Pandemrix was found to be associated with an increased risk of narcolepsy[6] following investigations by Swedish and Finnish health authorities[7] and had higher rates of adverse events than other vaccines for H1N1.[8] This resulted in several legal cases.[9]Stanford University studies suggested that narcolepsy is an autoimmune disease[10] and that it appears to be triggered by upper airway respiratory infections.[11]
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.[12]
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 formaldehyde, sodium deoxycholate, and sucrose.[13]
Use of adjuvant
While other 2009 H1N1 vaccines have been developed, the use of a proprietary 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.[13]
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."[14]
Dosage
The vaccine is supplied in separate vials, one containing the adjuvant, and the other the inactivated virus,[15] which require mixing before intramuscular injection. Originally it was thought that two doses given 21 days apart would be required for full efficacy.[16] 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.[17]
Availability
Pandemrix was given to around 70 million individuals, including 31 million Europeans following the 2009 swine flu pandemic.[18][19]
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.[20]
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).[21]
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,[22] from the pediatric clinical trial,[23] and the response from the elderly population.[24]
Side effects
According to GlaxoSmithKline's Patient Information Leaflet,[25] the following side effects may occur (sorted by rate of occurrence):[citation needed]
Very common (affects more than 1 in 10 people)
Headache
Tiredness
Pain, redness, swelling or a hard lump at the injection site
Pandemrix was found to be associated with 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.[6] In 2018, it was demonstrated that T-cells stimulated by Pandemrix were cross-reactive by molecular mimicry with part of the hypocretin peptide, the loss of which is associated with type I narcolepsy.[26]
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.”[8]
There were multiple legal cases by individuals who attributed medical conditions to the Pandemrix vaccination.[9] 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.[27]
In summer 2010, the MPA and THL received reports from Swedish and Finnish healthcare professionals that 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 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.[citation needed]
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.[28] THL later raised this figure to 17; the expected average annual occurrence is 6 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.[29]
On 27 August 2010, the 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"[30] reported in Finland and Sweden, so as to "determine whether there is evidence for a causal association".[31]
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."[32]
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.[33][34][35]
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."[36] 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.[citation needed]
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."[11] Since narcolepsy is now believed to be an autoimmune disease,[10] 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.[citation needed]
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".[37] However, the original scientific article claiming that 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.[38] However, further investigations indicated that "antibodies to influenza nucleoprotein cross-react with human hypocretin receptor 2".[39][40]
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.[41]
In 2015, it was reported that the British Department of Health was paying for 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.[42]
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.[43]
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 molecular mimicry with the same part of the hypocretin peptide.[26]
See also
Oseltamivir and Zanamivir – antiviral drugs used in the treatment and prophylaxis of influenza
GSK plc is a British multinational pharmaceutical and biotechnology company with headquarters in London. It was established in 2000 by a merger of Glaxo Wellcome and SmithKline Beecham, which was itself a merger of a number of pharmaceutical companies around the Smith, Kline & French firm.
Influenza A virus (IAV) is the only species of the genus Alphainfluenzavirus of the virus family Orthomyxoviridae. It is a pathogen with strains that infect birds and some mammals, as well as causing seasonal flu in humans. Mammals in which different strains of IAV circulate with sustained transmission are bats, pigs, horses and dogs; other mammals can occasionally become infected.
Influenza vaccines, colloquially known as flu shots, are vaccines that protect against infection by influenza viruses. New versions of the vaccines are developed twice a year, as the influenza virus rapidly changes. While their effectiveness varies from year to year, most provide modest to high protection against influenza. Vaccination against influenza began in the 1930s, with large-scale availability in the United States beginning in 1945.
Swine influenza is an infection caused by any of several types of swine influenza viruses. Swine influenza virus (SIV) or swine-origin influenza virus (S-OIV) refers to any strain of the influenza family of viruses that is endemic in pigs. As of 2009, identified SIV strains include influenza C and the subtypes of influenza A known as H1N1, H1N2, H2N1, H3N1, H3N2, and H2N3.
Influenza A virus subtype H1N1 (A/H1N1) is a subtype of influenza A virus (IAV). Some human-adapted strains of H1N1 are endemic in humans and are one cause of seasonal influenza (flu). Other strains of H1N1 are endemic in pigs and in birds. Subtypes of IAV are defined by the combination of the antigenic H and N proteins in the viral envelope; for example, "H1N1" designates an IAV subtype that has a type-1 hemagglutinin (H) protein and a type-1 neuraminidase (N) protein.
An influenza pandemic is an epidemic of an influenza virus that spreads across a large region and infects a large proportion of the population. There have been six major influenza epidemics in the last 140 years, with the 1918 flu pandemic being the most severe; this is estimated to have been responsible for the deaths of 50–100 million people. The 2009 swine flu pandemic resulted in under 300,000 deaths and is considered relatively mild. These pandemics occur irregularly.
