Unequipped to Cure
The Nation
Dr. Marc Siegel
Vaccine-making resources in the United States are stretched alarmingly thin. There are only three manufacturers responsible for making more than 80 million doses of the human flu vaccine each year, with no guarantee that the entire supply will be sold or adequately distributed. In 2004 the entire 50 million-dose batch made by Chiron (a US company whose manufacturing plant is in Britain) had to be discarded because it was found to be contaminated with a common bacteria known as serratia.
As recently as the 1970s, there were thirty-seven vaccine makers in the United States. But because of the narrow profit margin and fear of litigation, many manufacturers left the game. Tommy Thompson, when he was Secretary of the US Department of Health and Human Services, attempted to corral funding to upgrade the country's capability of making flu vaccine. Concerned about the possibility of a pandemic, Thompson requested $100 million in 2002 for the purpose of helping the vaccine industry switch over from using chicken eggs to make vaccine to the latest cell-based method that relies on genetic technology. In 2002, his request was denied. In 2003, $50 million was approved. Finally, in 2004, it took the public panic over a flu vaccine shortage to put enough pressure on Congress to approve the entire $100 million allocation.
But even at a time of such great difficulty with the flu vaccine supply, in the post-9/11 era, lawmakers have focused their attention elsewhere. In early 2005, a powerful group of Republican lawmakers began pushing Project BioShield 2 through Congress. The original Project BioShield, signed into law in July 2004, allocated $5.6 billion over ten years to the Department of Homeland Security for the purchase of countermeasures against anthrax, smallpox and other terrorist threats. This expenditure includes allocation for 75 million doses of a second-generation anthrax vaccine to be made available for stockpiling.
BioShield 2 also proposes to shield the drug companies against lawsuits, one of the major disincentives against making vaccines, while expanding by several billion the money allocated for an ultra-expensive anthrax vaccine against a theoretical threat that remains remote.
Last fall, the federal government's vaccine focus switched dramatically to bird flu, when articles in Nature and Science disclosed the final sequencing of the 1918 Spanish Flu H1N1 molecules. The fact that the Spanish flu originated in birds had been known for at least thirty years, and the exact way it made its jump to humans was known for at least a year. Nevertheless, these studies, combined with the continued spread of the H5N1 virus among birds migrating from Asia to Europe, fueled a concern that was useful to public health officials who wanted more attention put on avian flu in general and on the bird flu vaccine in particular.
A vaccine against H5N1 had already been developed using a virus isolated from a Vietnamese patient in 2004. In 2005 the National Institutes of Health began testing this vaccine against humans; preliminary results showed that it was effective at causing an immune response.
But with the odds of a bird flu pandemic looking very slim this year, it would appear to be far more cost effective to improve the ability to respond to a future pandemic. One of the weakest links in our preparation chain is vaccine production. When we vaccinate, a dead or weakened virus is injected into a person, where it generates an immune response, but without causing any symptoms of the disease. The body then carries, for some extended period of time, the specific antibodies for that virus or bacteria and has the capacity to make more if actually challenged by the actual virus or bacteria.
Genetic recombinant techniques have routinely been used since the 1980s to develop vaccines for hepatitis, in which E. coli bacteria is "programmed" to make a viral antibody. But the United States still currently produces all influenza vaccines, including potential bird flu vaccines being tested in humans, using a method created almost fifty years ago. First, scientists identify the live virus from the blood of a victim. Next, it must be injected into a fertilized chicken egg. Once it's been grown in chicken eggs, it has to be injected into more chicken eggs, until millions of eggs have been injected with the virus. Then the virus is harvested, purified and neutralized. It may take half a year--or more--to identify the strain, develop and release the first set of vaccine doses to the public. Ironically, the H5N1 bird flu virus is so deadly to chicken embryos that it interferes with the process to make a vaccine against itself. The eggs have to be specially treated so they can be used.
More advanced technology is available, but it is expensive to change over to state-of-the-art methods. The most commonly used methods involve reverse genetics and cell cultures. In reverse genetics, using the structure of the bird flu virus, scientists can genetically engineer an existing influenza virus by inserting strips of genetic material and turning one viral strain into another. Then, instead of injecting that genetically manipulated strain into a million eggs, they grow it with cell cultures.
