sharon sanders
Editor-in-Chief & President
Recently I interviewed David Fedson, M.D., an expert in pandemic preparedness and vaccine issues, regarding his latest paper: "Meeting the challenge of influenza pandemic preparedness in developing countries". (link <http://www.cdc.gov/eid/content/15/3/pdfs/08-0857.pdf> )
He earned his medical degree from Yale University in 1965. Later he obtained a fellowship studying smallpox in India, and interned at the Osler Medical Service at The Johns Hopkins Hospital. He was a Clinical Associate in the Laboratory of Clinical Investigation at the National Institutes of Health and was a Chief Medical Resident at the University of Chicago. He has held faculty appointments at the University of Chicago and also the University of Virgina, where he was the Harry T. Peters, Jr. Professor of Medicine and Head of the Division of General Medicine.
In 1995, Dr. Fedson joined the Medical Department of Aventis Pasteur MSD. There he concentrated his work on the epidemiology and cost-effectiveness of influenza and pneumococcal vaccination. In 1999, he received the Research Achievement Award in Adult Immunization in the United States, bestowed by the Centers for Disease Control and Prevention and the National Coalition on Adult Immunization. He participated in the establishment of the Influenza Vaccine Supply (IVS) International Task Force in 2001 which considers vaccine topics for the next influenza pandemic. He retired in November 2002 and has continued to work on influenza and pneumococcal vaccination issues. He organized the Macroepidemiology of Influenza Vaccination (MIV) Study Group. Dr. Fedson has published over 160 scientific articles and papers on issues concerning adult immunization.
SS -- Dr. Fedson, thank you for giving this interview. In your paper you urge the leaders of developing countries, scientists, and international organizations to begin the research into inexpensive generic agents to mitigate an influenza pandemic, what response have you received?
DSF — I’ve received no response. Since I work alone and am not affiliated with an institution or organization, I’ve not expected to be contacted directly, However, the idea for conducting research on inexpensive generic agents is one that I have been “peddling” to international organizations, health agencies and influenza investigators for almost five years. I’ve received very few expressions of interest. For example, on four separate occasions I‘ve asked WHO to hold a technical consultation to review the scientific merits of the generics approach and, if it seems reasonable, to set forth a research agenda. On each occasion, WHO has turned me down. The Gates Foundation has not been interested. I even met with a senior advisor to the Indonesian Health Minister to introduce him to these ideas, but I don’t think our conversation led to anything. However, I have been encouraged by the response of a well-positioned Chinese investigator. When we discussed these ideas last fall, he said he would take them back to Beijing and get to work. He understands better than I that with 1.3 billion people to look after and few prospects for adequate supplies of pandemic vaccines and antivirals, his country will need one or more effective alternatives. Since several of the generic agents I’ve discussed are produced in China, Chinese health officials have a strong incentive to take the generics approach seriously. And China has many experienced investigators who are capable of doing the research.
SS --You have suggested the possibility of using statins, peroxisome proliferator-activated receptor (PPAR)a and PPARg agonists (fibrates and glitazones, respectively), chloroquine, resveratrol, catechins, and curcumin for treating pandemic influenza. Why do you think research is lacking in determining the effectiveness of these agents to mitigate a pandemic?
DSF — From what we know of the molecular biology of these agents, they are among the most promising candidates for testing in research laboratories. However, they are not by any means the only ones. What characterizes them is that, with one exception, they are generically produced in developing countries and consequently they are inexpensive and could be made widely available. Of course, because they are generic agents, no pharmaceutical company is interested in sponsoring such research.
Influenza virologists are not studying these agents because they are experts on the virus and seek to develop either vaccines or antiviral agents. The generic agents I talk about affect the host response, and this is something that, with the exception of the immune response, influenza virologist know little about.
Not long ago, I asked a group of distinguished influenza scientists if any of them had heard of heme oxygenase-1 or high molecular group box 1 protein. None of them had. Yet anyone who studies the molecular biology of sepsis or acute lung injury will be familiar with these terms, and will know that they must be included in any serious discussion of the host response to infection.
Donald Rumsfeld once said, “There are known knowns, ... (the) ... things we know that we know. There are known unknowns, ... (the) things that we know we don't know. But there are also unknown unknowns, ... (the) ... things we don't know we don't know.”
