By Regina Patrick, RPSGT

In May 2010, scientists first reported to the National Vaccine Adverse Event Register of the Finnish National Institute for Health and Welfare (THL) an apparent link between narcolepsy and the influenza vaccine Pandemrix.1 By January 24, 2011, the THL had received reports of 57 cases of narcolepsy or narcolepsy with cataplexy that were apparently linked to Pandemrix.1 In response, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency reviewed all available data on the suspected link between narcolepsy and Pandemrix. Based on the CHMP findings, scientists now recommend that Pandemrix should be used only in adults but not in children since children seem to be at an increased risk of developing narcolepsy after receiving the vaccine.2 Despite this recommendation, scientists are not sure there is a link between this vaccine and narcolepsy.

Vaccines often contain a booster (ie, adjuvant) to enhance the immune response. An adjuvant may be a chemical, oil emulsion, modified toxin, or virus-derived protein. Adjuvants can enhance immune response by several means. For example, an adjuvant may trap the antigen at the injection site, which slows the removal of the antigen and allows more antibodies to be produced, thereby enhancing the immune response; or an adjuvant may bind with an antigen to form a large molecule that stimulates the activity of certain immune cells; or an adjuvant may be incorporated in chemical pathways that play a role in the production of immune substances.

Pandemrix is an adjuvanted vaccine that was released in Europe for the 2009–2010 flu season to combat the H1N1 flu virus (more commonly called the swine flu). In Finland and Sweden, the vaccine was administered as part of nationwide vaccination programs. The pharmaceutical company GlaxoSmithKline developed the vaccine, and in September 2006 patented the vaccine.5 Pandemrix contains an adjuvant called ASO3 (which stands for adjuvant system 3). Because Pandemrix contains an adjuvant, it was not used for vaccination programs in the United States—the US Food and Drug Administration has not approved the use of adjuvanted vaccines.

The estimated prevalence of narcolepsy is 0.05% (ie, 1 in 2,000 people has the disorder).1 Approximately 1.4 new cases of narcolepsy per 100,000 people are diagnosed each year (ie, an incidence of 0.0014%).1 Narcolepsy diagnosed in children younger than 10 years old is very rare. For example, in Finland, at most one child younger than 10 years old is normally diagnosed each year.6

In late December 2009, a Finnish boy, who had been vaccinated with Pandemrix, manifested symptoms of narcolepsy (primarily excessive daytime sleepiness).5 He had had no other infections or flu-like illnesses. In February 2010, he was diagnosed as having narcolepsy. His physician suspected that the boy’s narcolepsy was linked to the vaccination. By August 2010, 14 cases of narcolepsy in children were confirmed in Finland.5 On August 15, 2009, the Swedish National Agency for Medicine published its observation on a cluster of narcolepsy cases that were apparently related to Pandemrix.1 Most children had the narcolepsy-cataplexy form of the disease.7

In the spring of 2010, the Medical Products Agency (MPA)—the Swedish national agency that oversees the regulation and surveillance of the development, manufacturing, and sale of drugs and other medicinal products—received more reports of cases of narcolepsy.7 On August 18, 2010, the MPA announced in a press release:

“The MPA has received six reports from health care professionals regarding narcolepsy as suspected adverse drug reaction following Pandemrix flu vaccination. The Agency will, in consultation with external experts, assess the possible relationship between the vaccination and the reported reactions. The MPA is in contact with other EU [European Union] member states to get information if there are any reports in other countries.”8

The MPA subsequently reviewed vaccination information from four counties in Sweden, and in March 2011 published their preliminary report. They found a fourfold increased risk of narcolepsy in children who had had the vaccine, but noted this risk did not affect adults.7

On January 31, 2011, a similar review of vaccination information in Finland was published by the National Institute for Health and Welfare. The THL found a 9.2-fold greater risk of narcolepsy in children who had been vaccinated with Pandemrix than in children who had not received the vaccination.1

On July 27, 2011, the European Medicines Agency—which authorizes and evaluates medicines for use in the European Union—released a health alert to the public concerning Pandemrix, based on the recommendation of its Committee for Medicinal Products for Human Use. The CHMP is a branch of the European Medicines Agency that is responsible for preparing opinions on questions concerning medicines for human use. The CHMP team reviewed epidemiological data from the Finnish and Swedish studies, safety surveillance data from other areas in Europe, case reports from throughout Europe, and the preliminary results of epidemiological studies from eight European Union states. All investigations were undertaken by the CHMP with advice from experts in pediatric neurology, vaccinology, immunology, sleep disorders, infectious diseases, and epidemiology. The committee also worked in collaboration with the World Health Organization, Health Canada, and the European Centre for Disease Prevention and Control. Based on the data, the CHMP concluded that because studies indicated a 6- to 13-fold increase in narcolepsy in children who had been vaccinated with Pandemrix, people younger than 20 years old should not receive the vaccine; however, the vaccine’s benefits otherwise outweigh its risks and it appears to be safe for use in adults.