Influenza A virus subtype H3N2 (A/H3N2) is a subtype of influenza A virus (IAV). Some human-adapted strains of A/H3N2 are endemic in humans and are one cause of seasonal influenza (flu). Other strains of H1N1 are endemic in pigs and in birds. Subtypes of IAV are defined by the combination of the antigenic H and N proteins in the viral envelope; for example, "H1N1" designates an IAV subtype that has a type-1 hemagglutinin (H) protein and a type-1 neuraminidase (N) protein.
H5N1 clinical trials are clinical trials concerning H5N1 vaccines, which are intended to provide immunization to influenza A virus subtype H5N1. They are intended to discover pharmacological effects and identify any adverse reactions the vaccines may achieve in humans.
In immunology, an adjuvant is a substance that increases or modulates the immune response to a vaccine. The word "adjuvant" comes from the Latin word adiuvare, meaning to help or aid. "An immunologic adjuvant is defined as any substance that acts to accelerate, prolong, or enhance antigen-specific immune responses when used in combination with specific vaccine antigens."
The 2009 swine flu pandemic, caused by the H1N1/swine flu/influenza virus and declared by the World Health Organization (WHO) from June 2009 to August 2010, was the third recent flu pandemic involving the H1N1 virus. The first identified human case was in La Gloria, Mexico, a rural town in Veracruz. The virus appeared to be a new strain of H1N1 that resulted from a previous triple reassortment of bird, swine, and human flu viruses which further combined with a Eurasian pig flu virus, leading to the term "swine flu".
This article covers the chronology of the 2009 novel influenza A (H1N1) pandemic. Flag icons denote the first announcements of confirmed cases by the respective nation-states, their first deaths, and relevant sessions and announcements of the World Health Organization (WHO), the European Union , and the U.S. Centers for Disease Control (CDC).
The pandemic H1N1/09 virus is a swine origin influenza A virus subtype H1N1 strain that was responsible for the 2009 swine flu pandemic. This strain is often called swine flu by the public media due to the prevailing belief that it originated in pigs. The virus is believed to have originated around September 2008 in central Mexico.
The 2009 flu pandemic in Europe was part of a pandemic involving a new strain of influenza, subtype H1N1. H1N1 is commonly called swine flu. The pandemic infected at least 125,550 people in Europe. There were 458 confirmed deaths in Turkey, 438 confirmed deaths in Russia, and 457 confirmed deaths in the United Kingdom.
The 2009 swine flu pandemic vaccines were influenza vaccines developed to protect against the pandemic H1N1/09 virus. These vaccines either contained inactivated (killed) influenza virus, or weakened live virus that could not cause influenza. The killed virus was injected, while the live virus was given as a nasal spray. Both these types of vaccine were produced by growing the virus in chicken eggs. Around three billion doses were produced, with delivery in November 2009.
AS03 is the trade name for a squalene-based immunologic adjuvant used in various vaccine products by GlaxoSmithKline (GSK). It is used, for example, in GSK's A/H1N1 pandemic flu vaccine Pandemrix. It is also in Arepanrix and the Q-pan for H5N1 influenza. A dose of AS03 adjuvant contains
2009 swine flu pandemic in Taiwan began on May 20, 2009, when a non-citizen who had been living in Taiwan returned from the United States via Hong Kong. By the end of September, more than 90% of influenza A detected in the community were Influenza A (H1N1).
A H5N1 vaccine is an influenza vaccine intended to provide immunization to influenza A virus subtype H5N1.
Nils Anders Tegnell is a Swedish civil servant and physician specialising in infectious disease. From 2013 until his resignation in March 2022 he was Sweden's state epidemiologist.
Type A influenza vaccine is for the prevention of infection of influenza A virus and also the influenza-related complications. Different monovalent type A influenza vaccines have been developed for different subtypes of influenza A virus including H1N1 and H5N1. Both intramuscular injection or intranasal spray are available on market. Unlike the seasonal influenza vaccines which are used annually, they are usually used during the outbreak of certain strand of subtypes of influenza A. Common adverse effects includes injection site reaction and local tenderness. Incidences of headache and myalgia were also reported with H1N1 whereas cases of fever has also been demonstrated with H5N1 vaccines. It is stated that immunosuppressant therapies would reduce the therapeutic effects of vaccines and that people with egg allergy should go for the egg-free preparations.
↑ WO 2006100109,Hanon, Emmanuel Jules&Stephenne, Jean,"Use of an influenza virus an oil-in-water emulsion adjuvant to induce CD4 T-cell and/or improved B-memory cell response",published 2006-09-28, assigned to Glaxosmithkline Biolog SA
1 2 Sarkanen TO, Alakuijala AP, Dauvilliers YA, Partinen MM (April 2018). "Incidence of narcolepsy after H1N1 influenza and vaccinations: Systematic review and meta-analysis". Sleep Medicine Reviews. 38: 177–186. doi:10.1016/j.smrv.2017.06.006. hdl:10138/300884. PMID28847694.
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