The war against intractable flu
Saturday, 23 May 2009
Syed Fattahul Alim
In the very advanced countries every year vaccines are developed that protect people from the attack of the seasonal flu. Seasonal flu is not a harmless disease. It kills. Every year different strains of seasonal flu take their toll on human lives. Some half a million people as a result die worldwide every year from various types of seasonal flu. The people of the least developed world are practically unprotected against the seasonal flu as the vaccines developed against those in the advanced countries remain beyond their reach. But the problem of producing the vaccines against seasonal flu is that the flu viruses mutate very vast. In consequence, the antidotes developed in one year become ineffective against the new strains developed in the next year. This is a big hurdle that comes in the way of reaching the flu vaccines to the less developed world. Moreover, they cannot themselves afford to conduct any research to develop such vaccines.
Amidst this endless fight against the known varieties of flu viruses, the pandemics like their latest version, the swine flu, has thrown a big challenge before producers of vaccines against flu. One may recall that a few years back another pandemic, the avian flu, caused great alarm worldwide. Now we have another pandemic, the swine flu that has pressed the panic button throughout the world. What is the probable protection against such kinds of pandemic? These viruses that jump the species barrier are very dangerous, but again they are also very apt at changing their shape very quickly like their regular seasonal brethren.
How will then researchers develop the appropriate vaccines that can effectively protect the people from the attack of these fast mutating flu viruses, whether they are the regular ones behind the different versions of seasonal flu or the new kinds of pandemics causing global alarms about every other year?
To face the threat of the seasonal kinds of flu or the pandemics at one go, scientists are trying to develop a new breed of vaccine that would protect the population against all the different variants of flu over a long time, if not forever like the anti-polio or anti-measles vaccines.
Andrew Pollack of the New York Times relates in the following the latest researches being conducted to develop a universal vaccine against all the different kinds of flu to protect the world against flu once and for all.
Two shots of measles vaccine given during childhood protect a person for life. Four shots of polio vaccine do the same. But flu shots must be taken every year. And even so, they provide less than complete protection.
The reason is that the influenza virus mutates much more rapidly than most other viruses. A person who develops immunity to one strain of the virus is not well protected from a different strain.
That is shaping up to be a major problem as the world prepares for a possible pandemic this fall from the new strain of swine flu. It is impossible to know how many people might die before a vaccine matched to that strain can be manufactured.
But scientists and vaccine manufacturers are hard at work on a so-called universal flu vaccine that would work against all types of flu. The goal is to provide protection for years, if not a whole lifetime, against all seasonal flu strains and pandemic strains, making flu inoculation much more like that for measles and polio.
"The universal would completely change the way flu vaccination would be done," said Sarah C. Gilbert, a vaccine expert at the University of Oxford. "The sooner we have a universal vaccine the better because we can stop worrying about what the next pandemic will be."
Such a one-shot-fits-all vaccine would also end the guessing game that now occurs at the beginning of each year as scientists decide which strains should be included in the seasonal vaccine for the following winter. If they guess wrong, the vaccine is less effective.
And it would make flu immunization practical for countries that now cannot afford a yearly effort. Seasonal flu is estimated to contribute to an average of 36,000 deaths in the United States and as many as half a million worldwide each year.
Unfortunately, a universal vaccine will not be ready soon enough to combat a possible pandemic from the new strain of swine flu that has already sickened thousands of people. The most advanced of the vaccines have been tested only in small clinical trials. It is likely to take several more years to show if the vaccines really work.
Indeed, the universal vaccines developed so far do not totally prevent infection, as the strain-specific vaccines can do. Rather, they limit severity and spread of the disease. Some experts say that would be sufficient, but others have their doubts.
"It wouldn't replace the seasonal flu vaccine," said Dr. Robert Belshe, director of the centre for vaccine development at Saint Louis University. "I think it would be considered a supplement to it."
Some experts say booster shots might still be needed every 10 years or so. It is also not clear if the vaccines would be able to provide protection against all strains, including animal-derived viruses like the new swine flu. Most of the universal vaccines under development do not even try to provide protection against influenza type B. They focus on type A, which tends to cause more severe disease and pandemics.
When someone is vaccinated or infected, the immune system makes antibodies that mostly attack a protein on the surface of the virus called hemagglutinin. But that protein is the fastest-changing part of the virus, so antibodies to one strain might not recognize another.
A universal vaccine would have to spur an immune system attack on part of the influenza virus that does not vary from strain to strain.
If that were easy to do, sceptics say, the immune system would have figured it out and people would have lasting protection. Vaccine researchers counter that some people might have immunity lasting at least a few years. And a vaccine can teach the immune system to do things it might not be able to do on its own.
"I don't see any reason it should be impossible," said Suzanne Epstein, a researcher at the Food and Drug Administration. "It works quite well in animals."
The big problem is that most of the flu virus proteins that do not vary much are on the inside of the virus, out of reach of antibodies. But there is one internal protein, called M2, that protrudes a bit from the virus. This external piece is not much of a target for antibodies, but it is the main focus of universal vaccine research.
