Experts Confront Obstacles in Containing Virulent
By KEITH BRADSHER and LAWRENCE K. ALTMAN
Published: September 30, 2004
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BANGKOK, Sept. 29 - With Thai and international experts confirming the
first probable human-to-human transmission of a virulent strain of avian
influenza in this country, public health officials around the world are
facing major hurdles as they try to prepare for a possible pandemic.
Scientists say they cannot predict how quickly, if at all, the strain
may develop the ability to spread easily among people, and whether it
will remain as lethal as it has proven so far.
The strain, A(H5N1), has killed 30 of the 42 Southeast Asians it
infected in the past year, and millions of chickens and wild birds,
across wide areas of Asia, and has infected some pigs, household cats
and even zoo tigers. A handful of cases of human-to-human transmission
may have occurred during bird flu outbreaks in Hong Kong in 1997 and in
Europe a year ago, but neither resulted in a pandemic.
Still, public health experts say it would be irresponsible not to
prepare for a worst-case situation. The so-called Spanish Flu pandemic
of 1918 to 1919 killed at least 20 million people, and that was before
the development of the modern transportation system, with its fleets of
jumbo jets linking remote areas of the world - and taking microbes with
them. By comparison, AIDS has killed an estimated 22 million since 1981,
according to the United Nations.
On Wednesday, the World Health Organization held a meeting in Geneva of
representatives of the drug industry to demand that they speed vaccine
production. In the United States, scientists with the federal Centers
for Disease Control and Prevention in Atlanta are racing to complete a
genetic sequence of the virus from this case to determine if it has
acquired any mammalian influenza genetic material, which could make it
more transmissible, and the government has ordered two million doses of
Health officials would normally look to vaccines and antiviral drugs to
control a pandemic, but in this case, those tools have yet to be fully
developed and tested. Conventional flu vaccines are not believed to
provide any protection against A(H5N1) avian influenza.
Human trials of the new vaccine ordered by the United States government
are not expected to begin until the end of this year, at best.
Washington, like the governments in Australia, Japan, New Zealand and a
few other countries, is also stockpiling the only antiviral medicine
that may work against the strain, Tamiflu, but there have been too few
human cases to document its effectiveness.
The symptoms of human bird flu appear to be indistinguishable from
severe cases of conventional flu, with fevers, sneezing, coughing and
aches. Scientists have yet to determine why the A(H5N1) strain is so
Dr. Anthony S. Fauci, the director of the National Institute of Allergy
and Infectious Diseases, said the United States government was "doing
everything that is technically and feasible to be done at this time -
essentially, loading up and stockpiling Tamiflu to the extent of almost
exhausting the manufacturer's capabilities."
But the absence of a tested vaccine and the scarcity of the antiviral
underline what many health officials say is a chronic mismatch of public
health needs and private control of production of vaccines and drugs.
"The market has failed here to drive companies into research, and we
believe that's something public health should be looking at much more
closely in the future," said Klaus Stöhr, the W.H.O.'s top influenza
expert, before Wednesday's meeting.
Only two large vaccine manufacturers, Aventis Pasteur, based in
Swiftwater, Pa., and the Chiron Corporation, based in Emeryville,
Calif., are braving a thicket of patent issues and financial concerns to
try to use advanced genetic techniques to develop vaccines against
so-called bird flu. And they have proceeded only with National Institute
of Health contracts to do so.
Other drug makers have given several reasons for not making vaccines:
that production is expensive and investment may not be recouped if there
is no pandemic, and that intellectual property rights on new techniques
used to make the vaccine remain unsettled. The standard method for
making flu vaccines - growing virus in chicken embryos - does not work
because the A(H5N1) virus is so deadly that it kills the developing
chicks before they can grow enough virus to be worth harvesting. The new
techniques alter the strain's genetics so it can be grown in the
Drug makers also worry that they could be exposed to considerable
liability if they put out a new vaccine without lengthy safety tests
Because the clinical trials have not been done, "nobody can go into
full-scale production now, nobody," Dr. Stöhr said.
When vaccines are not available, doctors can turn only to the antiviral
Tamiflu. But it is expensive and may work only if it is given in the
first two days after the onset of symptoms.
Tamiflu is made only by Roche Holding, a Swiss company, at a single
small factory in Europe, although the company has said in recent months
that it plans to build another production line in the United States.
Some public health experts are strongly critical of Roche for not
increasing production of Tamiflu sooner, saying the company should have
expanded production early this year, when avian influenza started
becoming a problem across much of Asia.
"You're dealing with very conservative Swiss bankers - to me, they don't
see the opportunity yet," said Arnold Monto, a University of Michigan
influenza expert, pointing out that Tamiflu not used for an avian
influenza pandemic could be used instead to make human influenza less
A Roche spokesman, in an e-mail message responding to questions, said
the company had been supplying Tamiflu at levels demanded by the market
and was now increasing its manufacturing capacity, but declined to
provide details. The company recommends that governments hold enough
Tamiflu in stockpiles to treat a quarter of their population - which
would translate into more than 70 million people in the United States -
but notes that few countries have shown much interest in such
stockpiles, at least until recently.
Stockpiles are expensive because the drug is costly: $68 at retail for a
10-capsule treatment course for one adult.
Dr. Julie L. Gerberding, director of the C.D.C., said that the federal
government had bought enough Tamiflu to treat one million Americans, but
added that if the manufacturing capacity were greater, "we would
certainly want to have a supply that was closer to 100 million than to a
Drawing on lessons from past pandemics, Dr. Fauci, the federal official,
said that an avian influenza pandemic might start with an initial wave
of cases in one region of the world, but that the epidemic, if it
occurred, might not become a global problem until the next year, giving
vaccine and pharmaceutical manufacturers more time to respond.
But it is not clear when the confusion may be resolved over the patents
on the reverse genetics process used to grow the new vaccine. Several
universities and an American company, MedImmune Inc., based in
Gaithersburg, Md., hold the patents and have allowed research using the
techniques. But no deal has been reached on how much money vaccine
makers would have to pay before beginning production.
Distributing limited stocks of vaccine and antivirals could also be
difficult in a pandemic, officials warn.
"It will be a very difficult decision to take by governments to decide
who is going to receive the vaccine, who is going to receive the
antivirals - or even more importantly, who is not going to receive the
vaccine or the antivirals," said Dr. Stöhr. "A simple question would be,
if we vaccinate health care workers, would the nurse also be allowed to
vaccinate his child? Would the nurse take the antivirals or would he
take it home? There will be limited resources and all this has to be
thought through now."
Research at Hong Kong University has found that the virus is more active
at cooler temperatures, suggesting that the slow spread of the disease
this summer may not mean it will move as slowly this coming winter. "It
is kind of a warning," said Malik Peiris, the leader of the research
team, "that we should be prepared particularly for bigger problems in
the months ahead."
Keith Bradsher reported from Bangkok for this article, and Lawrence K.
Altman from Bangkok and New York.