GLOBAL MARKETS-Asia stocks rise, euro steady as relief from French vote buoys sentiment
* Asia ex-Japan, Nikkei post gains as market euphoria persists
LONDON Feb 7 Mounting evidence of a link between GlaxoSmithKline's Pandemrix flu shot and a spike in narcolepsy cases among children in Europe is putting one of the vaccine's key ingredients, AS03, under intense scrutiny.
The ingredient is one of a class of pharmaceuticals known as adjuvants, or boosters, designed to turbo charge the potency of a vaccine and the body's immune response to it.
AS03 was widely used in Europe during the 2009-2010 H1N1 flu pandemic and is also contained in a GSK adjuvanted flu vaccine which in November last year became the first of its kind to be recommended for approval by the normally adjuvant-wary United States Food and Drug Administration (FDA)
There's little doubt AS03 does its job well.
Pandemrix, the flu vaccine under suspicion for the narcolepsy link, needs only a fraction of the antigen - the part that actually does the immunisation - of other flu shots to give sufficient protection.
This means the manufacturer - in this case GSK - can produce multiple times the number of vaccine doses without needing to spend valuable time making large amounts of the antigen.
In a pandemic situation in which the lives of millions around the world are under threat, that could make the difference between having enough vaccines to protect entire populations, or having to decide how to ration them out.
Yet some experts believe the turbo-charged immune response AS03 generates, or the ingredients that drive it, may also be the answer to why almost 800 cases of the incurable sleeping disorder narcolepsy have been linked to Pandemrix's use in Europe during the 2009/2010 H1N1 pandemic.
"The adjuvant in the Pandemrix vaccine is very potent and we think it may have played a role," says Markku Partinen, a neurologist at the Helsinki Sleep Clinic in Finland who has spent the past few years investigating what might be behind the link between the vaccine and narcolepsy.
If it is the reason for the spike in the disease, Partinen and other researchers think it may be because the adjuvant's strength boosted not just a good immune response but possibly an adverse one too.
Partinen was one of the first scientists to pick up a signal that something might be going awry in children in Finland vaccinated with Pandemrix in a nationwide immunisation campaign against the H1N1 flu.
Since then studies in Sweden, Finland, Ireland and now Britain have found the risk of developing narcolepsy is between seven and 13 times higher in children who were immunised with Pandemrix than in those who were not.
Among the 800 cases of Pandemrix-related narcolepsy reported so far across Europe, many are children who say the life-long and incurable disease has all but wrecked normal life.
Narcolepsy's most common symptoms are bouts of daytime sleepiness, but in its severe forms it also brings nightmares, hallucinations, sleep paralysis and cataplexies - when strong emotions trigger a sudden loss of muscle strength.
Doctors and researchers who have been treating and analysing cases of Pandemrix-linked narcolepsy say a common feature is that quite severe symptoms come on abruptly in these patients.
Pandemrix's maker GlaxoSmithKline says it accepts the evidence of a statistical link but wants to see more research into whether the vaccine or any of its ingredients are implicated in actually causing narcolepsy.
"There is absolutely no doubt that people vaccinated with our vaccine were shown in published studies to be more likely to develop narcolepsy than people who were not. As a statistical association that's clear. It's a very different thing, though, to say that then means A causes B," said Norman Begg, chief medical officer at GSK's vaccines division.
Regulators - both those at the European Medicine's Agency (EMA) which licenses Pandemrix, and those at the FDA whose advisory panel recently recommended approval of a GSK pandemic vaccine with the same adjuvant - say that for now suspicions about AS03 remain just that and offer no reason to put a stop to its use.
"There are so many theories behind what is happening here," said Tomas Salmonson, who is both an official at the Swedish Medicines Agency and head of EMA's Committee for Medicinal Products for Human Use, which advises on drugs' safety and efficacy.
FDA spokeswoman Rita Chappelle said the regulator could not discuss Pandemrix since it is not licensed in the United States. Asked about the GSK pandemic vaccine containing the same adjuvant which the FDA has been advised to recommend, she said the FDA evaluates each drug license application "based on the merits of the safety and efficacy data submitted".
After being instructed by the EMA to investigate further, GSK is conducting a study in Canada where around 2 million doses of a GSK vaccine called Arepanrix - very similar to Pandemrix and containing the same AS03 adjuvant - were used to immunise children during the H1N1 pandemic.
"Narcolepsy has a number of different potential contributory factors," Begg said. "Disentangling those potential confounding variables is something that really hasn't yet been done."
Independent groups of researchers around the world working hard to do that are homing in on AS03 and its super immune response boosting capability.
The adjuvant is not a single ingredient, but a combination of three - squalene, an oil derived from shark livers, a form of vitamin E called DL-alpha-tocopherol, and an emulsifier, or mixing agent, called polysorbate 80.
