http://www.reuters.com/article/2013/01/ ... 7H20130122
http://www.ctvnews.ca/w5/sleeping-sickn ... -1.1524420
Insight: Evidence grows for narcolepsy link to GSK swine flu shot
By Kate Kelland, Health and Science Correspondent
STOCKHOLM | Tue Jan 22, 2013 7:26am EST
STOCKHOLM (Reuters) - Emelie Olsson is plagued by hallucinations and nightmares. When she wakes up, she's often paralyzed, unable to breathe properly or call for help. During the day she can barely stay awake, and often misses school or having fun with friends. She is only 14, but at times she has wondered if her life is worth living.
Emelie is one of around 800 children in Sweden and elsewhere in Europe who developed narcolepsy, an incurable sleep disorder, after being immunized with the Pandemrix H1N1 swine flu vaccine made by British drugmaker GlaxoSmithKline in 2009.
Finland, Norway, Ireland and France have seen spikes in narcolepsy cases, too, and people familiar with the results of a soon-to-be-published study in Britain have told Reuters it will show a similar pattern in children there.
Their fate, coping with an illness that all but destroys normal life, is developing into what the health official who coordinated Sweden's vaccination campaign calls a "medical tragedy" that will demand rising scientific and medical attention.
Europe's drugs regulator has ruled Pandemrix should no longer be used in people aged under 20. The chief medical officer at GSK's vaccines division, Norman Begg, says his firm views the issue extremely seriously and is "absolutely committed to getting to the bottom of this", but adds there is not yet enough data or evidence to suggest a causal link.
Others - including Emmanuel Mignot, one of the world's leading experts on narcolepsy, who is being funded by GSK to investigate further - agree more research is needed but say the evidence is already clearly pointing in one direction.
"There's no doubt in my mind whatsoever that Pandemrix increased the occurrence of narcolepsy onset in children in some countries - and probably in most countries," says Mignot, a specialist in the sleep disorder at Stanford University in the United States.
30 MILLION RECEIVED PANDEMRIX
In total, the GSK shot was given to more than 30 million people in 47 countries during the 2009-2010 H1N1 swine flu pandemic. Because it contains an adjuvant, or booster, it was not used in the United States because drug regulators there are wary of adjuvanted vaccines.
GSK says 795 people across Europe have reported developing narcolepsy since the vaccine's use began in 2009.
Questions about how the narcolepsy cases are linked to Pandemrix, what the triggers and biological mechanisms might have been, and whether there might be a genetic susceptibility are currently the subject of deep scientific investigation.
But experts on all sides are wary. Rare adverse reactions can swiftly develop into "vaccine scares" that spiral out of proportion and cast what one of Europe's top flu experts calls a "long shadow" over public confidence in vaccines that control potential killers like measles and polio.
"No-one wants to be the next Wakefield," said Mignot, referring to the now discredited British doctor Andrew Wakefield who sparked a decades-long backlash against the measles, mumps and rubella (MMR) shot with false claims of links to autism.
With the narcolepsy studies, there is no suggestion that the findings are the work of one rogue doctor.
Independent teams of scientists have published peer-reviewed studies from Sweden, Finland and Ireland showing the risk of developing narcolepsy after the 2009-2010 immunization campaign was between seven and 13 times higher for children who had Pandemrix than for their unvaccinated peers.
"We really do want to get to the bottom of this. It's not in anyone's interests if there is a safety issue that needs to be addressed," said GSK's Begg.
Emelie's parents, Charles and Marie Olsson, say she was a top student who loved playing the piano, taking tennis lessons, creating art and having fun with friends. But her life started to change in early 2010, a few months after she had Pandemrix. In the spring of 2010, they noticed she was often tired, needing to sleep when she came home from school.
But it wasn't until May, when she began collapsing at school, that it became clear something serious was happening.
As well as the life-limiting bouts of daytime sleepiness, narcolepsy brings nightmares, hallucinations, sleep paralysis and episodes of cataplexy - when strong emotions trigger a sudden and dramatic loss of muscle strength.
In Emelie's case, having fun is the emotional trigger. "I can't laugh or joke about with my friends any more, because when I do I get cataplexies and collapse," she said in an interview at her home in the Swedish capital.
Narcolepsy is estimated to affect between 200 and 500 people per million and is a lifelong condition. It has no known cure and scientists don't really know what causes it. But they do know patients have a deficit of a brain neurotransmitter called orexin, also known as hypocretin, which regulates wakefulness.
