9
PREPARATION FOR PANDEMIC INFLUENZA: FILLING THE GAPS IN KNOWLEDGE AND UNDERSTANDING

Moderator—Dr. Harvey Fineberg

DR. FINEBERG: The premise of this meeting is about research gaps and developing new knowledge needed to prepare better for pandemic flu, with a minimum time horizon of one to two years. Let me invite others, to share their thought about this meeting or what may have been missing from the meeting.

PARTICIPANT: There have been some excellent representatives of industry who have attended this meeting, but noticeably absent are the large pharmaceutical firms, who have a vested interest in the well being of the public health of our country. This issue is very fundamental. As a group of academic scientists, we can have grand designs about producing drug X or drug Y; however, it is actually the industry that is going to have to produce the drugs. The hurdles that we have talked about in terms of public health delivery or in terms of the academic challenges are not as insignificant as they would be for producing the drug that is going to be required by our society. In the future as these meetings continue, the senior management of the large pharmaceuticals who really do want to participate in this effort should be invited and should have a seat at the table.

PARTICIPANT: I think there are some more industry representatives which I was glad to see. I think partnership is the theme of the times. And I think back over three decades of looking at it from both sides. If we think about partnership 30 years ago, it was there. We were doing it, but it is much more so now. I think there is a sincere interest and belief that partnership is not only the way to go, but it is essential, and I think that is happening. I think as we look around, we see that the academic-government-industry partnership is working. It is high maintenance. It is a ton of work, and it can be exhausting, and there can be partnerships that simply do not work, but that is the way we are going.

I think we need to see some innovation in looking at how these things work, especially on the funding side. Simple grants and contracts are not going to do it anymore, and I think the question of how to pay for stockpiles is a good example. Clearly, stockpiling in one sense is something that companies want to do. They want to make stuff for stockpiles. On the other hand, let me remind everyone that the last thing companies want is inventory. Inventory is evil in all its forms, as they say in the industry. And the stockpile is the ultimate inventory. So, rather than say we need to have a ton of capacity, we have got to find ways to do that without—and novel ways to fund it. For example, the payment may not be for the drug or the device in the stockpile. It may be for maintaining the inventory and different ways to do that.

I think the issue of indemnity remains an important one, and we have to wrestle with that. I do not believe it has been answered, and it comes up all the time. It came up yesterday; we need to deal with that issue. We are in a time when novel approaches are welcome, and I think the door is open.



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John R. La Montagne Memorial Symposium on Pandemic Influenza Research: Meeting Proceedings 9 PREPARATION FOR PANDEMIC INFLUENZA: FILLING THE GAPS IN KNOWLEDGE AND UNDERSTANDING Moderator—Dr. Harvey Fineberg DR. FINEBERG: The premise of this meeting is about research gaps and developing new knowledge needed to prepare better for pandemic flu, with a minimum time horizon of one to two years. Let me invite others, to share their thought about this meeting or what may have been missing from the meeting. PARTICIPANT: There have been some excellent representatives of industry who have attended this meeting, but noticeably absent are the large pharmaceutical firms, who have a vested interest in the well being of the public health of our country. This issue is very fundamental. As a group of academic scientists, we can have grand designs about producing drug X or drug Y; however, it is actually the industry that is going to have to produce the drugs. The hurdles that we have talked about in terms of public health delivery or in terms of the academic challenges are not as insignificant as they would be for producing the drug that is going to be required by our society. In the future as these meetings continue, the senior management of the large pharmaceuticals who really do want to participate in this effort should be invited and should have a seat at the table. PARTICIPANT: I think there are some more industry representatives which I was glad to see. I think partnership is the theme of the times. And I think back over three decades of looking at it from both sides. If we think about partnership 30 years ago, it was there. We were doing it, but it is much more so now. I think there is a sincere interest and belief that partnership is not only the way to go, but it is essential, and I think that is happening. I think as we look around, we see that the academic-government-industry partnership is working. It is high maintenance. It is a ton of work, and it can be exhausting, and there can be partnerships that simply do not work, but that is the way we are going. I think we need to see some innovation in looking at how these things work, especially on the funding side. Simple grants and contracts are not going to do it anymore, and I think the question of how to pay for stockpiles is a good example. Clearly, stockpiling in one sense is something that companies want to do. They want to make stuff for stockpiles. On the other hand, let me remind everyone that the last thing companies want is inventory. Inventory is evil in all its forms, as they say in the industry. And the stockpile is the ultimate inventory. So, rather than say we need to have a ton of capacity, we have got to find ways to do that without—and novel ways to fund it. For example, the payment may not be for the drug or the device in the stockpile. It may be for maintaining the inventory and different ways to do that. I think the issue of indemnity remains an important one, and we have to wrestle with that. I do not believe it has been answered, and it comes up all the time. It came up yesterday; we need to deal with that issue. We are in a time when novel approaches are welcome, and I think the door is open.