Using this cell culture technique, scientists grow animal cells or human cells in big vats of nutrient solution. Then they inject the newly created virus strain into the cells. As the cells reproduce, so does the virus. Eventually, the outer wall of cell is removed, and the viruses are harvested, purified and then neutralized or killed. Once dead, they can safely be injected into subjects as a vaccine, inducing an animal or person to make antibodies against this "manufactured" virus. Using this method, the interval between the identifying a strain and producing the first batch of vaccines can be measured in days instead of months.
So why do we still rely on the chicken eggs? Vaccine manufacturers, though they use these techniques routinely for other viruses, have been reluctant to switch with flu vaccines because of expense as well as potential liability. Simply put, they don't know what side effects will occur until they start to test people. So they would rather stick to obsolete techniques that have been proven safe rather than use existing technology to venture into unknown legal territory.
On the horizon are other exciting advanced techniques, including one that targets the M2 protein of the influenza molecule. Since that molecule doesn't change, this kind of a vaccine might provide immunity to all flus (including bird flu) for a decade, rather than one flu for a year only. Urgent pandemic preparation or stockpiling would be rendered obsolete, since a vaccinated individual would carry an immunity to all flus.
And then there's Jose Galarza. In a tiny lab perched above the Hudson River, Galarza, a lone researcher who has the reputation in the vaccine world as a maverick, has been experimenting with tiny specks of genetic matter for nearly ten years. He works with microscopic blobs of genes (called viral-like particles known as VLPs) from which he fashions painless, oral vaccines more rapidly than traditional methods. In fact, Galarza believes he can command his VLPs to knock out bird flu in lab animals-- and potentially in humans--more quickly and safely than conventional vaccines.
Work such as Galarza's is evidence that the human flu shot can be modernized, both for the yearly flu as well as for the more remote H5N1 bird flu, given the rare chance that it could mutate into a form that could routinely affect humans. Stockpiling vaccine now using the old methods has limited value since this virus may well not mutate, and even if it does, it may change to a form that renders the current bird flu vaccine ineffective. If a worst-case scenario were to occur, we would need a modern vaccine to be able to combat it.
One of the major problems in the United States is that we rely on the motivation of vaccine manufacturers who are neither motivated nor altruistic. Our country could learn a great deal about vaccine production from the countries of Western Europe, where the government controls the production and distribution of vaccines. Relying on corporate good will and a large supply of vaccine with a small profit margin is a dangerous strategy where public health and safety are involved.
Dr. Marc Siegel
Vaccine-making resources in the United States are stretched alarmingly thin. There are only three manufacturers responsible for making more than 80 million doses of the human flu vaccine each year, with no guarantee that the entire supply will be sold or adequately distributed. In 2004 the entire 50 million-dose batch made by Chiron (a US company whose manufacturing plant is in Britain) had to be discarded because it was found to be contaminated with a common bacteria known as serratia.
As recently as the 1970s, there were thirty-seven vaccine makers in the United States. But because of the narrow profit margin and fear of litigation, many manufacturers left the game. Tommy Thompson, when he was Secretary of the US Department of Health and Human Services, attempted to corral funding to upgrade the country's capability of making flu vaccine. Concerned about the possibility of a pandemic, Thompson requested $100 million in 2002 for the purpose of helping the vaccine industry switch over from using chicken eggs to make vaccine to the latest cell-based method that relies on genetic technology. In 2002, his request was denied. In 2003, $50 million was approved. Finally, in 2004, it took the public panic over a flu vaccine shortage to put enough pressure on Congress to approve the entire $100 million allocation.
But even at a time of such great difficulty with the flu vaccine supply, in the post-9/11 era, lawmakers have focused their attention elsewhere. In early 2005, a powerful group of Republican lawmakers began pushing Project BioShield 2 through Congress. The original Project BioShield, signed into law in July 2004, allocated $5.6 billion over ten years to the Department of Homeland Security for the purchase of countermeasures against anthrax, smallpox and other terrorist threats. This expenditure includes allocation for 75 million doses of a second-generation anthrax vaccine to be made available for stockpiling.
BioShield 2 also proposes to shield the drug companies against lawsuits, one of the major disincentives against making vaccines, while expanding by several billion the money allocated for an ultra-expensive anthrax vaccine against a theoretical threat that remains remote.
Last fall, the federal government's vaccine focus switched dramatically to bird flu, when articles in Nature and Science disclosed the final sequencing of the 1918 Spanish Flu H1N1 molecules. The fact that the Spanish flu originated in birds had been known for at least thirty years, and the exact way it made its jump to humans was known for at least a year. Nevertheless, these studies, combined with the continued spread of the H5N1 virus among birds migrating from Asia to Europe, fueled a concern that was useful to public health officials who wanted more attention put on avian flu in general and on the bird flu vaccine in particular.