For influenza scientists and the host response, there are lots of unknown unknowns.That’s why I say in my article that pandemic preparedness is too important to leave to the influenza scientists alone. We must enlist the support of scientists in other fields – sepsis, critical care, cardiovascular and pulmonary diseases, metabolic disorders, mitochondrial function. They must tell influenza scientists what they know is known and unknown about the host response to infection.
GM -- What is the possible role for quinine (antimalarial) and derivatives for treatment of influenza infections during pandemics, addressing the issue of possible treatment failures that caused health authorities to refrain for using these compounds - theoretically useful even in chikungunya epidemics, for example - so far. Further, can ribarivin and protease inhibitors (ie: Rebetol and Kaletra) be seen as synergistic therapeuticals in addition to neuraminidase inhibitors?
DSF – I have no opinion on the potential for using quinine for pandemic treatment. Chloroquine, or better hydroxychloroquine, should be considered because for at least some influenza viruses, these agents prevent the acidification of the endosome and this means that influenza virus genetic material can’t be released into the cytoplasm of an infected cell. If hydroxychloroquine were shown to be of benefit, it would be very, very inexpensive.
Regarding additional agents such as ribavirin and protease inhibitors, several influential influenza virologists have recently called for treating individual patients with more than one antiviral agent. Their recommendation is an obvious response to the development of resistance to oseltamivir (Tamiflu) in almost all isolates of seasonal H1N1 influenza viruses, and a recognition that the same thing might occur with a pandemic virus. But we should stop for a moment and ask: would adequate supplies of ribavirin and protease inhibitors be available at affordable prices if and when a pandemic virus appears? The answer to that question is most certainly they wouldn’t be. I point out in my article that global supplies of oseltamivir, the most widely stockpiled antiviral agent, will be sufficient to treat about 1% of the people who live in countries that don’t produce vaccines. If this is true for oseltamivir, it’s my guess that supplies of ribarivin and protease inhibitors will probably be much more limited. While a recommendation for combination antiviral treatment is sensible from a purely scientific point of view, it has virtually no chance of ever being implemented in populations. Recommendations on how to confront a pandemic in populations must be relentlessly practical; if they are anything less, they shouldn’t be taken seriously.
SS -- In your paper you say, "In Indonesia, physicians have reported that everyone infected with the clade 2 influenza virus A (H5N1) who did not receive antiviral treatment has died". In your opinion do we have time for the lengthy process to quantify and approve such a protocol as you suggest for treatment of pandemic (potentially H5N1) influenza? Would it be possible to establish a treatment protocol for humans after initial tests/findings on mice?
DSF — If we had started doing the animal research several years ago, by now we would have identified one or more treatment regimens that might be promising (or perhaps shown that none of them would work). We could still do the research in mice, ferrets and nonhuman primates and get many of the answers we need within six to twelve months. The cost would not be very high, but it would require some serious organization and the collaborative efforts of many scientists, along the lines of the international collaboration that quickly led to the identification of the SARS coronavirus. As I point out in my article, this WHO initiative for SARS was spectacularly successful. I don’t understand why WHO hasn’t seen the need to do something similar for pandemic preparedness. The stakes are immeasurably higher.
Testing promising treatments in ferrets and at least some nonhuman primates should be the goal; basing decisions on which regimens to test in man on mouse data alone could be misleading. But no matter how much animal research precedes human testing, the protocols for clinical trials must be in place before the next pandemic virus emerges. Ideally they should be drawn up by an international group of scientists and clinical investigators, but this would require an organization like WHO or the NIH to bring them together. If this doesn’t happen (which is likely), individual institutions will undertake trials on their own. Recently I spoke with investigators at my local university hospital, and they said they would seek approval from their hospital ethics committee for a clinical trial protocol that could be implemented when they admit their first pandemic patient. It will be unfortunate in the extreme if we have to rely solely on the ad hoc efforts of a few individual investigators to provide us with critical information on how to manage a global pandemic.
I should add that clinical investigators in the US, the UK and Australia are already conducting randomized controlled trials of statins in the treatment of sepsis, and at least one study on statin treatment of ICU patients with pneumonia will soon to be completed in South Korea. These trials should provide important information to guide clinical trials of pandemic treatments.