Research has found that some people are born with a variant in a gene known as HLA that means they have low hypocretin, making them more susceptible to narcolepsy. Around 25 percent of Europeans are thought to have this genetic vulnerability.
When results of Emelie's hypocretin test came back in November last year, it showed she had 15 percent of the normal amount, typical of heavy narcolepsy with cataplexy.
The seriousness of her strange new illness has forced her to contemplate life far more than many other young teens: "In the beginning I didn't really want to live any more, but now I have learned to handle things better," she said.
Scientists investigating these cases are looking in detail at Pandemrix's adjuvant, called AS03, for clues.
Some suggest AS03, or maybe its boosting effect, or even the H1N1 flu itself, may have triggered the onset of narcolepsy in those who have the susceptible HLA gene variant.
Angus Nicoll, a flu expert at the European Centre for Disease Prevention and Control (ECDC), says genes may well play a part, but don't tell the whole story.
"Yes, there's a genetic predisposition to this condition, but that alone cannot explain these cases," he said. "There was also something to do with receiving this specific vaccination. Whether it was the vaccine plus the genetic disposition alone or a third factor as well - like another infection - we simply do not know yet."
GSK is funding a study in Canada, where its adjuvanted vaccine Arepanrix, similar to Pandemrix, was used during the 2009-2010 pandemic. The study won't be completed until 2014, and some experts fear it may not shed much light since the vaccines were similar but not precisely the same.
It all leaves this investigation with far more questions than answers, and a lot more research ahead.
WAS IT WORTH IT?
In his glass-topped office building overlooking the Maria Magdalena church in Stockholm, Goran Stiernstedt, a doctor turned public health official, has spent many difficult hours going over what happened in his country during the swine flu pandemic, wondering if things should have been different.
"The big question is was it worth it? And retrospectively I have to say it was not," he told Reuters in an interview.
Being a wealthy country, Sweden was at the front of the queue for pandemic vaccines. It got Pandemrix from GSK almost as soon as it was available, and a nationwide campaign got uptake of the vaccine to 59 percent, meaning around 5 million people got the shot.
Stiernstedt, director for health and social care at the Swedish Association of Local Authorities and Regions, helped coordinate the vaccination campaign across Sweden's 21 regions.
The World Health Organisation (WHO) says the 2009-2010 pandemic killed 18,500 people, although a study last year said that total might be up to 15 times higher.
While estimates vary, Stiernstedt says Sweden's mass vaccination saved between 30 and 60 people from swine flu death. Yet since the pandemic ended, more than 200 cases of narcolepsy have been reported in Sweden.
With hindsight, this risk-benefit balance is unacceptable. "This is a medical tragedy," he said. "Hundreds of young people have had their lives almost destroyed."
PANDEMICS ARE EMERGENCIES
Yet the problem with risk-benefit analyses is that they often look radically different when the world is facing a pandemic with the potential to wipe out millions than they do when it has emerged relatively unscathed from one, like H1N1, which turned out to be much milder than first feared.
David Salisbury, the British government's director of immunization, says "therein lies the risk, and the difficulty, of working in public health" when a viral emergency hits.
"In the event of a severe pandemic, the risk of death is far higher than the risk of narcolepsy," he told Reuters. "If we spent longer developing and testing the vaccine on very large numbers of people and waited to see whether any of them developed narcolepsy, much of the population might be dead."
Pandemrix was authorized by European drug regulators using a so-called "mock-up procedure" that allows a vaccine to be authorized ahead of a possible pandemic using another flu strain. In Pandemrix's case, the substitute was H5N1 bird flu.
When the WHO declared a pandemic, GSK replaced the mock-up's strain with the pandemic-causing H1N1 strain to form Pandemrix.
GSK says the final H1N1 version was tested in trials involving around 3,600 patients, including children, adolescents, adults and the elderly, before it was rolled out.
The ECDC's Nicoll says early warning systems that give a more accurate analysis of a flu strain's threat are the best way to minimize risks of this kind of tragedy happening in future.
Salisbury agrees, and says progress towards a universal flu vaccine - one that wouldn't need last-minute changes made when a new strain emerged - would cuts risks further.
"Ideally, we would have a better vaccine that would work against all strains of influenza and we wouldn't need to worry about this ever again," he said. "But that's a long way off."
With scientists facing years of investigation and research, Emelie just wants to make the best of her life.
She reluctantly accepts that to do so, she needs a cocktail of drugs to try to control the narcolepsy symptoms. The stimulant Ritalin and the sleeping pill Sobril are prescribed for Emelie's daytime sleepiness and night terrors. Then there's Prozac to try to stabilize her and limit her cataplexies.
