]]
* '''Common''' (affects at least 1 in 100 people)
** Warmth, itching or bruising at the injection site
** Increased sweating, shivering, flu-like symptoms
** Swollen glands in the neck, armpit or groin
* '''Uncommon'''  (affects at least 1 in 1,000 people)
** Tingling or numbness of the hands or feet
** General constitutional upset of sleepiness or sleeplessness, generally feeling unwell, dizziness.
** Diarrhea, vomiting, stomach pain, feeling sick
** Skin reactions of itching, rash or urticaria (hives)
* '''Rare''' (affects at least 1 in 10,000 people)
** Serious generalised allergic reactions of [[Medicine:Anaphylaxis|anaphylaxis]]
** Fits
** Severe stabbing or throbbing pain along one or more nerves
** [[Medicine:Thrombocytopenia|Low blood platelet count]] which can result in bleeding or bruising
* '''Very Rare''' (affects less than 1 in 10,000 people)
** [[Medicine:Vasculitis|Vasculitis]]
** Neurological disorders such as encephalomyelitis, [[Medicine:Neuritis|neuritis]] or [[Medicine:Guillain–Barré syndrome|Guillain–Barré syndrome]] temporary paralysis

==Adverse outcomes==
===Narcolepsy===
Pandemrix was found to be associated with [[Medicine:Narcolepsy|narcolepsy]] from observational studies, increasing the risk of narcolepsy by 5-14 times in children and 2-7 times in adults. The increased risk of narcolepsy due to vaccination in children and adolescents was around 1 incident per 18,400 doses.<ref name=":0">{{cite journal | vauthors = Sarkanen TO, Alakuijala AP, Dauvilliers YA, Partinen MM | title = Incidence of narcolepsy after H1N1 influenza and vaccinations: Systematic review and meta-analysis | journal = Sleep Medicine Reviews | volume = 38 | pages = 177–186 | date = April 2018 | pmid = 28847694 | doi = 10.1016/j.smrv.2017.06.006 | hdl-access = free | hdl = 10138/300884 }}</ref> In 2018, it was demonstrated that T-cells stimulated by Pandemrix were cross-reactive by [[Biology:Molecular mimicry|molecular mimicry]] with part of the hypocretin peptide, the loss of which is associated with type I narcolepsy.<ref name= "mignot2018">{{cite journal | vauthors = Luo G, Ambati A, Lin L, Bonvalet M, Partinen M, Ji X, Maecker HT, Mignot EJ | display-authors = 6 | title = Autoimmunity to hypocretin and molecular mimicry to flu in type 1 narcolepsy | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 115 | issue = 52 | pages = E12323–E12332 | date = December 2018 | pmid = 30541895 | doi = 10.1073/pnas.1818150116 | pmc = 6310865 | bibcode = 2018PNAS..11512323L | doi-access = free }}</ref>

The ''British Medical Journal'' (BMJ) obtained adverse event report data from GSK and conducted an analysis of that data, which showed that Pandemrix was associated with adverse events much more frequently than the two other GSK H1N1 vaccines. The risk of adverse events after Pandemrix was more than five times higher than the risk after the other two GSK H1N1 vaccines. Vaccination had continued after the figures that allowed this analysis became available. In the Irish parliament, TD Clare Daly commented that, “The Health Service Executive (HSE) decided to purchase Pandemrix and continued to distribute it even after they knew it was dangerous and untested, and before most of the public in Ireland received it.”<ref name=":1">{{cite journal | title = Pandemrix vaccine: why was the public not told of early warning signs? | journal = BMJ | volume = 362 | pages = k3948 | date = 2018-09-20 | pmid = 30237282 | doi = 10.1136/bmj.k3948 | s2cid = 52308748 | last1 = Doshi | first1 = Peter }}</ref>

