The International Herald Tribune
A success in search for avian flu vaccine
By Lawrence K. Altman and Keith Bradsher The New York Times
MONDAY, AUGUST 8, 2005
WASHINGTON U.S. government scientists say they have successfully tested in people a vaccine that they believe can protect against the strain of avian influenza that is spreading in birds through Asia and Russia.
Officials have been racing to develop a vaccine because they worry that if that strain mutated and combined with a human influenza virus to create a new virus, it could spread rapidly.
Tens of millions of birds have died from infection with the virus and from culling to prevent the spread of the virus. About 100 people have been infected, and about 50 have died from this strain of the avian influenza virus, called A(H5N1). So far there has been no sustained human-to-human transmission, but that is what health officials fear, because it could cause a pandemic.
The director of the National Institute of Allergy and Infectious Diseases in the United States, Dr. Anthony Fauci, said that while the vaccine that has undergone preliminary tests could be used on an emergency basis if a pandemic developed, it would still be several months before that vaccine was tested further and, if licensed, offered to the public.
"It's good news," Fauci said. "We have a vaccine."
But he cautioned: "We don't have all the vaccine we need to meet the possible demand. The critical issue now is, 'Can we make enough vaccine, given the well-known inability of the vaccine industry to make enough vaccine?"'
An earlier human vaccine against A(H5N1) avian influenza virus was prepared after the virus first appeared in the world, in Hong Kong in 1997.
That vaccine was never fully developed or used, and the strain has mutated since then.
In Taiwan, Dr. Kuo Hsu-sung, director general of the Center for Disease Control, said that authorities in Taiwan were so concerned about the long-term risks of an influenza pandemic, as well as the annual harm from more routine outbreaks of human influenza, that the island planned to build its own human influenza vaccine factory.
Eight companies attended a planning meeting last month on the factory, and the government of Taiwan will take bids this winter for the project.
But building a factory and putting it into production will take four years, Kuo warned. For now, Taiwan has a supply of Tamiflu adequate to treat 1 percent of its population, and the Legislature approved additional spending last month for this stockpile to be nearly quadrupled, he said.
Kuo said that if further research confirmed the need for two very large doses to be administered to achieve full immunization, existing methods for growing flu vaccines from chicken embryos would not provide adequate production. New techniques that are still in the experimental stages, like growing vaccine in cell cultures, will become necessary, he said.
Dr. Lai Ching-te, an internal medicine specialist who is the chief whip in the Legislature for the ruling Democratic Progressive Party and used to be the chairman of the Legislature's health, environment and labor committee, said that there was strong support in the Legislature to begin the manufacture of influenza vaccine in Taiwan.
"We do worry about avian influenza," because it has struck several nearby countries in Asia, he said.
Medical experts in Asia, where all of the human and poultry cases of bird flu have occurred, cautioned on Sunday that formidable obstacles remained before the new vaccine would become a useful tool in preventing a pandemic.
The biggest impediment may be the rapid evolution of the virus itself.
Dr. Guan Yi, a Hong Kong University microbiologist, said that the flu virus that has just appeared this summer among migratory birds roosting on an island in Qinghai Lake in western China had quite a few genetic differences from previous viruses that had circulated in Southeast Asia.
The previous viruses appear to have been used in the successful vaccine tests this spring and summer in the United States.
"It keeps changing, it keeps evolving," he said. "We don't know how much the vaccine matches."
Another problem lies in initial test results in the United States showing that the new vaccine requires two doses. Moreover, each dose may have to contain several times more material than a conventional human influenza vaccine dose. Vaccine manufacturers already struggle to produce enough human influenza vaccine each winter, even producing a small, single dose for each patient.
The need for two very large doses may make the vaccine prohibitively expensive for many people in Asia, even if the vaccine can be manufactured in adequate quantities, said Guan, the microbiologist at Hong Kong University.