"That's one of the things that makes me feel most uncomfortable," she explains. "Before I got this condition I didn't take any pills, and now I have to take lots - maybe for the rest of my life. It's not good to take so many medicines, especially when you know they have side effects."
(This story has been corrected to insert full name in first paragraph)
(Reporting by Kate Kelland; Editing by Will Waterman)
Sleeping Sickness: A W5 investigation into the sudden rise in childhood narcolepsy
Avis Favaro & Elizabeth St. Philip, W5
Published Saturday, November 2, 2013 9:00AM EDT
Last Updated Saturday, November 2, 2013 11:14PM EDT
It's a medical mystery. Why are children all around the world developing severe narcolepsy -- a rare sleeping disorder with no known cure?
It is a question that Christine and Ian pondered after their perfectly healthy daughter developed symptoms, shortly after being hospitalized with a flu like infection in 2011.
Makenna was once an alert and active young girl but now she falls asleep without warning.
Her parents took Makenna off her medication temporarily to show W5 the effects of the disorder. As they play a board game in the kitchen, her head starts to bob and then Makenna face hits the table.
Then there is a bizarre related symptom called cataplexy, which also affects her. Makenna suddenly loses muscle control and collapses when she laughs or feels strong emotions, something that happens to the eight-year-old several times a day.
When her mother hugs her, Makenna simply drops. She's awake but paralyzed. Her parents make it safe for her to have these symptoms at home, but out in the world, it's a different matter.
"We do a lot to keep her safe, but I worry about her when she is on her own," said her mother, Christine, who asked W5 not to reveal their last name or home town to preserve their privacy.
"We had to take her out of swimming, if she had an episode she would quickly drown. All of those things you do every day, walking down the stars, what if she loses her legs and just goes limp?" said her father Ian.
Makenna is now on several medications to keep her alert during the day, so she can take part in school and gymnastics. But this bright articulate girl wonders what lies ahead.
“What kind of job am I going get? And if I am going to be able to drive or not, and how will I handle a baby, if I can even have one,” said Makenna.
In Alberta, 11 year-old Matthew also suffers from bouts of extreme sleepiness and cataplexy. His symptoms suddenly emerged a year ago.
“As a parent our hearts kind of dropped to our stomach we were not prepared for something like that,” said his father Jeff, who did not want the family’s last name used.
“As we started to understand the diagnosis a bit more we started to realize that it wasn’t just something you could cure overnight, it was a lifelong challenge for Matthew and it was going to involve a lot of structure in his life.”
Matthew now takes five pills a day to help control his narcolepsy and cataplexy and must nap at school to stay alert. His parents still wonder what caused his condition to appear so suddenly.
“We are curious and we wonder why it happened and we like to know where it originated from” said Jeff.
His mother Sherri added, “It would be nice to know how so it can help others from getting it.”
So what caused the illness that has stricken these two children?
Blood tests suggest those who develop narcolepsy have a genetic susceptibility. But doctors know that narcolepsy needs an environmental trigger -- a virus or infection that destroys cells that regulate the wake sleep cycle.
Makenna's parents now wonder about two events in her childhood. She was vaccinated against the H1N1 virus during the pandemic flu outbreak in 2009. Over a year later she developed a severe flu-like infection. Her symptoms began four weeks later.
"We thought okay, we'll something happened there and this appears to be a fallout from that," said Ian.
Pediatric sleep medicine specialist Dr. Manisha Witmans told W5 she has seen a baffling spike in cases among patients at her clinic, the Synergy Wellness Centre in Edmonton. Narcolepsy is a rare condition, and Witmans usually treats only two cases annually. In the last year and a half, however, she has diagnosed 10 pediatric cases, with four to five more awaiting definitive tests.
"I was shocked," said Witmans. "I noticed that the cases were more severe and in that most of the children that I see now have cataplexy and that can be unusual in children."
Witmans told W5 that she's not alone in seeing a sudden surge, as colleagues in Toronto, Seattle, Washington and Philadelphia are reporting similar increases in this rare brain disorder. She is now collecting data and hopes to make her report public in the coming months.
The H1N1 Link
The spike in narcolepsy, particularly among children, has also been reported outside North America, with cases in China and across Europe. The symptoms, like Makenna’s began abruptly and are often severe.
“I was swamped," said Dr. Catherine Crowe, a sleep specialist at the Mater hospital in Dublin.
