By Toni Clarke
March 7 (Reuters) - Growing evidence of a link betweenGlaxoSmithKline Plc's pandemic flu vaccine and anincrease in narcolepsy cases among children who received it inEurope, is giving pause to health regulators weighing approvalof a similar vaccine in the United States.
Data published recently in the British Medical Journal foundthat children in England who received GSK's Pandemrix vaccineduring the 2009-10 H1N1 swine flu pandemic had a 14-foldheightened risk of developing narcolepsy, a chronic andpotentially debilitating sleep disorder that can causehallucinations, daytime sleepiness and cataplexy, a form ofmuscle weakness precipitated by strong emotion.
Authors of the study - whose results echo those of similarstudies in Sweden, Finland and Ireland - said the data hadimplications for the approval and use of future vaccines that,like Pandemrix, contain AS03, a new adjuvant, or booster, thatturbo-charges the body's immune response to the vaccine.
Scientists believe AS03 may be the culprit in the narcolepsycases though they have yet to decipher the precise nature of theassociation.
That uncertainty poses a challenge for the U.S. Food andDrug Administration, which is considering an AS03-containingvaccine for use in the event of an H5N1 bird flu epidemic. LikePandemrix, which has not been approved in the United States, itis made by GSK and is almost identical in structure.
A 14-member panel of advisors to the FDA voted unanimouslyin November to recommend the vaccine to protect against birdflu. The panel considered early studies from Europe showing anincrease in the number of narcolepsy cases but concluded thatthe potential benefit of the vaccine outweighed the risk.
WORSE THAN THOUGHT?
Since then, however, new data, including the study resultsfrom Britain, suggest the scale and strength of the narcolepsylink could be greater than first thought. At least one committeemember would like the FDA to reconvene the panel.
"I personally think the panel should be reconvened now thatwe have new data," said Dr. Ambrose Cheung, professor ofMicrobiology and Immunology at Geisel School of Medicine atDartmouth College in New Hampshire. "This is an issue worthre-examining."
According to GSK, some 30 million doses of the vaccine wereadministered across Europe and 800 people, mostly children,developed narcolepsy. While acknowledging an association, thecompany says there is insufficient evidence to prove Pandemrixis the cause.
A new meeting of the advisory committee would notnecessarily lead panelists to change their vote. Bird flu killsnearly 60 percent of those it infects. As a result, theimperative to find a vaccine is high.
"This is an evolving situation so there will continue to bemore information to inform the decision making process," saidadvisory committee member Dr. Melinda Wharton, acting directorof the National Center for Immunization and Respiratory Diseasesat the U.S. Centers for Disease Control and Prevention (CDC).
"Given that, I think this is a situation where therisk/benefit assessment could still favor the use of thevaccine, particularly in adults, as we are looking at a diseasewith an extremely high mortality rate."
The CDC is sponsoring an international study on the linksbetween adjuvanted flu vaccines and narcolepsy, which isexpected to be completed in 2014.
HIGHER MORTALITY RATE
The H5N1 bird flu virus was first isolated in a human inHong Kong in 1997 and it began to spread throughout SoutheastAsia in 2003.
A 2011 report by the World Health Organization showed only566 people have been infected with bird flu worldwide, againstthe millions infected with the 2009 H1N1 swine flu virus.
However, bird flu has a significantly higher mortality rate;of those infected, 59 percent died, according to WHO. Thatcompares with fewer than 1 percent of those infected with H1N1who have lost their lives, which alters the equation for the FDAversus the European regulators who authorized Pandemrix for theH1N1 virus.
"We gave a favorable vote to a vaccine that we hope willnever be used and to protect the public against a disease thathas a better than 50 percent mortality rate," said Dr. RobertDaum, chairman of the FDA's advisory committee and a professorof pediatrics, microbiology and molecular medicine at theUniversity of Chicago. "That is a very special situation."
Still, Daum said he welcomed the opportunity to discuss anynew information if the FDA were to reconvene the panel.
"I have had several discussions with FDA personnel about theissue of adjuvanted vaccines and there are many unansweredquestions," he said. "If they came to us and said we would likeyou to reconvene and consider the new data, I'd be in favor."
FDA officials declined to be interviewed.
A spokeswoman, Rita Chappelle, said in a statement that theFDA "will continue to monitor the situation, and considerregulatory options as needed."
The FDA is not obliged to follow the recommendation of itsadvisory panel, though it typically does.
NEW ADJUVANTS
Regardless of whether the bird flu vaccine is approved foruse in the United States, the narcolepsy issue has raisedconcerns within the broader scientific community about thefuture of novel adjuvants.
"We are taking this very seriously," said Dr. KathrynEdwards, director of the vaccine research program at VanderbiltUniversity, who did not sit on the bird flu vaccine panel thoughshe has served on FDA advisory panels in the past. "We wouldlike to understand this."
Adjuvants have been used in vaccines for diseases such asdiphtheria and tetanus for decades. A new, more powerfulgeneration of adjuvants, including AS03, is being developedwhose safety is relatively untested, which is why the Pandemrixexperience could be pivotal.
"The whole adjuvant story is an important one because thereare going to be vaccines that we may be able to use to prevent diseases, if we are able to use adjuvants, that we could notprevent otherwise," Edwards said.
Edwards said U.S. experts felt that traditional,non-adjuvanted H1N1 vaccines made by Sanofi SA andothers offered enough protection against the virus. A study bythe CDC showed traditional vaccines have not been associatedwith any spike in the number of people with narcolepsy.
In the case of bird flu, however, regulators currently haveno other choices as scientists have not developed a vaccinecapable of protecting against bird flu.
GSK's super-charged vaccine is the first to show it canconfer protection and could potentially save countless lives inthe event of a pandemic. European regulators have approved itunder the brand name Pumarix.
Assessing the relative risk versus benefit is a complex taskand the calculation can change over time. Scientists are onlyjust beginning to investigate the long-term effects ofPandemrix.
Narcolepsy is widely considered to be an autoimmune disease,in which the body's immune system mistakenly attacks its ownorgans. One question now being raised by scientists is whetherPandemrix may be associated over the long term with an increasein other autoimmune diseases such as rheumatoid arthritis,multiple sclerosis, psoriasis and lupus.
Indeed, the FDA panel, which looked to the Pandemrix datafor clues on the safety of the bird flu vaccine, noted aslightly elevated number of cases of irritable bowel syndromeand rheumatoid arthritis, said Cheung. But the panel felt theseevents could easily have been due to chance.
"These kind of events," Cheung said, "can only be addressedafter a longer period of time."
Glaxosmithkline (GSK)