There were multiple legal cases by individuals who attributed medical conditions to the Pandemrix vaccination.<ref name=":2">{{Cite news|date=2015-06-10|title=Boy wins £120,000 damages for narcolepsy triggered by swine flu vaccine |first=Hannah |last=Devlin |url=http://www.theguardian.com/uk-news/2015/jun/10/boy-wins-120000-damages-narcolepsy-swine-flu-vaccine-glaxosmithkline|access-date=2020-11-20|website=the Guardian|language=en}}</ref> One well known example was the case of Katie Clack, a nurse who committed suicide after developing narcolepsy after receiving a vaccination. Clack was required to be vaccinated against her wishes in order to continue her job as a nurse.<ref>{{Cite news|agency=Press Association |date=2016-08-11|title=Swine flu jab 'most likely' led to narcolepsy in nurse who killed herself – coroner|language=en-GB|newspaper=The Guardian|url=https://www.theguardian.com/uk-news/2016/aug/11/swine-flu-jab-most-likely-led-to-narcolepsy-in-nurse-who-killed-herself-coroner|access-date=2020-11-20|issn=0261-3077}}</ref>

In August 2010, [[Organization:Medical Products Agency (Sweden)|The Swedish Medical Products Agency (MPA)]] and The Finnish National Institute for Health and Welfare (THL) launched investigations regarding the development of [[Medicine:Narcolepsy|narcolepsy]] as a possible side effect to Pandemrix flu vaccination in children.<ref name="lakemedelsverket.se" />

In summer 2010, the MPA and THL received reports from Swedish and Finnish healthcare professionals that [[Medicine:Narcolepsy|narcolepsy]] was a suspected adverse drug reaction to the Pandemrix flu vaccination. The reports concern children 12 to 16 years old, whose symptoms occurred one to two months after vaccination. The symptoms were later confirmed to be compatible with [[Medicine:Narcolepsy|narcolepsy]]. Consumer reports describing similar symptoms were also received. Both organizations, in consultation with external experts, have assessed the possible relationship between the vaccination and the reported reactions. MPA and THL have been in contact with other EU member states to enquire whether there have been any similar reports in other countries.{{cn|date=November 2020}}

THL recommended that further Pandemrix vaccinations be discontinued pending further investigation into 15 cases of recently vaccinated children who developed narcolepsy in late 2009 and early 2010.<ref>{{cite news | url=http://www.thl.fi/en_US/web/en/pressrelease?id=22930 | work=National Institute of Health and Welfare | title=National Institute for Health and Welfare recommends discontinuation of Pandemrix vaccinations | date=2010-08-25 | access-date=2010-08-26 | archive-url=https://web.archive.org/web/20100827075134/http://www.thl.fi/en_US/web/en/pressrelease?id=22930 | archive-date=2010-08-27 | url-status=dead }}</ref> THL later raised this figure to 17; the expected average annual occurrence is 6 cases.<!-- I think it's correct to say 6 not six, per the MOS. All the numerals here are #s of cases --> In Sweden, MPA has discovered 12 confirmed cases and another 12 suspected cases. Additionally, MPA says it is aware of individual case reports from France, Norway and Germany.<ref>{{cite news| url=http://www.lakemedelsverket.se/Alla-nyheter/NYHETER-2010/Aktuell-information-om-utredningen-av-fall-av-narkolepsi-efter-vaccination-med-Pandemrix/ |archive-url=https://web.archive.org/web/20181215132122/http://www.lakemedelsverket.se/Alla-nyheter/NYHETER-2010/Aktuell-information-om-utredningen-av-fall-av-narkolepsi-efter-vaccination-med-Pandemrix/ |archive-date=15 December 2018 |language=sv |work=Medical Products Agency | title=Aktuell information om utredningen av fall av narkolepsi efter vaccination med Pandemrix | date=2010-08-26 | access-date=2010-08-26}}</ref>

On 27 August 2010, the [[Organization:European Medicines Agency|European Medicines Agency]] announced that the agency's Committee for Medicinal Products for Human Use would be launching a review of Pandemrix in light of the "limited number of cases"<ref>{{cite news|url=https://medicalxpress.com/news/2010-08-eu-probes-swine-flu-vaccine.html |title=EU regulator probes swine flu vaccine over narcolepsy fears|publisher=medicalxpress.com |date=2010-08-27|access-date=2010-08-28}}</ref> reported in Finland and Sweden, so as to "determine whether there is evidence for a causal association".<ref>{{cite news|url=https://www.independent.co.uk/life-style/health-and-families/health-news/swine-flu-vaccine-link-to-narcolepsy-probed-2063869.html |archive-url=https://ghostarchive.org/archive/20220524/https://www.independent.co.uk/life-style/health-and-families/health-news/swine-flu-vaccine-link-to-narcolepsy-probed-2063869.html |archive-date=2022-05-24 |url-access=subscription |url-status=live|title=Swine flu vaccine link to narcolepsy probed|newspaper=The Independent|date=2010-08-27|access-date=2010-08-28 | location=London | first1=Jane | last1=Kirby}}</ref>