"There were so many patients coming, normally I would see a few patients a year. And here I was having young narcoleptic patients every week," she told W5. "I was just amazed. Nothing like it obviously, this was terrible seeing all these little children like this."
"For me it has all the elements of a detective story," said Dr. Emmanuel Mignot, director of the Stanford Center for Sleep Sciences and Medicine, and one of the world’s leading experts on narcolepsy.
Dr. Mignot is on the hunt to understand the cause of the phenomenon, collecting blood samples from children with the disorder from around the globe. In China he reviewed narcolepsy cases following the 2009 H1N1 pandemic. He discovered that China had a threefold increase in the sleep disorder. The majority were children.
His theory is that in some cases, the H1N1 virus itself triggered the immune system to destroy hypocretin cells in the brain that run the sleep-wake cycle, research he published in the Annals of Neurology in 2011.
"Before H1N1 we were getting closer but we could not really find (the trigger)," he said. “And then with H1N1 it was clear that the flu had to be involved at least for this outbreak.”
His research is also showing most of the children affected by the outbreak -- had a genetic predisposition to narcolepsy.
Dr. Mignot hopes to turn this insight into a new diagnostic tests and possibly new treatments for a long neglected disorder. He hopes to publish his research next year.
But the swine flu virus appears to be only one part of the puzzle.
The disorder, the virus and the vaccine
In 2009, new vaccines had been introduced at the height of H1N1 pandemic when world health officials feared that the swine virus could sicken and kill millions. By 2010, researchers from Sweden and Finland were reporting a link between narcolepsy and a H1N1 flu vaccine named Pandemrix – a vaccine manufactured by GlaxoSmithKline and used in 47 countries.
By 2013, there were 800 children with narcolepsy who had been linked to vaccination against the flu across Europe, with doctors reporting more cases emerging in adults. The Scandinavian studies were supported by research from France, Norway, Ireland and the UK with some scientists reporting a seven to 13-times higher risk of narcolepsy after vaccination.
Pandremix contained a deactivated part of H1N1 virus. But it also had a novel adjuvant, or booster, called ASO3 that could induce a powerful immune reaction. The advantage is that adjuvants allow vaccine doses to be made quickly and with a worldwide pandemic threatened the World Health Organization had asked for speeded up delivery.
Mignot believes the combination may have created a perfect storm -- a virus that could trigger narcolepsy, children with a genetic predisposition to the disorder and a vaccine containing a potent adjuvant that may have made those children all the more susceptible.
"What happened is the adjuvant really does its job. It is something that is supposed to boost the immune response and together with the H1N1 it just produced a too strong immune response and then it increased the risk of developing narcolepsy," said Mignot.
Other researchers are also investigating the sudden increase and the possible vaccine link. Dr. Jeff Kwong, a scientist with the University of Toronto and the Institute for Clinical and Evaluative Studies there, is examining records of children aged four to 19 vaccinated in Ontario during 2009 and 2010 to see if there is an increase in narcolepsy cases.
Glaxo SmithKline is investigating the link between its vaccine and narcolepsy. But they believe there is insufficient evidence to draw any conclusions.
In an e-mailed statement to W5 they wrote: “Epidemiological data currently available to GSK suggest an increased risk of narcolepsy following vaccination with Pandemrix (H1N1).
"Further research is needed to determine whether the observed risk is related to the vaccine, environmental effects, genetic factors, other factors or a combination of them."
In Europe, parents of children affected have formed support groups to demand answers and compensation.
W5 traveled to Dublin to meet members of Sufferers of Unique Narcolepsy Disorder (SOUND), a group representing 60 children struggling with narcolepsy and cataplexy.
"Jenna was a perfectly healthy before she ever had her vaccine, and overnight she turned around and slept 75 per cent of her life away," said Mark Haide, whose daughter was three when she was vaccinated.
Tom Matthews' 16-year-old daughter Ellen began having symptoms just weeks after she got vaccinated.
"I would say in our case, the incidence of a healthy child becoming a sick child, the main event was the vaccination. There was no other measure that took place, said Matthews.
Ray Donovan's eight-year-old son Alex has the sleep disorder. He now suffers from depression and said he "wishes he was never born".
In Canada there many questions remain. What is the total number of new pediatric narcolepsy cases since the swine flu? Are they linked to the virus or the vaccine?
Documents reviewed by W5 reveal that eleven million doses of a Glaxo SmithKline vaccine called Arepanrix – were used in 2009 and 2010 during massive public health inoculation programs. Arepanrix contained a similar ASO3 adjuvant to that is being studied in Europe.
