When a swine flu pandemic took the world by storm in 2009, drugmakers raced to prepare a vaccine capable of reducing the spread of the virus – but did this same drug cause an increase in narcolepsy amongst those who received it?
In April 2009, reports of a new flu virus began to emerge from Mexico. This new virus had a unique composition of flu genes never seen before in animals or humans, according to the US Centres for Disease Control and Prevention.
By the 15th of April 2009, the first U.S case was detected in California and shortly afterwards, further cases were reported in California, Texas and New York. The virus quickly gained momentum, with cases being reported more frequently in both Mexico and North America.
The World Health Organisation declared the virus a "public health emergency of international concern" towards the end of April, and by June 2009, labelled the outbreak a pandemic.
Read: If you had flu it was most likely swine flu
Race to create vaccines
Amidst the rising global panic, pharmaceutical giants joined the race to develop a vaccination capable of protecting the public from the 2009 H1N1 virus.
By August 2010, the 2009 H1N1 outbreak was considered to be in the "post-pandemic" period, with the number of reported cases rapidly declining.
According to Medical News Today, figures from the World Health Organisation placed the number of deaths resulting from the outbreak at around 200 000, but a study published in The Lancet places these figures closer to 300 000, taking into consideration cardiovascular deaths attributable to the virus.
While the worst of the swine flu outbreak was over, reports of narcolepsy began to emerge among those who had been vaccinated.
Narcolepsy is a disabling neurological disorder of sleep regulation that affects the control of sleep and wakefulness. Symptoms most commonly include excessive daytime sleepiness, cataplexy, sleep paralysis and hypnagogic hallucinations.
While narcolepsy can be managed through behavioural therapy and medication, there is currently no cure for the condition.
Interestingly, almost all cases of narcolepsy occurred in Europe and Asia while the U.S appeared to be unaffected. This seemed particularly strange considering the virus was first detected in North America.
Read: Worrying dip in US child vaccinations
Why was America unaffected?
The answer lies in the actual vaccines used on the different continents.
One of the most widely-used vaccines was Pandemrix, developed by GlaxoSmithKline. In pandemic situations such as the swine influenza outbreak, vaccines need to be developed as quickly as possible to curb transmission of the disease.
Because of this, Emergency Use Authorisations were issued by various drug regulatory bodies, allowing the Pandemrix vaccine to be used on patients in 47 different countries, before the vaccine had undergone the extensive testing usually required for pharmaceutical drugs.
While Pandemrix was used extensively in Europe, it was never approved for use in the United States.
Read: Parents still concerned about the safety of vaccines
The link to narcolepsy
The European Centre for Disease Control and Prevention (ECDC) compiled a technical report after analysing a number of European studies investigating the link between Pandemrix and narcolepsy.
The report concluded that there was an increased incidence of narcolepsy following the Pandermix vaccination campaign in 2009. The association was most noticeable among children and adolescents from Finland and Sweden.
The researchers believe that the vaccine may have interacted with specific environmental or genetic factors, resulting in an increased risk in these countries. Interestingly, Pandemrix was the only H1N1 vaccine available in Finland and Sweden.
While the risk of developing narcolepsy after being vaccinated with Pandemrix is low, the ECDC recommended that the use of Pandremix be restricted.
Their recommendations suggested that people below the age of twenty should only receive Pandemrix if immunisation against H1N1 is still required and the seasonal trivalent influenza vaccine is not available.
Watch what its like to live with narcolepsy:
Read: Flu vaccine linked to rare sleep disorder
A closer look at Pandemrix
The Pandemrix vaccine contains an emulsion known as an adjuvant, called ASO3. Adjuvants are added to increase the body's immune response to the vaccine. AS03 is made up of three components; an oil derived from shark liver, squalene and DL-alpha-tocopherol, a form of vitamin E.
Professor Rose Burnett, a Public Health scientist at the University of Limpopo's Department of Virology, explains why adjuvants are added to vaccines:
"Adjuvants are added to some vaccines to increase the immune response to the vaccine. This is especially necessary for diseases where natural infection does not result in host immunity, which is not the case with flu.