Both the squalene and the vitamin E are there to boost the response of the immune system to the H1N1 antigen - the molecule the immune system needs to learn to recognise in order to protect against infection in future.
At Stanford University in the United States, professor of psychiatry and narcolepsy expert Emmanuel Mignot believes the mistake may have been in putting the H1N1 virus, which itself produces a strong immune response and is used in the vaccine, together with such a potent booster combination.
"It's clear that H1N1 is a key ingredient. But it's also clear that if you didn't have the adjuvant you also didn't have this dramatically increased risk (of developing narcolepsy)," said Mignot, who is being funded by GSK to conduct further research into the links.
"So my opinion is that it was a combination of both in Pandemrix that made it very nasty for narcolepsy."
Asked about the questions surrounding AS03 and Pandemrix at a briefing for journalists in London this week, GSK's chief executive Andrew Witty said his firm is exploring all avenues but is unlikely to be able to come to a conclusion soon.
"We are all over this...in terms of trying to help figure out what's going on here," he said. "We're taking it very seriously and we're focused on trying to understand any link there is and come to a conclusion as soon as we can. I think it's equally important we don't rush to the wrong conclusion."
While narcolepsy is a mysterious disease with some uncertainty about its precise cause, the consensus view among scientists is that it is an autoimmune disorder - one in which the immune system is stimulated to attack the body's own cells.
Narcolepsy patients have low levels of a neurotransmitter called hypocretin, which regulates wakefulness, and scientists believe this deficit is most likely due to hypocretin-containing cells being destroyed by an autoimmune attack.
Because both narcolepsy and vaccines are linked to the function of the immune system, the biological plausibility of a link between the disorder and a vaccine with such an effective adjuvant has a sound scientific basis, says Outi Vaarala of the Immune Response Unit at Finland's National Institute for Health and Welfare, who has been studying links between narcolepsy and Pandemrix since cases appeared there in 2010.
Narcolepsy is also strongly linked to a variant in a gene called HLA, which controls the function of a subtype of white blood cells. White blood cells are key to the immune system and experts say this link underpins the theory that narcolepsy is most likely an autoimmune disease.
Around 25 percent of people in northern and central Europe are thought to have the HLA genetic vulnerability to narcolepsy, with a lower percentage in southern European countries.
Vaarala is investigating the details of the vaccine's ingredients and, like others, thinks the answer may lie in the way certain children's immune systems responded to the antigen and then had that response supercharged by AS03.
Vaarala's studies also raise questions over whether GSK's own investigations, which are centred on use of Arepanrix in Canada, may turn out to be a something of a red herring.
There is no evidence so far of increases in narcolepsy cases in children in Canada. While this could reflect variables like differences in the genetic makeup of those vaccinated, or the timing of when they got their shots during the pandemic, some believe the answer may lie tiny differences between the Arepanrix and Pandemrix vaccines.
Ingredients lists for Pandemrix and Arepanrix show the two vaccines have the same antigen and the same adjuvant, but GSK's Begg says the two products have some "minor formulation differences" because they were manufactured at different sites.
Pandemrix was made in at a manufacturing plant in Dresden, Germany, while Arepanrix was made at one in Quebec, Canada.
In studies she has yet to submit for peer review and publication, Vaarala says she has found differences in the way antibodies from Pandemrix-vaccinated children bind to the virus antigen in the Dresden-made shot and the way they do in the Canadian-made version.
"Our findings of the immunological differences between Pandemrix and Arepanrix virus antigen are important clues to the mechanism of Pandemrix-related narcolepsy," she told Reuters.
GSK says its is exploring all aspects of the issue, but says that for now it has seen no indication that the manufacturing process for Pandemrix is involved.
Although Pandemrix is no longer recommended for use in children and adolescents under 20, it is still licensed for use in Europe in immunising adults against H1N1.
The EMA's Salmonson notes the many unanswered questions surrounding AS03, but says it would be wrong to halt its use until scientists know more.
"We may speculate that this specific antigen together with a very potent adjuvant could be the cause for all this. But that's only one of several possible explanations," he said. "The fact that we today do not understand the underlying mechanism shows how complex this is."
* Asia ex-Japan, Nikkei post gains as market euphoria persists
To access the newsletter, click on the link: http://share.thomsonreuters.com/assets/newsletters/Indiamorning/MNC_IN_04252017.pdf If you would like to receive this newsletter via email, please register at: https://forms.thomsonreuters.com/india-morning/ FACTORS TO WATCH 10:00 am: Farm Minister Radha Mohan Singh at an event in New Delhi. 11:00 am: DIPP Joint Secretary Rajeev Aggarwal at an event in New Delhi. 11:00 am: Revenue Secretary Hasmukh Adhia to brief