SS -- If an influenza pandemic strikes before a treatment protocol is established via traditional methodology, do you have a suggested course of treatment?
DSF — I have a good sense of which agents I personally might wish to test first, but this would be like placing a bet on a favorite horse. Our approach should be more rational.
In my article I outline a five-point agenda for research on generic agents that should be undertaken before the emergence of a new pandemic virus. The first two steps describe the laboratory research that must be conducted in mice, ferrets and non-human primates. I emphasize that this research must seek to identify promising regimens at can be used to manage a pandemic. Explaining precisely how these agents work is of secondary importance. We should keep in mind that Jenner didn’t understand the germ theory of disease when he vaccinated against smallpox. Knowing so little, he nonetheless achieved so much.
SS - In today's depressed economic climate, in your opinion, what or which, global entities could fund the parallel studies/research as suggested in your paper?
DSF — The amounts of money that we would need to first test promising treatment regimens in mice would not be very large. I’ve been told by one investigator who works with mice that studies in 5000 mice would cost no more than $250,000, not counting the costs for personnel. Keep in mind that Ian Clark and his colleagues in Australia used fewer than 100 mice to show that gemfibrozil, a fibrate, reduced mortality H2N2-infected mice by more than 50%. With 5000 mice, we could undertake 50 similar trials. Tests in 300 ferrets could probably be done for $500,000. Compared with what is now being spent by governments to rescue their banks, these amounts are less than trivial. But someone will have to come up with the money, and it will have to be either a national government, the US being far and away the most likely, or institutions like the Gates Foundation or the Wellcome Trust. But they will have to get interested first. Thus far, they have focused their support on developing vaccines and antiviral agents. Unfortunately, I don’t think they understand the arithmetic of the limited supplies of vaccines and antivirals , and the potential for much larger and much more affordable supplies of generic agents.
SS - What can the average citizen do to promote a "bottom-up" approach based on inexpensive generic agents for preparation of an influenza pandemic?
DSF —The average citizen can follow Flu Trackers closely, write to his or her Congressman or Congresswoman and Senator, and contact the local newspaper and media. We need to get more political support for this idea if we are to move it along. This means that a lot more people are going to have to start making a lot more noise.
by Sharon Sanders
Contributors:
Sally Furniss
Giuseppe Michieli
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for FluTrackers.com
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He earned his medical degree from Yale University in 1965. Later he obtained a fellowship studying smallpox in India, and interned at the Osler Medical Service at The Johns Hopkins Hospital. He was a Clinical Associate in the Laboratory of Clinical Investigation at the National Institutes of Health and was a Chief Medical Resident at the University of Chicago. He has held faculty appointments at the University of Chicago and also the University of Virgina, where he was the Harry T. Peters, Jr. Professor of Medicine and Head of the Division of General Medicine.
In 1995, Dr. Fedson joined the Medical Department of Aventis Pasteur MSD. There he concentrated his work on the epidemiology and cost-effectiveness of influenza and pneumococcal vaccination. In 1999, he received the Research Achievement Award in Adult Immunization in the United States, bestowed by the Centers for Disease Control and Prevention and the National Coalition on Adult Immunization. He participated in the establishment of the Influenza Vaccine Supply (IVS) International Task Force in 2001 which considers vaccine topics for the next influenza pandemic. He retired in November 2002 and has continued to work on influenza and pneumococcal vaccination issues. He organized the Macroepidemiology of Influenza Vaccination (MIV) Study Group. Dr. Fedson has published over 160 scientific articles and papers on issues concerning adult immunization.
SS -- Dr. Fedson, thank you for giving this interview. In your paper you urge the leaders of developing countries, scientists, and international organizations to begin the research into inexpensive generic agents to mitigate an influenza pandemic, what response have you received?