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John R. La Montagne Memorial Symposium on Pandemic Influenza Research: Meeting Proceedings PARTICIPANT: I think it is a little unrealistic to ask industry to increase capacity to the surge that would be needed for a pandemic, especially when we have to recognize that we are not controlling inter-influenza now. I think the burden on us is to increase demand. Right now the ACIP recommendations include 185 million people. And you know how much vaccine we regularly distribute here. So, if we were distributing anywhere near the amount that we recommend, a lot of that supply problem would be taken care of. The same goes for antivirals. I do not think we are using antivirals nearly as effectively as we could to supply vaccine. And if we were doing that, recognizing flu in the community has occurred, and treating it appropriately, we would increase the demand, and therefore increase the supply. So, I think that is something we need to work on, and help industry work toward the goals that we have for pandemic preparedness. DR. FINEBERG: Do you think it is imaginable that there could be an experimental demonstration, or does it just have to happen gradually across the country? Could there be a state or a region which said we are going to take this seriously. We are going to get our professional groups, we are going to get industry, we are going to get the public health authorities, we are going to have a community education program, we are going to make sure every family knows how important this is, et cetera, could that be imaginable? PARTICIPANT: I think it is not only imaginable, I think that is what we are trying to do now. And I would just like to have more support and other groups to join us. PARTICIPANT: I have actually seen a number of pharmaceutical people here, more than I thought might be here. I've seen leaders from GSK, Chiron, and Merck. I am really glad for the opportunity to be here and be part of this dialogue. I just wanted to say even though we do not currently have a flu vaccine on the market, we certainly did have one in the past. Our interest in influenza has never waned, whether it is a vaccine or the antiviral efforts. And there are different roles for different aspects of the industry. I do not know that it is the best thing at this time to be a contract manufacturer for egg-based vaccines. Certainly in an emergency we will do whatever needs to be done. What we focused on, particularly in the last decade in the 15 years among other things, is trying to come up with new ways of making better flu vaccines and getting broader immunity is really the goal of our work. That may or may not be something that is going to be feasible in our lifetimes, but certainly there is unmet need there, and that is something the world needs. And we are looking for ways to not only continue our efforts; we are looking for support and communication with groups like this one to do a better with this. DR. FINEBERG: Thank you for your comment. I think you also in these remarks, highlight the transitions in capacities and interests that are represented I would say in universities, as in industry and in government increasingly as well. And thinking afresh about the relative contributions that can be made I think is a very important reminder, and a very welcome one. PARTICIPANT: I would just like to highlight a theme that has been mentioned several times in the course of these meetings, but perhaps one that needs emphasis. And that is, this is an international event with which we would be dealing for this. And certainly one of the issues that needs a top priority, if not in terms of resource commitment, at least in terms of policy evaluation is if there is indeed a limited supply of antivirals, and that is possessed by the more developed countries, what is that commitment to the developing world? Because this is where at least most