Chastened by its difficulties in handling SARS, or sudden acute respiratory syndrome, two years ago, the Hong Kong government has been especially active in stockpiling doses of the only medicine known to work against bird flu, Tamiflu. But a government spokeswoman said Sunday that no plans had been made to buy a human vaccine against the disease, although government doctors were monitoring work on vaccines.
"It is only an experimental one, so they will keep an eye on it," the spokeswoman said.
In interviews over recent days, Fauci of the National Institute of Allergy and Infectious Diseases has said that tests so far have shown that the new vaccine produced a strong immune response among the small group of healthy adults under age 65 who volunteered to receive it, although the doses needed were higher than in the standard influenza vaccine offered each year. The vaccine, developed with genetic engineering techniques, is intended to protect against infection, not to treat those who are sick.
Further tests are expected to be conducted among two groups - people 65 and older, and children - over the next several months.
Fauci expressed confidence that they would confirm the success of the first tests and answer remaining scientific questions.
Because the vaccine is made in chicken eggs, "a potential major stumbling block" to successful mass production is the number of eggs farmers can supply manufacturers, Fauci said.
If manufacturers can overcome such hurdles, the new vaccine could go far in averting a possible pandemic of human influenza, Fauci said.
Only a small number of human cases of A(H5N1) influenza have been found. Although a few cases may have been transmitted from person to person in Asia, the A(H5N1) strain has not garnered enough strength to spread widely among humans anywhere.
As of Friday night, according to the World Health Organization in Geneva, the avian strain has killed 57 of the 112 people it has been known to infect in four countries. The countries are Cambodia, with four cases; Indonesia, one case; Thailand, 17 cases; and Vietnam, 90 cases.
The additional tests are needed to determine the optimal dose of vaccine, how many shots people will need for protection, and whether adding another ingredient called an adjuvant to the vaccine could raise the potency of lower doses, stretching the number of people that could be protected. Even when these tests are completed, more time will be needed before the U.S. Food and Drug Administration can license the human vaccine and before policy makers determine when and how it should be administered.
Government researchers and others developed the vaccine, which is produced by Sanofi Pasteur, a French vaccine company that is part of Sanofi-Aventis. The government could decide to release the product under emergency conditions if an A(H5N1) influenza pandemic struck before the testing process was completed.
Although cautioning that the vaccine has not been fully tested, Fauci said that the initial test findings have given the U.S. government enough confidence to start the process of adding millions more doses of the vaccine to the two million it has bought. The present supply is stored in bulk form, and "we cannot put it in vials until we find out what the right dose is," Fauci said.
The manufacturer needs to know the dose and regimen to determine how much more vaccine it can make.
The American vaccine is derived from a strain that Dr. Robert Webster helped isolate from a human case in Vietnam. He is an internationally known influenza expert at St. Jude Children's Research Hospital in Memphis, Tennessee, whose work is supported in part by Fauci's institute.
Because the A(H5N1) strain is lethal for chickens and so could not be grown in eggs, Webster had to use a recently developed technique known as reverse genetics to remove the gene that made the virus deadly. This altered seed virus was used by Sanofi Pasteur to produce the vaccine in chicken eggs under contract from the government.
Fauci's institute received the first batch of 8,000 doses from Sanofi Pasteur in the spring. In April, doctors injected the vaccine into 452 healthy volunteers at three centers: the University of Maryland in Baltimore, the University of Rochester in New York, and the University of California at Los Angeles.
Doctors at these centers drew blood from the volunteers to document that they had no antibody to A(H5N1) before they received the first of two injections of the vaccine. Then the doctors drew another blood sample four weeks later when the volunteers received a second injection of the vaccine.
Fauci said his team was considering drawing a fourth blood sample to measure the antibody response over a longer period. He also said that the team was considering adding a third dose of vaccine to determine the maximum response that the vaccine could elicit.
Keith Bradsher reported from Hong Kong.
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