March 7 Growing evidence of a link between GlaxoSmithKline Plc's pandemic flu vaccine and an increase in narcolepsy cases among children who received it in Europe, is giving pause to health regulators weighing approval of a similar vaccine in the United States.
Data published recently in the British Medical Journal found that children in England who received GSK's Pandemrix vaccine during the 2009-10 H1N1 swine flu pandemic had a 14-fold heightened risk of developing narcolepsy, a chronic and potentially debilitating sleep disorder that can cause hallucinations, daytime sleepiness and cataplexy, a form of muscle weakness precipitated by strong emotion.
Authors of the study - whose results echo those of similar studies in Sweden, Finland and Ireland - said the data had implications for the approval and use of future vaccines that, like Pandemrix, contain AS03, a new adjuvant, or booster, that turbo-charges the body's immune response to the vaccine.
Scientists believe AS03 may be the culprit in the narcolepsy cases though they have yet to decipher the precise nature of the association.
That uncertainty poses a challenge for the U.S. Food and Drug Administration, which is considering an AS03-containing vaccine for use in the event of an H5N1 bird flu epidemic. Like Pandemrix, which has not been approved in the United States, it is made by GSK and is almost identical in structure.
A 14-member panel of advisors to the FDA voted unanimously in November to recommend the vaccine to protect against bird flu. The panel considered early studies from Europe showing an increase in the number of narcolepsy cases but concluded that the potential benefit of the vaccine outweighed the risk.
WORSE THAN THOUGHT?
Since then, however, new data, including the study results from Britain, suggest the scale and strength of the narcolepsy link could be greater than first thought. At least one committee member would like the FDA to reconvene the panel.
"I personally think the panel should be reconvened now that we have new data," said Dr. Ambrose Cheung, professor of Microbiology and Immunology at Geisel School of Medicine at Dartmouth College in New Hampshire. "This is an issue worth re-examining."
According to GSK, some 30 million doses of the vaccine were administered across Europe and 800 people, mostly children, developed narcolepsy. While acknowledging an association, the company says there is insufficient evidence to prove Pandemrix is the cause.
A new meeting of the advisory committee would not necessarily lead panelists to change their vote. Bird flu kills nearly 60 percent of those it infects. As a result, the imperative to find a vaccine is high.
"This is an evolving situation so there will continue to be more information to inform the decision making process," said advisory committee member Dr. Melinda Wharton, acting director of the National Center for Immunization and Respiratory Diseases at the U.S. Centers for Disease Control and Prevention (CDC).
"Given that, I think this is a situation where the risk/benefit assessment could still favor the use of the vaccine, particularly in adults, as we are looking at a disease with an extremely high mortality rate."
The CDC is sponsoring an international study on the links between adjuvanted flu vaccines and narcolepsy, which is expected to be completed in 2014.
HIGHER MORTALITY RATE
The H5N1 bird flu virus was first isolated in a human in Hong Kong in 1997 and it began to spread throughout Southeast Asia in 2003.
A 2011 report by the World Health Organization showed only 566 people have been infected with bird flu worldwide, against the 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. That compares with fewer than 1 percent of those infected with H1N1 who have lost their lives, which alters the equation for the FDA versus the European regulators who authorized Pandemrix for the H1N1 virus.
"We gave a favorable vote to a vaccine that we hope will never be used and to protect the public against a disease that has a better than 50 percent mortality rate," said Dr. Robert Daum, chairman of the FDA's advisory committee and a professor of pediatrics, microbiology and molecular medicine at the University of Chicago. "That is a very special situation."
Still, Daum said he welcomed the opportunity to discuss any new information if the FDA were to reconvene the panel.
"I have had several discussions with FDA personnel about the issue of adjuvanted vaccines and there are many unanswered questions," he said. "If they came to us and said we would like you 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 the FDA "will continue to monitor the situation, and consider regulatory options as needed."
The FDA is not obliged to follow the recommendation of its advisory panel, though it typically does.
Regardless of whether the bird flu vaccine is approved for use in the United States, the narcolepsy issue has raised concerns within the broader scientific community about the future of novel adjuvants.
"We are taking this very seriously," said Dr. Kathryn Edwards, director of the vaccine research program at Vanderbilt University, who did not sit on the bird flu vaccine panel though she has served on FDA advisory panels in the past. "We would like to understand this."
Adjuvants have been used in vaccines for diseases such as diphtheria and tetanus for decades. A new, more powerful generation of adjuvants, including AS03, is being developed whose safety is relatively untested, which is why the Pandemrix experience could be pivotal.
"The whole adjuvant story is an important one because there are going to be vaccines that we may be able to use to prevent diseases, if we are able to use adjuvants, that we could not prevent otherwise," Edwards said.
Edwards said U.S. experts felt that traditional, non-adjuvanted H1N1 vaccines made by Sanofi SA and others offered enough protection against the virus. A study by the CDC showed traditional vaccines have not been associated with any spike in the number of people with narcolepsy.
In the case of bird flu, however, regulators currently have no other choices as scientists have not developed a vaccine capable of protecting against bird flu.
GSK's super-charged vaccine is the first to show it can confer protection and could potentially save countless lives in the event of a pandemic. European regulators have approved it under the brand name Pumarix.
Assessing the relative risk versus benefit is a complex task and the calculation can change over time. Scientists are only just beginning to investigate the long-term effects of Pandemrix.
Narcolepsy is widely considered to be an autoimmune disease, in which the body's immune system mistakenly attacks its own organs. One question now being raised by scientists is whether Pandemrix may be associated over the long term with an increase in other autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, psoriasis and lupus.
Indeed, the FDA panel, which looked to the Pandemrix data for clues on the safety of the bird flu vaccine, noted a slightly elevated number of cases of irritable bowel syndrome and rheumatoid arthritis, said Cheung. But the panel felt these events could easily have been due to chance.
"These kind of events," Cheung said, "can only be addressed after a longer period of time."