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John R. La Montagne Memorial Symposium on Pandemic Influenza Research: Meeting Proceedings people feel the initial outbreak is likely to occur. That is something that should be worked out very early in the course of this. The second point is with respect to modeling. I would encourage you to go beyond the national borders when you consider modeling. Look at the downstream effects of this, not only in terms of who takes care of the kids that are no longer in school, but going across international borders, what is the effect on this on our commerce, of our agriculture, of our energy supply? How does this come back to affect this country or the world in a fairly short-term perspective? DR. FINEBERG: Thank you for your comment. If I may, I think your remarks focused on modeling but apply with equal force to our general discussion about research strategy. That is defining the research strategy also can benefit from looking at it from a global or different country perspective, as well as from any one national perspective. And I think the force of those comments apply equally to all of our thinking about research strategy. PARTICIPANT: Just to follow-up on the issue of funding and how we are going to do this. I personally think that we have exhausted the situation of trying to get what we need on inter-pandemic flu preparedness. If you extrapolate the line of increase, it will be about 90 years from now that we will reach some kind of moderate worldwide capability of producing flu vaccines and antiviral drugs. I think we have to take a step back, because we are talking about an issue of international security and economic consequences that are unlike anything that humankind has seen. And you can say, well, do not say that, because you will scare people. I think we have to be willing today to say we are not going to say it is H5N1, but a pandemic influenza situation is going to occur unless somebody is convinced that water now flows uphill.It is Mother Nature. It has been there. It is going to happen. We have already discussed you do not need an H5N1 in a world of 6.5 billion people today to create economic chaos for 12-18 months. As a world, we invest all the time in things that are insurance policies. Today, some of the best funded fire departments in this United States exist in our major metropolitan airports; airports that have not had a plane crash in 50 years. Airports that have incredible equipment, and never can leave the airport compound, because they have to be there. And we pay for that day in and day out, because we have made a decision if it ever does happen, you have to be able to respond in the force that is equivalent for a plane crash. We do that with our federal oil reserves. We have spent billions of dollars stockpiling oil in the salt domes of the Gulf States. I think we have to change our mind set to say that this is an insurance policy that we are not going to sit here and try to scare you and say this H5N1, although many of us think that still is a real possibility, but it is going to happen. And we need a Manhattan-like project that encompasses many of the issues that have been discussed here today; it is going to be an economic insurance policy. To follow-up on the previous comment about the international piece, I would remind people that if we totally protected ourselves, if we had 300 million doses or 600 million, depending on the two dose regimen in the United States, we would still be devastated, because the economic consequences of a worldwide pandemic minus the United States would still have incredible implications. We saw it during SARS. The computer industry of this country shut down, because no one realized that 95 percent of the computer chips in the world were made in the Kwong Dong province of China. And when they couldn't travel, nothing else traveled. And if you start looking at the consequences here, we can demonstrate to our policymakers that this is in fact a very wise use of resources.

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John R. La Montagne Memorial Symposium on Pandemic Influenza Research: Meeting Proceedings And so, I would urge us to take a step back, get away from this idea that if we could just keep expanding inter-pandemic flu, not that no one does not want to do that, because that is like motherhood and apple pie. But I think we are ready for a sea change. We are at a point where if we do not do it now, we are not going to it. And then I would just add one last piece. I have absolutely no doubt about it, and all of you in this room will be part of it, there will be a post 9/11-like commission one day that will ask the questions why we did not do what we could have done, when we could have, because people were afraid that we would scare people, or that somehow we would be seen as scare mongers, that we have not put it together. And I guarantee you, just as many of the very fine people who pre-9/11 said I wish I had done more, ended up being identified and well documented in that 9/11 commission report. There will be post-pandemic flu commission, make no doubt about it and the people in this room are going to be the people who are on the front line. So, it is time that we either make a decision that we are going to actually not live for another 20 or 30 years, whenever the pandemic occurs, trying to do this, and actually for once set out an international policy that says to our world leaders you can not afford not to do this. PARTICIPANT: In terms of things that we are missing from the meeting, I did think that more of a focus on what the economic impacts of a pandemic might be would be something that would strengthen the overall case.A study of the economic impacts of disease, emerging disease in particular is being done. There has already been about a $10-12 billion impact on Southeast Asia as a result of H5N1, which is a significant impact. It compares to what we estimate to be a $30-50 billion direct impact from SARS, so it is getting there. I wrote an op-ed piece which did not get published several months ago about H5N1 in which I pointed out that if you did have an influenza pandemic, the economic impact would be utterly unlike anything we have ever seen before. And the analogy that I used that I think would be powerful is an analogy to the first world oil price shock. You will remember back in the 1970s we had been in a sustained period of relative calm and low prices in oil, and then we had a shock to the system which created an enormous concern about our vulnerability to oil prices. Now, it took the shock to make the International Energy Agency happen, but it did happen, and there was a sort of Manhattan-like project organized internationally around the paucity of information that existed, and standardized information and data on in this case, energy and energy statistics. I would suggest, after having gone through the exercise of trying to find good data on the economic impact of emerging infectious diseases over the past 30 years, the data is terrible. There is no standard data out there. There are no standard metrics. And it would not be a bad idea for the world community to take seriously the idea that there needs to be a collaborative approach to gathering standard surveillance data sets, as well as other data sets that could be tremendously important in the event that we did get an emergence. The final comment is just that in a practical sense, for the last six months I have been trying to bring together major corporations, including the pharmaceutical industry, but also the biotechnology industry, and many other sectors of the economy to take seriously the idea of planning or thinking ahead about the potential impacts of an avian influenza pandemic. And I can tell you that it is fascinating, because when we began this work really around SARS, at that time major corporations really did not take the possibility of disease emergence as being a