"The trick is you've got to have a system that will raise a robust immune response against this puny little protein that's not present in any abundance," said Alan Shaw, president of VaxInnate, a small company trying to develop a universal vaccine that combines the external part of M2 with a bacterial protein that stimulates the immune system.
VaxInnate, Merck and Acambis, which is owned by Sanofi-Aventis, have each run a small test of their M2 vaccines on healthy volunteers. Vaccinated people do make antibodies to M2. But those antibodies do not totally prevent infection. It will take much larger tests to see if vaccines actually work to ameliorate disease during a real flu season.
Another issue is that the M2 protein in animal influenza viruses can be somewhat different from that in human viruses. That raises questions about how well an M2 vaccine might work, say, against the new swine flu, which is known formally as H1N1.
"The new H1N1 virus could throw a little bit of a wrench into things," said Andrew Pekosz, an associate professor of molecular microbiology and immunology at Johns Hopkins University.
Earlier this year, two teams of researchers reported independently that there might be another non-varying region on the outside of the virus. It is in the stick of the lollipop-shaped hemagglutinin protein rather than the constantly changing head.
One of the groups showed that antibodies isolated from human blood that bound to this part of the stick protected mice against many strains of flu, including the 1918 pandemic Spanish flu and the H5N1 bird flu.
But experts say it will be very difficult to isolate this part of the protein from the virus to use in a vaccine, or to manufacture it using genetic engineering.
"My first thought was, 'Oh, you have to make the vaccine,' " said Dr. Hildegund C. J. Ertl, a universal vaccine researcher at the Wistar Institute in Philadelphia who was not involved in the discovery. "But then when I looked at the sequence, it wasn't straightforward at all."
An alternative would be to use the antibodies themselves as a medicine, though antibodies are expensive to manufacture and time-consuming to infuse into patients.
With constant regions outside the virus hard to find, some efforts aim at non-changing proteins inside the virus, like one called nucleoprotein. Antibodies cannot get at these proteins to prevent an infection. So the idea is to spur other soldiers of the immune system called T cells to quickly kill the infected cells before they could make new viruses. That would limit disease severity.
Dr. Epstein of the F.D.A. said a vaccine based on a nucleoprotein from a human H1N1 virus was able to protect animals from a lethal dose of the H5N1 bird flu, the virus which stoked pandemic fears a few years ago. Oxford University has tested a T cell vaccine in 28 healthy adults and found it did increase T cell responses.
Ultimately, the best results might come from combining the techniques. Dynavax, a California biotechnology company, hopes to begin trials next year of a vaccine designed to spur antibodies against M2 and T cells against nucleoprotein.
In the very advanced countries every year vaccines are developed that protect people from the attack of the seasonal flu. Seasonal flu is not a harmless disease. It kills. Every year different strains of seasonal flu take their toll on human lives. Some half a million people as a result die worldwide every year from various types of seasonal flu. The people of the least developed world are practically unprotected against the seasonal flu as the vaccines developed against those in the advanced countries remain beyond their reach. But the problem of producing the vaccines against seasonal flu is that the flu viruses mutate very vast. In consequence, the antidotes developed in one year become ineffective against the new strains developed in the next year. This is a big hurdle that comes in the way of reaching the flu vaccines to the less developed world. Moreover, they cannot themselves afford to conduct any research to develop such vaccines.
Amidst this endless fight against the known varieties of flu viruses, the pandemics like their latest version, the swine flu, has thrown a big challenge before producers of vaccines against flu. One may recall that a few years back another pandemic, the avian flu, caused great alarm worldwide. Now we have another pandemic, the swine flu that has pressed the panic button throughout the world. What is the probable protection against such kinds of pandemic? These viruses that jump the species barrier are very dangerous, but again they are also very apt at changing their shape very quickly like their regular seasonal brethren.
How will then researchers develop the appropriate vaccines that can effectively protect the people from the attack of these fast mutating flu viruses, whether they are the regular ones behind the different versions of seasonal flu or the new kinds of pandemics causing global alarms about every other year?
To face the threat of the seasonal kinds of flu or the pandemics at one go, scientists are trying to develop a new breed of vaccine that would protect the population against all the different variants of flu over a long time, if not forever like the anti-polio or anti-measles vaccines.
Andrew Pollack of the New York Times relates in the following the latest researches being conducted to develop a universal vaccine against all the different kinds of flu to protect the world against flu once and for all.
Two shots of measles vaccine given during childhood protect a person for life. Four shots of polio vaccine do the same. But flu shots must be taken every year. And even so, they provide less than complete protection.
The reason is that the influenza virus mutates much more rapidly than most other viruses. A person who develops immunity to one strain of the virus is not well protected from a different strain.
That is shaping up to be a major problem as the world prepares for a possible pandemic this fall from the new strain of swine flu. It is impossible to know how many people might die before a vaccine matched to that strain can be manufactured.
But scientists and vaccine manufacturers are hard at work on a so-called universal flu vaccine that would work against all types of flu. The goal is to provide protection for years, if not a whole lifetime, against all seasonal flu strains and pandemic strains, making flu inoculation much more like that for measles and polio.
