By Toni Clarke
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
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
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
"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
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."