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John R. La Montagne Memorial Symposium on Pandemic Influenza Research: Meeting Proceedings serious business issue. It was something that maybe there was a chief medical officer who worried about disease emergence from the point of view of what should I tell my human resources people about our travel policy, or something like that, or how does it affect my insurance? But it was not seen as fundamentally a business disruption issue. SARS changed that fundamentally. GE, for example, just hired a global security officer to be a bridge between the chief medical officer and the business planning people, a similar thing is going on for at Kraft Food, or any one of a number of other Fortune 500 or Fortune 1,000 companies. My suggestion is that we involve not only the chief medical officers, but also people who are increasingly tasked inside these major companies with the job of understanding what the business impacts are going to be. DR. FINEBERG: Thank you. I think that point about the interest and willingness of industry to support this work also gets to the question of mobilizing the kind of political movement that would lead to public decision-making, because it goes hand-in-hand, one with the other. PARTICIPANT: I would just like to second the comment about engaging politicians. I have spoken in this National Academy many times to the choir, if you like. And I am encouraged that I am speaking now to some of the politicians who can influence what is being done on the Hill. This is a very important step forward, because over the past five years we have seen the scientists have pushed this field forward. We have got good antivirals. We have got strategies to make vaccines. We can make any influenza virus we wish now for good or for bad. And we have to keep that in mind, for good or for bad. And so, I am encouraged that the science is in place, but there are many questions that are not in place. They are all man made—liability, the willingness to stockpile, how to use these things. I am very encouraged by the meeting today, the modeling, and the modeling of the use of the antivirals that I pushed for in this room many times, to see this put in place is most encouraging. This is a monumental event as far as I am concerned, one of the grandfathers of this whole business. And so, I compliment you and Mike and the others for making this take place. I also come back to having just returned from Hong Kong, I was in Hong Kong, at the time, May, when the SARS was at its peak. I came through Hong Kong, and those that know Hong Kong, I was the only person from overseas entering Hong Kong. I had the luxury of sleeping in the Mandarin. There was no food available in the Mandarin. I met with the chief executive, he said, tell me one thing that I can do. The economy is in a tail spin. Just one thing, I will do anything to turn this economy around. The economy was in disaster. How many people died of SARS? A handful, compared with what would happen whether it is H5N1 or H9N2 or H2N2. It is going to happen, we know that, sooner or later. And so, yes, do put a plan in place, because going back to Hong Kong, there has just been a commission in Hong Kong looking at why SARS was not correctly handled in Hong Kong. And the senior people have lost their jobs. So, yes, take this opportunity and finish the job that you are just beginning. PARTICIPANT: My introduction into influenza was in 1957, when the first pandemic came along, and we had no flu surveillance program at CDC. And so, I was charged with setting that up, and following that epidemic along through the summer, and then along came autumn.