So far five cases of childhood narcolepsy following vaccination have been officially reported to the Public Health Agency of Canada, which concluded that the data so far "does not suggest a vaccine safety concern." Furthermore, the vaccine is no longer in use now that the pandemic is over, confirmed by Glaxo SmithKline.
Researchers in Quebec have reported a four-times increased risk of narcolepsy after vaccination, compared to those who did not receive the vaccine. In that province GlaxoSmithKline is supporting.
According to Dr. Philippe de Wals, an epidemiologist at the Université Laval, it amounts to one case of narcolepsy for every one million doses of vaccine, a very remote risk. He said the data also suggests that some of the cases are only linked to infection with the H1N1 virus.
"Further research is needed to evaluate the potential association between GSK's adjuvanted H1N1 pandemic flu vaccine and narcolepsy in a country where a similar vaccine to Pandemrix™ (H1N1) was used," the company said in its e-mailed statement.
The preliminary results of this study are anticipated to be published by early 2014. But doctors interviewed by W5 predicted that this story is just beginning.
Whitmans said some of her patients in Alberta developed narcolepsy symptoms after the vaccination with Arepanrix. Others recently diagnosed were never inoculated and may have only been exposed to the flu virus. Many took months to get a proper diagnosis. Ultimately, she believes there may be many children who are suffering from narcolepsy but have not yet been formally diagnosed.
"I think there are a lot more kids out there that are affected that are out there that we don’t know," said Witmans. “We need to work together so we can identify these individuals and learn from them and figure out what are the factors that made them vulnerable and how to help them.”
That's why Makenna's family came forward with their story hoping to connect with other affected Meantime, Dr. Mignot wants the public to understand that the increase in narcolepsy cases seems to be the result of a perfect medical storm -- a powerful flu virus, narcolepsy and a vaccine that set out to protect millions around the world, but which may have produced collateral damage.
Dr. Mignot worries the cases may raise unfounded fears about all vaccines. He remains a staunch supporter of childhood vaccines for whooping cough, measles and mumps as well as the annual flu vaccination which he stresses save lives and remain very safe.
RAPID RESPONSES FOR:
Risk of narcolepsy in children and young people receiving AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine: retrospective analysis
Re: Risk of narcolepsy in children and young people receiving AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine: retrospective analysis
29 March 2013
Theodore Tsai, pediatrician
Giuseppe Del Giudice, Antonio Crucitti, John Weil, Vas Narasimhan
Novartis Vaccines and Diagnostics, 350 Massachusetts Ave Cambridge, MA 02139 USA
Competing interests: All authors are full time employees of Novartis Vaccines and Diagnostics, a manufacturer of adjuvanted pandemic influenza vaccines.
We read with interest the findings of Miller and colleagues on the association of narcolepsy with the AS03-adjuvanted pandemic A(H1N1)pdm09 vaccine in England and, in particular, their call for investigations of other A(H1N1)pdm09 vaccines to ascertain their risk to cause narcolepsy.1 Risk estimates above ten are unusual, and in pharmacoepidemiology lead to the suspicion of unknown confounding factors. The UK data, confirming previous reports,2,3 considerably lessens the likelihood of confounding. However, the mechanisms by which the AS03-adjuvanted pandemic vaccine’s components may have contributed to an increased risk for narcolepsy are unclear and may be difficult to dissect, as the still uncertain pathogenesis of Guillain Barre syndrome (GBS) following influenza vaccination illustrates.
Previous observations suggest that similar vaccines may have subtle differences that manifest themselves in different ways or in different seasonal formulations – e.g., oculorespiratory syndrome has been associated prominently with one split seasonal vaccine product but not with others4, and perhaps appropriate in the context of narcolepsy cases occurring in 2009-10, the incidence of GBS associated with seasonal influenza vaccines has fluctuated though never to as high an incidence as was seen in 1976, in association with the A/New Jersey/76 (Hsw1n1) pandemic vaccine.5 In addition, as noted by Miller, one observation suggested that the pandemic infection itself may have triggered an increase in narcolepsy cases.6,7 Thus, the pandemic virus, or its antigens, cannot be excluded as having contributed to the origin of narcolepsy in pandemic vaccine-associated cases in 2009-10.