In August 2010 the Swedish MPA issued a statement which included the following: "An investigation is ongoing, but any relationship between the vaccination and the reported symptoms can not be concluded."<ref>{{cite web|url=http://www.lakemedelsverket.se/english/All-news/NYHETER-2010/Current-information-on-the-investigation-of-cases-of-narcolepsy-after-vaccination-with-Pandemrix/ |archive-url=https://web.archive.org/web/20181215132001/http://www.lakemedelsverket.se/english/All-news/NYHETER-2010/Current-information-on-the-investigation-of-cases-of-narcolepsy-after-vaccination-with-Pandemrix/ |archive-date=15 December 2018 |title=Current information on the investigation of cases of narcolepsy after vaccination with Pandemrix - Swedish Medical Products Agency|website=Lakemedelsverket.se|access-date=8 September 2018}}</ref>

In February 2011, THL concluded that there is a clear connection between the Pandemrix vaccination campaign of 2009 and 2010 and the narcolepsy epidemic in Finland. The probability of developing narcolepsy was determined to be nine times higher in those who received the Pandemrix vaccination than those who didn't. A total of 152 cases of narcolepsy have been found in Finland during 2009–2010, and ninety percent of them had received the Pandemrix vaccination. Authorities believe that the number of cases may still increase.<ref>{{cite web|url=https://www.mtvuutiset.fi/artikkeli/thl-pandemrixilla-ja-narkolepsialla-on-selva-yhteys/1942288 |title=THL: Pandemrixilla ja narkolepsialla on selvä yhteys|website=Mtv3.fi |date=1 February 2011 |access-date=8 September 2018 |language=fi }}</ref><ref>{{cite web|url=http://www.thl.fi/en_US/web/en/pressrelease?id=24103|title=Terveyden ja hyvinvoinnin laitos - THL|website=Terveyden ja hyvinvoinnin laitos|access-date=8 September 2018|archive-url=https://web.archive.org/web/20120905230223/http://www.thl.fi/en_US/web/en/pressrelease?id=24103|archive-date=5 September 2012|url-status=dead}}</ref><ref>{{cite web|url=http://www.thl.fi/fi_FI/web/fi/rokotteet/narkolepsia_ja_sikainfluenssarokote|title=Narkolepsia ja sikainfluenssarokote - THL|website=Terveyden ja hyvinvoinnin laitos|access-date=8 September 2018|archive-url=https://web.archive.org/web/20130517225553/http://www.thl.fi/fi_FI/web/fi/rokotteet/narkolepsia_ja_sikainfluenssarokote|archive-date=17 May 2013|url-status=dead}}</ref>

At the end of March 2011, an MPA press release stated: "Results from a Swedish registry based cohort study indicate a 4-fold increased risk of narcolepsy in children and adolescents below the age of 20 vaccinated with Pandemrix, compared to children of the same age that were not vaccinated."<ref>{{cite web|url=http://www.lakemedelsverket.se/english/All-news/NYHETER-2011/A-Swedish-registry-based-cohort-study-provides-strengthened-evidence-of-an-association-between-vaccination-with-Pandemrix-and-narcolepsy-in-children-and-adolescents-/ |archive-url=https://web.archive.org/web/20190911170137/https://lakemedelsverket.se/english/All-news/NYHETER-2011/A-Swedish-registry-based-cohort-study-provides-strengthened-evidence-of-an-association-between-vaccination-with-Pandemrix-and-narcolepsy-in-children-and-adolescents-/ |archive-date=11 September 2019 |title=A Swedish registry based cohort study provides strengthened evidence of an association between vaccination with Pandemrix and narcolepsy in children and adolescents - Swedish Medical Products Agency|website=Lakemedelsverket.se|access-date=8 September 2018}}</ref>
The same study found no increased risk in adults who were vaccinated with Pandemrix. While cautioning that the increase in risk for children is still uncertain in magnitude, it recommends they not be vaccinated.{{cn|date=August 2022}}