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John R. La Montagne Memorial Symposium on Pandemic Influenza Research: Meeting Proceedings A lot of work was being done to develop a vaccine, and indeed through the summer things were relatively quiet. About the 15th of September all hell broke loose, and we had a huge epidemic that went across the country. The vaccine final began arriving, as I recall at that time, about the 1st of November. The epidemic ended toward the end of November. And as I look at it today, we are not much better shape today. If we got the strain today at about the same time we did in 1957, we would be getting the vaccine pretty close to the same time. We had a wake up call in 1968, with the next pandemic, and I know there is a lot of enthusiasm about getting on and doing something, a spasm of interest. Things disappeared, and we came up to 1978. I think that was my first major influenza meeting. Much was said, many thoughts were there about what we could and couldn't do, and another spasm of interest. Tissue cell culture was just around the corner, two to three years. I remember that very well. And that is something I think is repeated at every meeting I have ever been. Then we had the swine flu affair, which certainly again stimulated a tremendous of interest, activity, what have you, pledges to do something, et cetera, et cetera. Then as we come up to this year, or last year and you look at the amount of money going into research in influenza even as recently as just two years ago, a year ago, it was pretty slim. It was not really until the H5N1 began spreading in South Asia that I think we really began to get increasingly concerned. I know Stewart Simonson and others in HHS were really deeply concerned about this, and managed to obtain quite an increase in funding for it, although certainly far from what I think is needed. Well, again, we have a great deal of interest and concern about pandemic flu. I think we all pretty much would agree that we are going to have a pandemic at some point. Is it going to be H5N1? That is hard to say, but if it were, I think it would be really serious. And we have never had anything quite like this H5N1 experience before, so it is a little hard to read at this point in time. I think, if there is anything that I felt was missing at this point in time, I just do not have the sense from the meeting that there is a sense of compelling concern about moving ahead with some sort of deliberate and fairly vigorous activity to at least prepare for the next pandemic ASAP, not somewhere down the road. So, I think for me this has been a great meeting in terms of outlining a lot of needs that we have in the research field. And I think a lot of people have very thoughtfully examined a real agenda out for 10 years. What I really have missed is a sense of urgency that maybe we ought to be doing something really serious, maybe more than we are doing now, and laying out an agenda which is going to take us down the road for 6 months from now, for 18 months from now if indeed H5N1 remains quiet. So, I would hope this is not another spasm, and that we all go back to our laboratories and that is it. But I hope we keep up something very vigorous at this point. I think we need it. PARTICIPANT: It is been a privilege to be a part of the discussions that have gone on over the last two days. And I undoubtedly share the views on urgency; I think urgency needs to be writ large in all of this. I have one question and I think one comment. The question really relates to the synthesis of what has happened over the last two days. The science has been highly informed, most interesting. I have learned. I am sure it is been very valuable to many people. The question that I have, is this going to be a portfolio that develops from all of this discussion that is a managed portfolio? Or is it business as usual, with some great ideas that need to be developed, and science will go its usual way in finding solutions? I hope it is clear which my preference

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John R. La Montagne Memorial Symposium on Pandemic Influenza Research: Meeting Proceedings would be, and my preference is that this would be a very clearly managed process that delivers outcomes in the shortest possible time. My comment builds onto that. Those of us who work in policy development and implementation are already working pretty hard towards how we will deliver antivirals to treat people, and how we will deliver vaccines to prevent any further harm to our societies.My plea is that the research that is taken forward is supportive of those requirements and perhaps the excitement of the science may be just bridled a little so that questions that will answer the difficult issues that we will have to face are those that come to the fore. PARTICIPANT: I think for me, pandemic planning is important, but what would be more important is to prevent a pandemic from happening. And I have heard a lot of good ideas I think at this meeting which could help doing that. For example, trying to contain the disease in the place where it is. Dr. Webster this morning clearly indicated to us that if you would be able to provide economic support to the people that are actually holding all these birds that are infected, or ducks that are infected, that you might be able to control in that place. The modeling that we have seen also indicates very clearly that you can do things to contain disease in certain areas by making antivirals available at the place where they need to be available. Another idea that I heard, and I really hope that that is going to get some very clear attention is to proactively add antigens to the licensed vaccine. I am thinking we have for five years been putting H1 New Caledonia in this vaccine. It wouldn't hurt so much for one year to put for example, H2 in there, of which I would be more concerned, because it has shown us that it can transfer very well from humans to humans. But then the next year put H5 in there. I have heard that a lot of people have suggested this. But I am very much afraid, because so many ideas have been posted here, that nothing really happens with, those ideas that deal with prevention of pandemics. And I am wondering who is doing what to make sure that somebody actually takes action? DR. FINEBERG: I will not take that as a purely rhetorical question, because it is central indeed to a number of the commentators. I would just say on that last point that what we hope to accomplish out of the discussion is to assemble the principal ideas. And I think one of the principal ideas which was just articulated is the need for a coherent strategy that is not nearly, if you will, an eclectic collection of whoever happens to think of a good idea that might be then supported, but rather a more concerted strategy. The question for me is what is it that we will do from a research point of view that will put us in a position in two to five years that is different than the position that we are in today, quite in addition to the very compelling and important messages we have heard about the need to prepare today for the possibility of the outbreak and the pandemic even in the coming season, much less before we have made any of these additional changes. When I said earlier that it is in a sense up to us to do things, I mean that quite literally, and not merely figuratively; those of us here, and those that we can influence. And I think that this will be an important consequence of this activity if indeed we carry it through. If we fail, then we will be subject rightly to the criticism of those who will look after and look back and see those who could have done more and failed to do it.