DSF — I’ve received no response. Since I work alone and am not affiliated with an institution or organization, I’ve not expected to be contacted directly, However, the idea for conducting research on inexpensive generic agents is one that I have been “peddling” to international organizations, health agencies and influenza investigators for almost five years. I’ve received very few expressions of interest. For example, on four separate occasions I‘ve asked WHO to hold a technical consultation to review the scientific merits of the generics approach and, if it seems reasonable, to set forth a research agenda. On each occasion, WHO has turned me down. The Gates Foundation has not been interested. I even met with a senior advisor to the Indonesian Health Minister to introduce him to these ideas, but I don’t think our conversation led to anything. However, I have been encouraged by the response of a well-positioned Chinese investigator. When we discussed these ideas last fall, he said he would take them back to Beijing and get to work. He understands better than I that with 1.3 billion people to look after and few prospects for adequate supplies of pandemic vaccines and antivirals, his country will need one or more effective alternatives. Since several of the generic agents I’ve discussed are produced in China, Chinese health officials have a strong incentive to take the generics approach seriously. And China has many experienced investigators who are capable of doing the research.
SS --You have suggested the possibility of using statins, peroxisome proliferator-activated receptor (PPAR)a and PPARg agonists (fibrates and glitazones, respectively), chloroquine, resveratrol, catechins, and curcumin for treating pandemic influenza. Why do you think research is lacking in determining the effectiveness of these agents to mitigate a pandemic?
DSF — From what we know of the molecular biology of these agents, they are among the most promising candidates for testing in research laboratories. However, they are not by any means the only ones. What characterizes them is that, with one exception, they are generically produced in developing countries and consequently they are inexpensive and could be made widely available. Of course, because they are generic agents, no pharmaceutical company is interested in sponsoring such research.
Influenza virologists are not studying these agents because they are experts on the virus and seek to develop either vaccines or antiviral agents. The generic agents I talk about affect the host response, and this is something that, with the exception of the immune response, influenza virologist know little about.
Not long ago, I asked a group of distinguished influenza scientists if any of them had heard of heme oxygenase-1 or high molecular group box 1 protein. None of them had. Yet anyone who studies the molecular biology of sepsis or acute lung injury will be familiar with these terms, and will know that they must be included in any serious discussion of the host response to infection.
Donald Rumsfeld once said, “There are known knowns, ... (the) ... things we know that we know. There are known unknowns, ... (the) things that we know we don't know. But there are also unknown unknowns, ... (the) ... things we don't know we don't know.”
For influenza scientists and the host response, there are lots of unknown unknowns.That’s why I say in my article that pandemic preparedness is too important to leave to the influenza scientists alone. We must enlist the support of scientists in other fields – sepsis, critical care, cardiovascular and pulmonary diseases, metabolic disorders, mitochondrial function. They must tell influenza scientists what they know is known and unknown about the host response to infection.
GM -- What is the possible role for quinine (antimalarial) and derivatives for treatment of influenza infections during pandemics, addressing the issue of possible treatment failures that caused health authorities to refrain for using these compounds - theoretically useful even in chikungunya epidemics, for example - so far. Further, can ribarivin and protease inhibitors (ie: Rebetol and Kaletra) be seen as synergistic therapeuticals in addition to neuraminidase inhibitors?
DSF – I have no opinion on the potential for using quinine for pandemic treatment. Chloroquine, or better hydroxychloroquine, should be considered because for at least some influenza viruses, these agents prevent the acidification of the endosome and this means that influenza virus genetic material can’t be released into the cytoplasm of an infected cell. If hydroxychloroquine were shown to be of benefit, it would be very, very inexpensive.
Regarding additional agents such as ribavirin and protease inhibitors, several influential influenza virologists have recently called for treating individual patients with more than one antiviral agent. Their recommendation is an obvious response to the development of resistance to oseltamivir (Tamiflu) in almost all isolates of seasonal H1N1 influenza viruses, and a recognition that the same thing might occur with a pandemic virus. But we should stop for a moment and ask: would adequate supplies of ribavirin and protease inhibitors be available at affordable prices if and when a pandemic virus appears? The answer to that question is most certainly they wouldn’t be. I point out in my article that global supplies of oseltamivir, the most widely stockpiled antiviral agent, will be sufficient to treat about 1% of the people who live in countries that don’t produce vaccines. If this is true for oseltamivir, it’s my guess that supplies of ribarivin and protease inhibitors will probably be much more limited. While a recommendation for combination antiviral treatment is sensible from a purely scientific point of view, it has virtually no chance of ever being implemented in populations. Recommendations on how to confront a pandemic in populations must be relentlessly practical; if they are anything less, they shouldn’t be taken seriously.