"The universal would completely change the way flu vaccination would be done," said Sarah C. Gilbert, a vaccine expert at the University of Oxford. "The sooner we have a universal vaccine the better because we can stop worrying about what the next pandemic will be."
Such a one-shot-fits-all vaccine would also end the guessing game that now occurs at the beginning of each year as scientists decide which strains should be included in the seasonal vaccine for the following winter. If they guess wrong, the vaccine is less effective.
And it would make flu immunization practical for countries that now cannot afford a yearly effort. Seasonal flu is estimated to contribute to an average of 36,000 deaths in the United States and as many as half a million worldwide each year.
Unfortunately, a universal vaccine will not be ready soon enough to combat a possible pandemic from the new strain of swine flu that has already sickened thousands of people. The most advanced of the vaccines have been tested only in small clinical trials. It is likely to take several more years to show if the vaccines really work.
Indeed, the universal vaccines developed so far do not totally prevent infection, as the strain-specific vaccines can do. Rather, they limit severity and spread of the disease. Some experts say that would be sufficient, but others have their doubts.
"It wouldn't replace the seasonal flu vaccine," said Dr. Robert Belshe, director of the centre for vaccine development at Saint Louis University. "I think it would be considered a supplement to it."
Some experts say booster shots might still be needed every 10 years or so. It is also not clear if the vaccines would be able to provide protection against all strains, including animal-derived viruses like the new swine flu. Most of the universal vaccines under development do not even try to provide protection against influenza type B. They focus on type A, which tends to cause more severe disease and pandemics.
When someone is vaccinated or infected, the immune system makes antibodies that mostly attack a protein on the surface of the virus called hemagglutinin. But that protein is the fastest-changing part of the virus, so antibodies to one strain might not recognize another.
A universal vaccine would have to spur an immune system attack on part of the influenza virus that does not vary from strain to strain.
If that were easy to do, sceptics say, the immune system would have figured it out and people would have lasting protection. Vaccine researchers counter that some people might have immunity lasting at least a few years. And a vaccine can teach the immune system to do things it might not be able to do on its own.
"I don't see any reason it should be impossible," said Suzanne Epstein, a researcher at the Food and Drug Administration. "It works quite well in animals."
The big problem is that most of the flu virus proteins that do not vary much are on the inside of the virus, out of reach of antibodies. But there is one internal protein, called M2, that protrudes a bit from the virus. This external piece is not much of a target for antibodies, but it is the main focus of universal vaccine research.
"The trick is you've got to have a system that will raise a robust immune response against this puny little protein that's not present in any abundance," said Alan Shaw, president of VaxInnate, a small company trying to develop a universal vaccine that combines the external part of M2 with a bacterial protein that stimulates the immune system.
VaxInnate, Merck and Acambis, which is owned by Sanofi-Aventis, have each run a small test of their M2 vaccines on healthy volunteers. Vaccinated people do make antibodies to M2. But those antibodies do not totally prevent infection. It will take much larger tests to see if vaccines actually work to ameliorate disease during a real flu season.
Another issue is that the M2 protein in animal influenza viruses can be somewhat different from that in human viruses. That raises questions about how well an M2 vaccine might work, say, against the new swine flu, which is known formally as H1N1.
"The new H1N1 virus could throw a little bit of a wrench into things," said Andrew Pekosz, an associate professor of molecular microbiology and immunology at Johns Hopkins University.
Earlier this year, two teams of researchers reported independently that there might be another non-varying region on the outside of the virus. It is in the stick of the lollipop-shaped hemagglutinin protein rather than the constantly changing head.
One of the groups showed that antibodies isolated from human blood that bound to this part of the stick protected mice against many strains of flu, including the 1918 pandemic Spanish flu and the H5N1 bird flu.
But experts say it will be very difficult to isolate this part of the protein from the virus to use in a vaccine, or to manufacture it using genetic engineering.
"My first thought was, 'Oh, you have to make the vaccine,' " said Dr. Hildegund C. J. Ertl, a universal vaccine researcher at the Wistar Institute in Philadelphia who was not involved in the discovery. "But then when I looked at the sequence, it wasn't straightforward at all."
An alternative would be to use the antibodies themselves as a medicine, though antibodies are expensive to manufacture and time-consuming to infuse into patients.
With constant regions outside the virus hard to find, some efforts aim at non-changing proteins inside the virus, like one called nucleoprotein. Antibodies cannot get at these proteins to prevent an infection. So the idea is to spur other soldiers of the immune system called T cells to quickly kill the infected cells before they could make new viruses. That would limit disease severity.
Dr. Epstein of the F.D.A. said a vaccine based on a nucleoprotein from a human H1N1 virus was able to protect animals from a lethal dose of the H5N1 bird flu, the virus which stoked pandemic fears a few years ago. Oxford University has tested a T cell vaccine in 28 healthy adults and found it did increase T cell responses.
Ultimately, the best results might come from combining the techniques. Dynavax, a California biotechnology company, hopes to begin trials next year of a vaccine designed to spur antibodies against M2 and T cells against nucleoprotein.