Other countries where Pandemrix has been used interestingly have not noted a correlation between the vaccine and the development of narcolepsy in children. Scientists are unclear why this correlation appeared in Finland and Sweden. The following are some possible explanations:

1. A faulty vaccine lot.1 Twenty-one vaccine lots were used in Finland and Sweden. Of these, four lots were associated with pediatric narcolepsy in both countries; 11 lots were associated with a single case of narcolepsy in Finland or Sweden alone; and 17 narcolepsy cases in Sweden were associated with two vaccine lots, but these vaccine lots were not distributed in Finland. From this, scientists concluded that the development of narcolepsy could not be attributed to a particular vaccine lot.

2. Genetics. The presence of the HLA-DBQ*0602 gene increases a person’s risk of having narcolepsy. In the THL study,1 all Finnish children with narcolepsy had the gene, indicating no genetic difference among the children who developed narcolepsy after receiving the Pandemrix vaccine.

3. Environmental factors. It may be that an unknown environmental factor in Finland and Sweden contributed to the development of narcolepsy in children.

4. Media bias. In August 2010, a Swedish tabloid notified the public of the link between narcolepsy and Pandemrix. This notification increased awareness and consequently may have increased diagnoses and reports of narcolepsy.

5. Adjuvant-induced pathology.9 It may be that a component in the adjuvant in the vaccine may have negatively altered the function of the immune system in the children who developed narcolepsy. Some research indicates that one component of ASO3—squalene (an organic compound originally derived from sharks)—may induce autoimmunity in some people. (In people with narcolepsy, specialized cells in the hypothalamus that play a role in wakefulness are apparently destroyed by an autoimmune process.)

6. Pre-existence of narcolepsy.9 It may be that the child already had pathophysiological factors for narcolepsy and the administration of Pandemrix may have accelerated—rather than caused—the onset of narcolepsy.

Scientists continue investigations to understand the apparent link between narcolepsy and Pandemrix vaccination in children. If a link is definitively proven, scientists will then need to determine how to produce a vaccine that will improve immunity against the influenza in children while not increasing their risk of developing narcolepsy. SR

Regina Patrick, RPSGT, is a contributing writer for Sleep Review. Questions for the author can be submitted to [email protected].

Vaccines: History and Types

The goal of vaccination is to increase a person’s immunity to a disease by first exposing the person to a less severe form of the disease. The widespread use of vaccination is often credited to English physician Edward Jenner, although various forms of vaccination existed before his famous vaccination experiment in 1796. In the experiment, Jenner took some fluid from the pustules of a person who had cowpox, dried it, and injected it by lancet into a boy. The boy developed symptoms of cowpox (eg, pus-filled blisters, fever, chills, swollen lymph nodes, muscle aches). Once the boy recovered, Jenner took matter from the lesions of a person who had had smallpox and injected it into him. The smallpox and cowpox viruses are similar. However, symptoms of cowpox infection are much milder and usually do not result in death; by contrast, smallpox is a more serious infection that can be fatal. The boy did not develop smallpox, indicating that the previous cowpox infection had made the boy immune to smallpox. In similar fashion, an influenza (ie, flu) vaccine first exposes a person to a milder form of a flu virus to strengthen their immunity against later exposure to a more deadly flu virus strain during a flu season.

A flu vaccine typically contains a whole virus (ie, a virus that contains a DNA or RNA core enclosed within a protein shell that in some viruses is then covered by a lipid envelope) or contains protein fragments from a disease-causing virus. The protein fragments are recognized as “foreign” (ie, as antigens) in the body, which induces the immune system to produce substances (ie, antibodies) that neutralize the effects of the antigen. Because the antibody is specific for an antigen, the immune system is able to recognize and respond to the antigen more quickly if a person is re-exposed to the virus. The faster immune response makes them more resistant to the effects of the flu strain.

To produce a flu vaccine, a virus is first introduced into a live cell such as an animal cell. Most flu vaccines are harvested from fertilized chicken eggs. A small sample of a flu virus is injected into the egg approximately 9 to 12 days after fertilization. The egg is then incubated in a warm humidified environment for 2 to 3 days, during which time the virus multiplies within the egg’s allantoic fluid (ie, a fluid that plays a role in the exchange of gases and in the elimination of liquid waste from the developing chick). The egg is then transferred to a cold environment (39°F), which kills the developing embryo. The virus-filled allantoic fluid is extracted from the egg. The fluid undergoes filtration and centrifugation to separate the virus from the fluid’s other components. The virus is then subjected to other processes, depending on the type of vaccine.

Killed virus vaccines, attenuated vaccines, split virus vaccines, subunit vaccines, and monovalent or polyvalent vaccines are different types of flu vaccines. They are described below.

Killed virus vaccine (also known as inactivated vaccine) contains a whole virus that has been destroyed with chemicals or heat, thereby destroying its virulence.