Novartis Vaccines and Diagnostics distributed approximately 107 million doses of two pandemic vaccines containing the emulsion adjuvant, MF59® (unpublished data, Novartis Vaccines and Diagnostics). In response to Miller et al, we briefly summarise the available data on the occurrence of narcolepsy cases in conjunction with the distribution of these vaccines. The MF59®-adjuvanted vaccines, containing egg or cell culture derived viral subunit antigens, were distributed in more than 17 countries, though the actual number of doses administered and their deployment by age are unknown to us. The association between narcolepsy and MF59-adjuvanted pandemic vaccine was investigated through active case finding only in the Netherlands, where an estimated 72% of individuals 5-64 years of age with risk factors were vaccinated with that vaccine.8 No MF59-adjuvanted vaccine associated-cases of narcolepsy were identified during the primary study period through active case finding at nine referral sleep centres.8
Passively-acquired data come from Argentina, where only an MF59-adjuvanted vaccine was used in the national pandemic response and high coverage was achieved in high risk persons 5-64 years-old, but no cases were reported to the Administración Nacional de Medicamentos, Alimentos y Tecnología Médica.9 A search of the Novartis Pharmacovigilance database disclosed one spontaneously reported case from Switzerland meeting a level 2 Brighton Collaboration and European Narcolepsy Network case definition of narcolepsy, and another with insufficient confirmatory information classified as > level 3 (Novartis data on file).10-12 Other events of special interest that included certain autoimmune and neurological diseases were not spontaneously reported at unusual frequency in connection with the adjuvanted pandemic vaccines or MF59-adjuvanted subunit seasonal vaccine, which was first licensed in 1997.13,14,
The absence of a narcolepsy signal in connection with pandemic vaccine adjuvanted with MF59 may reflect differences in adjuvant compositions (Table 1) and mechanisms of action. 15,16 Notably, MF59 is comprised of a single emulsified oil, squalene, and does not contain alpha-tocopherol. While MF59 is a local activator only of the mouse transcriptome in muscle at the injection site, it does not upregulate genes controlling innate immunity distally, in draining lymph nodes.15 In contrast, AS03, which contains squalene co-emulsified with the ‘immunomodulator’ alpha-tocopherol, activates innate immune responses in the draining lymph nodes of immunized mice, independently of antigen.16 Its more generalized immune potentiation is mediated directly by alpha-tocopherol which further amplifies the adjuvant activity of AS03, making it more potent than a squalene only adjuvant.16 But, as alluded to above, other factors may be operative. The association of narcolepsy, which is believed to be an autoimmune disorder, with the AS03-adjuvanted vaccine may not be due strictly to the vaccine adjuvant. Reporting rates for autoimmune disorders (not including narcolepsy) within EudraVigilance were no greater for adjuvanted pandemic vaccines (including both MF59 and AS03-adjuvanted vaccines) than for nonadjuvanted pandemic vaccines.17
In summary, the available but limited observations have not signalled an increased risk of narcolepsy associated with MF59-adjuvanted pandemic vaccines. The aetiology of cases in 2009-10 appears complex and contributory roles of the pandemic virus or vaccine antigens should not be excluded, while attributing the elevated risk associated with AS03-adjuvanted vaccine solely to the adjuvant may be premature.
Table 1. Composition of MF59 and AS03: oil-in-water emulsion adjuvants that are components of licensed adjuvanted vaccines (mg/dose)
23 April 2013
Lennart Waldenlind, MD, PhD, Pharmacovigilance assessor
Birgitta Grundmark, Faranak Azarbayjani, Andreas Börjesson, Hans Olaisson
Department of Pharmacovigilance, Medical Products Agency, Uppsala, Sweden, PO Box 26, SE-751 03 Uppsala, Sweden
Competing interests: None declared
We have with great interest read the article by Miller et al regarding Pandemrix and narcolepsy in England (Miller E, Andrew N, Stellitano L, Stowe J, Winstone AM, Shneerson J, Verity C. Risk of narcolepsy in children and young people receiving AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine: retrospective analysis. BMJ. 2013;346:1-11). The authors find, in line with previous studies, an increased risk of narcolepsy after vaccination with AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine; OR 16.2 (95% CI 3.1-84.5) and call for further studies to assess if any similar association exists also for other influenza vaccines.