A vaccine against H5N1 had already been developed using a virus isolated from a Vietnamese patient in 2004. In 2005 the National Institutes of Health began testing this vaccine against humans; preliminary results showed that it was effective at causing an immune response.
But with the odds of a bird flu pandemic looking very slim this year, it would appear to be far more cost effective to improve the ability to respond to a future pandemic. One of the weakest links in our preparation chain is vaccine production. When we vaccinate, a dead or weakened virus is injected into a person, where it generates an immune response, but without causing any symptoms of the disease. The body then carries, for some extended period of time, the specific antibodies for that virus or bacteria and has the capacity to make more if actually challenged by the actual virus or bacteria.
Genetic recombinant techniques have routinely been used since the 1980s to develop vaccines for hepatitis, in which E. coli bacteria is "programmed" to make a viral antibody. But the United States still currently produces all influenza vaccines, including potential bird flu vaccines being tested in humans, using a method created almost fifty years ago. First, scientists identify the live virus from the blood of a victim. Next, it must be injected into a fertilized chicken egg. Once it's been grown in chicken eggs, it has to be injected into more chicken eggs, until millions of eggs have been injected with the virus. Then the virus is harvested, purified and neutralized. It may take half a year--or more--to identify the strain, develop and release the first set of vaccine doses to the public. Ironically, the H5N1 bird flu virus is so deadly to chicken embryos that it interferes with the process to make a vaccine against itself. The eggs have to be specially treated so they can be used.
More advanced technology is available, but it is expensive to change over to state-of-the-art methods. The most commonly used methods involve reverse genetics and cell cultures. In reverse genetics, using the structure of the bird flu virus, scientists can genetically engineer an existing influenza virus by inserting strips of genetic material and turning one viral strain into another. Then, instead of injecting that genetically manipulated strain into a million eggs, they grow it with cell cultures.
Using this cell culture technique, scientists grow animal cells or human cells in big vats of nutrient solution. Then they inject the newly created virus strain into the cells. As the cells reproduce, so does the virus. Eventually, the outer wall of cell is removed, and the viruses are harvested, purified and then neutralized or killed. Once dead, they can safely be injected into subjects as a vaccine, inducing an animal or person to make antibodies against this "manufactured" virus. Using this method, the interval between the identifying a strain and producing the first batch of vaccines can be measured in days instead of months.
So why do we still rely on the chicken eggs? Vaccine manufacturers, though they use these techniques routinely for other viruses, have been reluctant to switch with flu vaccines because of expense as well as potential liability. Simply put, they don't know what side effects will occur until they start to test people. So they would rather stick to obsolete techniques that have been proven safe rather than use existing technology to venture into unknown legal territory.
On the horizon are other exciting advanced techniques, including one that targets the M2 protein of the influenza molecule. Since that molecule doesn't change, this kind of a vaccine might provide immunity to all flus (including bird flu) for a decade, rather than one flu for a year only. Urgent pandemic preparation or stockpiling would be rendered obsolete, since a vaccinated individual would carry an immunity to all flus.
And then there's Jose Galarza. In a tiny lab perched above the Hudson River, Galarza, a lone researcher who has the reputation in the vaccine world as a maverick, has been experimenting with tiny specks of genetic matter for nearly ten years. He works with microscopic blobs of genes (called viral-like particles known as VLPs) from which he fashions painless, oral vaccines more rapidly than traditional methods. In fact, Galarza believes he can command his VLPs to knock out bird flu in lab animals-- and potentially in humans--more quickly and safely than conventional vaccines.
Work such as Galarza's is evidence that the human flu shot can be modernized, both for the yearly flu as well as for the more remote H5N1 bird flu, given the rare chance that it could mutate into a form that could routinely affect humans. Stockpiling vaccine now using the old methods has limited value since this virus may well not mutate, and even if it does, it may change to a form that renders the current bird flu vaccine ineffective. If a worst-case scenario were to occur, we would need a modern vaccine to be able to combat it.
One of the major problems in the United States is that we rely on the motivation of vaccine manufacturers who are neither motivated nor altruistic. Our country could learn a great deal about vaccine production from the countries of Western Europe, where the government controls the production and distribution of vaccines. Relying on corporate good will and a large supply of vaccine with a small profit margin is a dangerous strategy where public health and safety are involved.