SS -- In your paper you say, "In Indonesia, physicians have reported that everyone infected with the clade 2 influenza virus A (H5N1) who did not receive antiviral treatment has died". In your opinion do we have time for the lengthy process to quantify and approve such a protocol as you suggest for treatment of pandemic (potentially H5N1) influenza? Would it be possible to establish a treatment protocol for humans after initial tests/findings on mice?
DSF — If we had started doing the animal research several years ago, by now we would have identified one or more treatment regimens that might be promising (or perhaps shown that none of them would work). We could still do the research in mice, ferrets and nonhuman primates and get many of the answers we need within six to twelve months. The cost would not be very high, but it would require some serious organization and the collaborative efforts of many scientists, along the lines of the international collaboration that quickly led to the identification of the SARS coronavirus. As I point out in my article, this WHO initiative for SARS was spectacularly successful. I don’t understand why WHO hasn’t seen the need to do something similar for pandemic preparedness. The stakes are immeasurably higher.
Testing promising treatments in ferrets and at least some nonhuman primates should be the goal; basing decisions on which regimens to test in man on mouse data alone could be misleading. But no matter how much animal research precedes human testing, the protocols for clinical trials must be in place before the next pandemic virus emerges. Ideally they should be drawn up by an international group of scientists and clinical investigators, but this would require an organization like WHO or the NIH to bring them together. If this doesn’t happen (which is likely), individual institutions will undertake trials on their own. Recently I spoke with investigators at my local university hospital, and they said they would seek approval from their hospital ethics committee for a clinical trial protocol that could be implemented when they admit their first pandemic patient. It will be unfortunate in the extreme if we have to rely solely on the ad hoc efforts of a few individual investigators to provide us with critical information on how to manage a global pandemic.
I should add that clinical investigators in the US, the UK and Australia are already conducting randomized controlled trials of statins in the treatment of sepsis, and at least one study on statin treatment of ICU patients with pneumonia will soon to be completed in South Korea. These trials should provide important information to guide clinical trials of pandemic treatments.
SS -- If an influenza pandemic strikes before a treatment protocol is established via traditional methodology, do you have a suggested course of treatment?
DSF — I have a good sense of which agents I personally might wish to test first, but this would be like placing a bet on a favorite horse. Our approach should be more rational.
In my article I outline a five-point agenda for research on generic agents that should be undertaken before the emergence of a new pandemic virus. The first two steps describe the laboratory research that must be conducted in mice, ferrets and non-human primates. I emphasize that this research must seek to identify promising regimens at can be used to manage a pandemic. Explaining precisely how these agents work is of secondary importance. We should keep in mind that Jenner didn’t understand the germ theory of disease when he vaccinated against smallpox. Knowing so little, he nonetheless achieved so much.
SS - In today's depressed economic climate, in your opinion, what or which, global entities could fund the parallel studies/research as suggested in your paper?
DSF — The amounts of money that we would need to first test promising treatment regimens in mice would not be very large. I’ve been told by one investigator who works with mice that studies in 5000 mice would cost no more than $250,000, not counting the costs for personnel. Keep in mind that Ian Clark and his colleagues in Australia used fewer than 100 mice to show that gemfibrozil, a fibrate, reduced mortality H2N2-infected mice by more than 50%. With 5000 mice, we could undertake 50 similar trials. Tests in 300 ferrets could probably be done for $500,000. Compared with what is now being spent by governments to rescue their banks, these amounts are less than trivial. But someone will have to come up with the money, and it will have to be either a national government, the US being far and away the most likely, or institutions like the Gates Foundation or the Wellcome Trust. But they will have to get interested first. Thus far, they have focused their support on developing vaccines and antiviral agents. Unfortunately, I don’t think they understand the arithmetic of the limited supplies of vaccines and antivirals , and the potential for much larger and much more affordable supplies of generic agents.
SS - What can the average citizen do to promote a "bottom-up" approach based on inexpensive generic agents for preparation of an influenza pandemic?
DSF —The average citizen can follow Flu Trackers closely, write to his or her Congressman or Congresswoman and Senator, and contact the local newspaper and media. We need to get more political support for this idea if we are to move it along. This means that a lot more people are going to have to start making a lot more noise.
by Sharon Sanders
Contributors:
Sally Furniss
Giuseppe Michieli
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for FluTrackers.com
<!--[endif]-->