Several influenza vaccines are available on the European market, both adjuvanted and non-adjuvanted. Suspected adverse vaccine reactions (ADR) are mandated to be reported to the soon fully publicly accessible (http://www.adrreports.eu
) Pan-European ADR database EudraVigilance (EV). Since public awareness of the Pandemrix-Narcolepsy signal was raised the first suspected association between a non-adjuvanted influenza vaccine and narcolepsy was reported to the EV in August 2010 from the health profession. The number has since accumulated to 18 cases by September 2012. The information quality in reported cases may vary due to the inherent character of ADR reports. Still, narcolepsy appears medically verified in 15 of the reported cases, in a majority of which an abrupt symptom development after onset of typical first symptoms (e.g. cataplexy, sleeping attacks), was reported similarly to what previously has been described for Pandemrix-related cases. Half of the cases originate from the EU area (9; 8 from US and 1 from Taiwan) and more than half (10/18) concern children/adolescents (≤ 18 year of age). In the latter group, a majority of cases tested positive (7/8) for the predisposing HLA gene DQB10606. Genotyping was not specified for any of the cases aged above 18 years. The time between vaccination and symptom onset was detailed in 13 of the 18 cases averaging 2-3 months. In another 3 cases onset time was estimated to be less than 3, 4-5 and 6 months, respectively.
Potential explanatory factors in the now reported cases could be Pandemrix use and/or influenza infection. In two cases Pandemrix was given either concomitantly with the non-adjuvanted influenza vaccine or one year before symptom onset while influenza infection was not reported in any of the cases. Thus, no potential confounding was reported in 16 of the 18 cases.
The mechanism of the Pandemrix-induced narcolepsy has not yet been established.
Different causes have been considered. In a review article Gilbert SC emphases that “It is important to note that influenza infection can also trigger narcolepsy, and that this is a property of the influenza virus antigens rather than any particular vaccine or its adjuvant
.” (Gilbert SC, Influenza vaccines and immunopathology. Expert Rev. Vaccines 2012;11(8): 873-875).
Narcolepsy is an extremely rare disease and the discovery of its association with Pandemrix from spontaneous reporting was facilitated by the short-term, massive exposure in relevant age groups. The cluster of cases arising during the last few years of suspected non-adjuvanted influenza vaccines, where a similar exposure situation does not exist, gives further insight into the view of Miller et al that further studies to assess the risk, if any, are needed for other influenza vaccines besides Pandemrix.
The views of this rapid response represent the authors and are not necessarily any official views of the Swedish Medical Products Agency where the authors are (partly) employed.
Just to confirm that no adjuvanted influenza vaccines are licensed in the United States
according to the CDC:
http://www.cdc.gov/vaccinesafety/Concer ... emrix.html
CDC statement on narcolepsy following Pandemrix influenza vaccination in Europe
An increased risk of narcolepsyExternal Web Site Icon was found following vaccination with Pandemrix, a monovalent 2009 H1N1 influenza vaccine that was used in several European countries during the H1N1 influenza pandemic. Narcolepsy is a chronic neurological disorder caused by the brain’s inability to regulate sleep-wake cycles normally. This risk was initially found in Finland, and then some other European countries also detected an association. Most recently, scientists at the United Kingdom’s (UK) Health Protection Agency (HPA) have found evidence of an association between Pandemrix and narcolepsy in children in England. The findings are consistent with studies from Finland and other countries.
Pandemrix is manufactured by GlaxoSmithKline in Europe and was specifically produced for pandemic 2009 H1N1 influenza. It was not used before 2009, and has not been used since the influenza pandemic season (2009-2010). It contains an oil-in-water emulsion adjuvant called ASO3. Adjuvants are substances added to a vaccine to increase the body's immune response to that vaccine.
Pandemrix was not licensed for use in the United States. In fact, no adjuvanted influenza vaccines are licensed in the United States, and no adjuvanted influenza vaccines were used in the United States during the influenza pandemic or in any other influenza season.
In response to the events in Europe, CDC reviewed data from the U.S. Vaccine Adverse Event Reporting System (VAERS) External Web Site Icon and the Vaccine Safety Datalink (VSD) and to date have found no indication of any association between U.S.-licensed H1N1 or seasonal influenza vaccine and narcolepsy.
CDC is currently sponsoring an international study on the associations between adjuvanted monovalent 2009 H1N1 influenza vaccines and narcolepsy. That study is expected to be completed in 2014.
Page last reviewed: February 26, 2013
Page last updated: March 27, 2013
Content source: Centers for Disease Control and Prevention
National Center for Emerging and Zoonotic Infectious Diseases (NCEZID)
Division of Healthcare Quality Promotion (DHQP)
That said, it seems that the adjuvant AS03 has been recommended for approval by an advisory committee of the FDA in a future
vaccine -- unless I've misunderstood the following. If licensed, the vaccine won't be marketed by the manufacturer (GSK) -- but by the U.S. government itself.