A study by the Stanford University School of Medicine examined the incidence of narcolepsy in relation to upper airway infection and a H1N1 vaccine (not Pandemrix) in Chinese patients. Their principal conclusion was that an increased incidence of narcolepsy was seen following a wave of upper airway infections (such as H1N1 influenza). They found no correlation between vaccination and narcolepsy. According to the authors, "the new finding of an association with infection, and not vaccination, is important as it suggests that limiting vaccination because of a fear of narcolepsy could actually increase overall risk."<ref name="Stanford_narcolepsy_flu">{{Cite web |url=https://med.stanford.edu/news/all-news/2011/08/study-draws-connection-between-narcolepsy-and-influenza.html |title=Study draws connection between narcolepsy and influenza |access-date=2012-10-01 |archive-url=https://web.archive.org/web/20121001212919/http://med.stanford.edu/ism/2011/august/narcolepsy.html |archive-date=2012-10-01 }}</ref>
Since narcolepsy is now believed to be an [[Medicine:Autoimmune disease|autoimmune disease]],<ref name="Stanford_narcolepsy_autoimmune">{{Cite web |url=https://med.stanford.edu/news/all-news/2009/05/narcolepsy-is-an-autoimmune-disorder-stanford-researcher-says.html |title=Narcolepsy is an autoimmune disorder, Stanford researcher says |access-date=6 October 2012 |date=3 May 2009 }}</ref> the authors suspect that these upper airway infections trigger an immune response which leads ultimately to narcolepsy in susceptible individuals. Pandemrix contains two adjuvants designed to provoke a stronger immune response; they were not in the vaccine used in China, however.{{cn|date=November 2020}}

In 2013, the New Scientist reported that "part of a surface protein on the pandemic virus looks very similar to part of a brain protein that helps keep people awake".<ref>{{cite news|url=https://www.newscientist.com/article/dn24772-flu-vaccine-helps-unravel-complex-causes-of-narcolepsy.html|title=Flu vaccine helps unravel complex causes of narcolepsy|publisher=New Scientist|date=2013-12-19|access-date=2014-01-03}}</ref> However, the original scientific article claiming that [[Biology:Hemagglutinin (influenza)|HA protein]] in both the virus and the vaccine could, in some people, trigger an immune reaction against hypocretin, was retracted in 2014 because the data could not be reproduced.<ref>{{cite news|url=http://blogs.nature.com/news/2014/07/journal-retracts-paper-linking-vaccine-and-narcolepsy.html|title=Journal retracts paper linking vaccine and narcolepsy|work=Nature News Blog|date=2014-07-31|access-date=2014-10-07|archive-date=2014-10-11|archive-url=https://web.archive.org/web/20141011200436/http://blogs.nature.com/news/2014/07/journal-retracts-paper-linking-vaccine-and-narcolepsy.html|url-status=dead}}</ref>
However, further investigations indicated that "antibodies to influenza nucleoprotein cross-react with human hypocretin receptor 2".<ref>{{cite journal | vauthors = Ahmed SS, Volkmuth W, Duca J, Corti L, Pallaoro M, Pezzicoli A, Karle A, Rigat F, Rappuoli R, Narasimhan V, Julkunen I, Vuorela A, Vaarala O, Nohynek H, Pasini FL, Montomoli E, Trombetta C, Adams CM, Rothbard J, Steinman L | display-authors = 6 | title = Antibodies to influenza nucleoprotein cross-react with human hypocretin receptor 2 | journal = Science Translational Medicine | volume = 7 | issue = 294 | pages = 294ra105 | date = July 2015 | pmid = 26136476 | doi = 10.1126/scitranslmed.aab2354 | doi-access = free }} {{free access}}</ref><ref>{{Cite web|url=https://www.science.org/content/article/why-pandemic-flu-shot-caused-narcolepsy|title = Why a pandemic flu shot caused narcolepsy}}</ref>

In 2014, a Finnish group published results that showed Pandemrix contained a higher amounts of structurally altered viral nucleoproteins than Arepanrix, a similar vaccine not associated with narcolepsy.<ref>{{cite journal | vauthors = Vaarala O, Vuorela A, Partinen M, Baumann M, Freitag TL, Meri S, Saavalainen P, Jauhiainen M, Soliymani R, Kirjavainen T, Olsen P, Saarenpää-Heikkilä O, Rouvinen J, Roivainen M, Nohynek H, Jokinen J, Julkunen I, Kilpi T | display-authors = 6 | title = Antigenic differences between AS03 adjuvanted influenza A (H1N1) pandemic vaccines: implications for pandemrix-associated narcolepsy risk | journal = PLOS ONE | volume = 9 | issue = 12 | pages = e114361 | year = 2014 | pmid = 25501681 | pmc = 4266499 | doi = 10.1371/journal.pone.0114361 | doi-access = free | bibcode = 2014PLoSO...9k4361V }}</ref>