"In the case of most of the A(H1N1) vaccines made for the 2009/2010 pandemic, adjuvants were added to increase immunity in the face of a shortage of vaccine antigen. This is called 'dose-sparing', and has to be done when there is a very large population to protect (the entire world wanted the A(H1N1) pandemic vaccine) and not enough antigen."
Some experts believe that the immune-boosting ASO3 may have affected both positive and negative aspects of the body's immune response.
Markku Partinen, a neurologist based at the Helsinki Sleep Centre in Finland was one of the first researchers to raise the alarm after seeing an increase of narcolepsy cases at his practice in early 2010.
A study conducted by Partinen and published in PLOS ONE found that the annual incidence of narcolepsy amongst Finnish children rose by 17-fold when comparing the annual incidence in 2010 to that from 2002-2009.
In the study, Partinen explains that narcolepsy in an "immune-mediated, autoimmune disorder" and hypothesises why the vaccine may have contributed to narcolepsy:
"The adjuvant (AS03) in the Pandemrix vaccine is very potent, since it frequently induces local inflammatory reactions and occasional systemic side effects like fever.
"We can speculate that the inflammatory response was so strong that it included central nervous system affection. It is, however, difficult to say whether the systemic response produced by the adjuvant could have caused cellular damage.
"The hypocretin-1 levels were very low or undetectable in our narcoleptic patients, which may indicate a rapid destruction of hypocretin cells within weeks or a few months after vaccination. This does not, however, mean that the adjuvant would be causing hypocretin cell damage directly.
"Rather, there is a possibility that already an ongoing autoimmune process was accelerated by the nonspecific inflammatory responses induced by the vaccine or its specific components leading to the destruction of hypocretin producing cells."
Professor Rose Burnett believes that instead of pointing the finger at ASO3 itself, the answer could lie in how the vaccine was prepared:
"It is doubtful that AS03 could have been a trigger, since it was also used in the Canadian A(H1N1) pandemic vaccines, yet there was no increased incidence of narcolepsy in Canada. Based on this fact, there is an hypothesis that the way that the antigen was prepared for Pandemrix may be the problem, as a different method was used for the Canadian vaccine.
"However, this does not explain why out of 47 countries that used Pandemrix, only Sweden, Finland, Norway, Ireland, England and France saw an increase in narcolepsy cases."
Read: Universal flu vaccine could prevent future flu pandemics
What could have been done to prevent Pandemrix-related narcolepsy?
Professor Burnett explains that narcolepsy is a very rare adverse effect of the Pandemrix vaccine. She suggests that even if Pandermix had been subject to more thorough safety testing, it is possible that the risk of narcolepsy still may not have been realised:
"Modern vaccines are subjected to very lengthy clinical trials that test for safety and efficacy, which these days can involve over 60 000 research participants, and take a few years. When a pandemic is declared by the WHO, the public cannot wait for such lengthy trials to be concluded, and must be protected as soon as the WHO ascertains that sufficient safety evidence has been gathered.
"However, narcolepsy following Pandemrix vaccination was a very rare adverse event (between 1 in 16 000 to 1 in 57 500 doses) that occurred in specific populations, so it is doubtful that narcolepsy would have been flagged as a possible adverse event during safety testing, even if Pandemrix had been tested on 60 000 people.
"During the pandemic about 31 million doses of Pandemrix were administered, and to date after intensive case-finding exercises conducted in all countries where the vaccine was used, 904 cases of narcolepsy have been found in six countries. On the other hand, it is estimated that there were more than 280 000 deaths due to wild A(H1N1) virus in the unvaccinated population during the 2009/2010 pandemic."
Where does South Africa fit in?
Professor Burnett explains that while Pandemrix was used in 47 countries around the world, it was not used locally in South Africa. That being said, there are many different type of adjuvanted vaccines that are used all over the world, including South Africa.
"The flu vaccines that we use in South Africa have an excellent safety profile. The WHO recommends that all high risk groups should receive an annual flu vaccine. Pregnant women should be prioritised as they are at the highest risk, but other high risk groups include healthcare workers, children younger than 5 years, the elderly, and people with HIV/AIDS, asthma, chronic lung disease, and chronic heart disease."
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