FDA Panel Supports H5N1 Adjuvant Vaccine
November 16, 2012
By unanimous vote, an advisory committee of the US Food and Drug Administration (FDA) recommended approval this week of GlaxoSmithKline's H5N1 adjuvanted influenza vaccine based on the strength of supporting data from 2 pivotal trials.
In an open session streamed live over the Internet on November 14, the FDA's 14-member Vaccines and Related Biological Products Advisory Committee agreed that the safety and immunogenicity data for the monovalent influenza A vaccine, which contains GlaxoSmithKline's proprietary adjuvant AS03, supports licensure of the active vaccine in individuals aged 18 years or older who are at risk for exposure to the H5N1 influenza virus subtype. The move brings the vaccine a step closer to becoming the first FDA-approved adjuvant influenza vaccine in the United States.
Development of the antigen-sparing vaccine was sanctioned by the US government through a contract with the manufacturer. As such, if licensed, the vaccine will be owned and distributed by the government in the event of a pandemic and will not be marketed by GlaxoSmithKline.
Compared with influenza vaccines without adjuvants, which contain 15 μg of antigen, the AS03-boosted vaccine contains 3.75 μg of antigen, according to a briefing document supplied by the FDA. If the vaccine's biologic license application successfully navigates the FDA's accelerated approval process, it will be included in the US pandemic emergency stockpile for distribution as per the US Department of Health and Human Services Pandemic Influenza Plan.
The accelerated approval protocol allows licensing decisions to be made on the basis of evidence of immunogenicity via antibody response rather than evidence of actual protection from clinical trials. The latter will be required if accelerated approval is granted, the briefing document explains.
The question of how such confirmation would be made was addressed by the panel, with at least 5 members advocating an efficacy study of the vaccine conducted during an H5N1 influenza pandemic. Other panel members suggested that data from an efficacy study of a seasonal influenza vaccine manufactured using the same process of the adjuvanted product would be more feasible.
Bruce Innis, vice president of vaccine discovery and development at GlaxoSmithKline, said the company plans to pursue the latter approach, suggesting that data from the efficacy study of FluLaval, the company's seasonal, unadjuvanted H1N1 vaccine, "uses the same manufacturing process and could be used to confirm the clinical benefit of Q-Pan H5N1," which is the informal name for the adjuvanted vaccine.
Need for 2 Doses Raises Flag
As part of the assessment of supporting evidence for the current recommendation, Andrea James, MD, from the FDA's Center for Biologics Evaluation and Research, discussed the findings of the 2 key North American multicenter trials, including a 680-participant study (in which the vaccine was compared with the same vaccine without the adjuvant) and a trial involving 4561 adults (in which the active vaccine was compared with placebo).
In the former study, "2 doses of the vaccine were required to achieve an adequate immune response based on the FDA criteria [defined as a titer greater than 1:40 measured by a hemagglutination inhibition assay]," Dr. James said.
The need for 2 doses raised a flag for at least 1 panel member, Pedro Piedra, MD, from Baylor College of Medicine in Houston, Texas, who acknowledged that although the Center for Biologics Evaluation and Research's definition for immunogenicity was met, "many individuals may only get 1 dose. One needs to think about how down the road we can do better than a 2-dose requirement."
The second study demonstrated achievement of a positive antibody response in 70% of adults aged 18 to 65 years and in 60% of those older than 65 years. "After 2 doses of the vaccine, the seroconversion rate among working-age adults was approximately 91%, and among older adults it was 74%," Dr. James reported. The respective seroconversion rates for the placebo recipients in both age groups were 1.3% and 2.5%, she said.
With respect to adverse events, "we saw more frequent local and systemic reactogenicity and more severe local reactogenicity associated with the vaccine in both trials," Dr. James said during the open session. Specifically, injection-site pain was 4 times more prevalent and myalgia twice as prevalent in the adjuvant group compared with in the no-adjuvant group in the first trial, and both events were twice as common in the vaccine group in the second trial.
Because mortality associated with influenza A H5N1 subtype viral infection is highest among children and young adults, GlaxoSmithKline is currently conducting studies of the vaccine in children older than 16 months and plans to expand the approval application accordingly, Innis stated.
The FDA expects to reach a final decision on the vaccine's approval in December 2012, according to the briefing document. "If approved, the vaccine is to be used only according to official guidance from the US Government."
Dr. James and Dr. Piedra have disclosed no relevant financial relationships.
Given that it was mostly children with a genetic predisposition to narcolepsy who were at possible risk with the 2009 H1N1 vaccine containing the adjuvant AS03, I would think this
would raise red flags.