Attenuated vaccine (also called live vaccine) contains a live whole virus that has weakened (ie, attenuated) virulence. The virus is exposed to conditions such as growing the virus in a foreign host cell (eg, egg or other animal cell) to induce mutations that disable its virulent property.

Split virus vaccines contain proteins from the lipid envelope of the virus. Chemicals are used to separate the virus from its envelope. The envelope proteins stimulate the immune response.

Subunit vaccines contain small protein fragments of a virus—rather than the whole virus—to induce an immune response. The antigenic proteins come from the viral protein coat, which is split apart by chemical or other means. The proteins constitute the “subunits.”

Monovalent/polyvalent vaccines (also called univalent/multivalent vaccines) contain one strain (monovalent) or several strains (polyvalent) of a virus. Multivalent vaccines are used to induce a strong immunity quickly.

The Characteristics of Narcolepsy

The sleep disorder narcolepsy consists of the following four characteristics:

  1. excessive daytime sleepiness;
  2. sleep paralysis;
  3. hypnagogic/hypnopompic hallucinations;
  4. cataplexy.

A person with narcolepsy does not have to have all four symptoms to be diagnosed with the disorder. Most people with narcolepsy struggle with excessive sleepiness. People with narcolepsy often have “sleep attacks” (ie, irresistible overwhelming desire to sleep) that can be relieved with a short nap.

Sleep paralysis is the inability to move on awakening or on going to sleep. Scientists believe sleep paralysis is the manifestation of a rapid eye movement (REM) sleep phenomenon occurring during wakefulness. During REM sleep, all skeletal muscles are normally paralyzed, which prevents a person from acting out dreams. If this aspect of REM sleep occurs simultaneously during wake, a person will be aware of being awake but unable to move.

Hypnagogic and hypnopompic hallucinations result from another phenomenon of REM sleep—dreaming—occurring simultaneously during wakefulness. REM sleep normally occurs approximately every 90 minutes, but in people with narcolepsy, the onset of REM sleep can occur with or soon after the onset of sleep. The dream imagery that occurs with the onset of sleep can be difficult to distinguish as real or dream imagery. (The term “hypnagogic hallucination” is sometimes used to refer to imagery that occurs with onset of sleep or on awakening; however, the distinction between hypnagogic and hypnopompic hallucinations is that hypnagogic hallucinations refer to dream imagery occurring with the onset of sleep and hypnopompic hallucinations refer to dream imagery occurring on awakening from sleep.)

Cataplexy is the sudden, temporary loss of skeletal muscle tone, usually in association with strong positive or negative emotions. The loss of muscle tone can be partial and affect only a few muscles, or it can be total and affect all skeletal muscles. In the latter case, a person will fall suddenly to the ground in an apparent faint. During an episode of cataplexy, which lasts for a few minutes, a person is aware of the environment but is paralyzed and can not respond to external stimuli until the episode is over. A person with narcolepsy who has cataplexy has the most debilitating form of the disease.

There are a few reports of narcolepsy developing after a bacterial or viral infection.3,4 Scientists estimate that approximately 15% of people with narcolepsy developed their symptoms after an infection.3


  1. National Institute for Health and Welfare. National narcolepsy task force interim report: January 31, 2011. Helsinki, Finland. 2011.
  2. European Medicines Agency. 2011. European Medicines Agency recommends restricting use of Pandemrix. (Press release.)
  3. Parkes J, Langdon N, Lock C. Narcolepsy and immunity. Br Med J. 1986;292(6517):359–360.
  4. Han F, Lin L, Warby SC, et al. Narcolepsy onset is seasonal and increased following the 2009 H1N1 pandemic in China. Ann Neurol. 2011;70(3):410-417.
  5. GlaxoSmithKline Biologicals, Inventor. Use of an influenza virus: an oil-in-water emulsion adjuvant to induce CD4 T-cell and/or improved B-memory cell response. September 28, 2006, International Publication Number: WO 2006/100109 A1.
  6. Partinen M, Saarenpaa-Heikkila O, Ilveskoski I, et al. Increased incidence and clinical picture of childhood narcolepsy following the 2009 H1N1 pandemic vaccination campaign in Finland. PloS One. 2012;7(3):e33723.
  7. Lakemedelsverket Medical Products Agency. Occurrence of narcolepsy with cataplexy among children and adolescents in relation to the H1N1 pandemic and Pandemrix vaccinations—results of a case inventory study by the MPA in Sweden during 2009-2010. 2011. Accessed March 8, 2013.
  8. Lakemedelsverket Medical Products Agency. The MPA investigates reports of narcolepsy in patients vaccinated with Pandemrix. August 18, 2010. Accessed March 8, 2013.
  9. Nohynek H, Jokinen J, Partinen M, et al. AS03 adjuvanted AH1N1 vaccine associated with an abrupt increase in the incidence of childhood narcolepsy in Finland. PloS One. 2012;7(3):e33536.