In 2015, it was reported that the  British Department of Health was paying for [[Biology:Sodium oxybate|sodium oxybate]] medication for 80 patients who are taking legal action over problems linked to the use of the swine flu vaccine, at a cost to the government of £12,000 per patient per year. Sodium oxybate is not available to patients with narcolepsy through the National Health Service.<ref>{{cite news|title=DH funds private prescriptions for drug denied to NHS patients|url=http://www.hsj.co.uk/5087926.article?WT.tsrc=email&WT.mc_id=Newsletter2#.Va1fOdBIgYA|access-date=20 July 2015|publisher=Health Service Journal|date=20 July 2015}}</ref>

In 2018, a multinational study including Centers for Disease Control and Prevention scientists published safety data on adjuvanted pH1N1 vaccines. Sweden was the only country where increased narcolepsy IRs were found in the period after vaccination campaigns. The ability of the researchers to evaluate the Pandemrix brand vaccine was limited.<ref name="National Library for Biotechnology">{{cite journal | vauthors = Weibel D, Sturkenboom M, Black S, de Ridder M, Dodd C, Bonhoeffer J, Vanrolleghem A, van der Maas N, Lammers GJ, Overeem S, Gentile A, Giglio N, Castellano V, Kwong JC, Murray BJ, Cauch-Dudek K, Juhasz D, Campitelli M, Datta AN, Kallweit U, Huang WT, Huang YS, Hsu CY, Chen HC, Giner-Soriano M, Morros R, Gaig C, Tió E, Perez-Vilar S, Diez-Domingo J, Puertas FJ, Svenson LW, Mahmud SM, Carleton B, Naus M, Arnheim-Dahlström L, Pedersen L, DeStefano F, Shimabukuro TT | display-authors = 6 | title = Narcolepsy and adjuvanted pandemic influenza A (H1N1) 2009 vaccines - Multi-country assessment | journal = Vaccine | volume = 36 | issue = 41 | pages = 6202–6211 | date = October 2018 | pmid = 30122647 | pmc = 6404226 | doi = 10.1016/j.vaccine.2018.08.008 | publisher = CDC }}</ref>

In December 2018, T-cells were demonstrated to be cross-reactive to both a particular piece of the pandemic 2009 H1N1 virus and the amidated terminal ends of hypocretin peptides, the loss of which is associated with type I narcolepsy. Genes associated with narcolepsy modulate the expression of the specific T cell receptor recognition involved in reaction to these antigens, suggesting H1N1 infection is a cause of narcolepsy in genetically susceptible individuals. T-cells stimulated by Pandemrix were cross-reactive by [[Biology:Molecular mimicry|molecular mimicry]] with the same part of the hypocretin peptide.<ref name= "mignot2018" />

== See also ==
* [[Chemistry:Oseltamivir|Oseltamivir]] and [[Chemistry:Zanamivir|Zanamivir]] – antiviral drugs used in the treatment and prophylaxis of influenza
* [[Medicine:Influenza vaccine|Influenza vaccine]]
* [[Medicine:2009 flu pandemic vaccine|2009 flu pandemic vaccine]]

== References ==
{{Reflist}}

== External links ==
* [https://www.cdc.gov/vaccinesafety/concerns/history/narcolepsy-flu.html CDC: Narcolepsy Following Pandemrix Influenza Vaccination in Europe]
* [https://web.archive.org/web/20160826115703/https://rxed.eu/en/p/Pandemrix/ Pandemrix: further information on product characteristics and studies]
* [https://journals.viamedica.pl/international_maritime_health/article/viewFile/26212/21006.pdf A study of side-effects of Pandemrix influenza (H1N1) vaccine on board a Norwegian naval vessel]

{{2009 swine flu}}
{{Influenza}}
{{Vaccines}}

[[Category:Influenza vaccines]]
[[Category:Influenza A virus subtype H1N1]]
[[Category:Influenza]]

de:Schweinegrippe-Impfung#Pandemrix

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