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John R. La Montagne Memorial Symposium on Pandemic Influenza Research: Meeting Proceedings PARTICIPANT: I have a comment and a request, and that is I found this meeting to be very enriching. I think a lot of great ideas have come through this. But I would like to echo the comments about that we know something is coming, and we ought to have a sense of urgency to start doing something about it. It would be very helpful to the industry to know what our role would be in case a pandemic happens in a year or two or five years. Therefore, I would like to see a meeting similar to this that looks really at preparing for a pandemic in practicalities. For example, if you are going to vaccinate 600 million people in the US, do you have the distribution infrastructure to do that? It is hard enough to try and get 80 million or 100 doses annually distributed.I heard through the grapevine that WHO might be organizing such a meeting, and I would urge them to do that rather urgently. DR. FINEBERG: I do not know if Klaus is still here. Do you want to comment on the plans, which I think you alluded to, Klaus, in your own comments? DR. STOHR: Well, I am not sure if I can give a good answer to your question, I think, which was very good. I believe that there are different partners who have different responsibilities. Without any doubt, however, for the delivery of a safe and effective vaccine in time for a pandemic requires a very strong partnership between the public health institutions and the industry. You may know that in November last year we invited the industry to come to the WHO to discuss at least as view it, the slow progress in vaccine development. We had a very good response by the industry. November of last year there were two companies which are considering the development of clinical batches of pandemic vaccine for testing, now there are 12 companies I think in 8 countries. So, I do believe a very strong partnership is necessary. In the end we have to look how we can jointly create an environment which is conducive towards insuring that at the right point of time a safe and effective vaccine is going to be available. DR. FINEBERG: Thank you very much, Klaus. PARTICIPANT: I also found this to be a terribly interesting and enriching meeting. And just thinking about your last comment, Harvey, about the synthesis, and thinking I guess also about your question about what kinds of things are missing, I am really struck by the fact that preparedness requires sort of a balanced portfolio if you will, of the kinds of research that we have been talking about today, planning, and figuring out not only how we are going to make a plan, but how we are going to operationalize it, which takes a lot of practice. It takes a lot of exercise. It takes understanding why we have not had traction on this, despite all the multiple efforts we have heard about before. And so, the other pieces that I just would like to put on the table in terms of research that need get done are really the kinds of questions about how do you best operationalize the plan? How do you best practice so that you can keep getting better? How do we answer the questions about if when we have vaccine, what are the more efficient ways to deliver it? And a whole variety of other questions that I think cross preparedness for lots of kinds of infectious diseases, and potentially other kinds of events. But we have not talked very much about a research agenda there. We talked a little bit in our group about issues related to population and human behavior, about trust, about stigmatized populations. All of those things I think are still not on the table to the degree that they should be. And then finally, something I do not think we talked about much at all is maybe getting some help from some political science types or others to answer the question about why so many people have been at this meeting so many times, and there has not been traction. Are there other

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John R. La Montagne Memorial Symposium on Pandemic Influenza Research: Meeting Proceedings lessons learned about the political system that would help us be able to move forward in the future? It can not be one or the other, but I think we need to balance the portfolio of the hope of many of the exciting discoveries and innovations we talked about today with some really practical, now, on the ground stuff. DR. FINEBERG: Thank you. It may be that those who commented on what is missing also were expressing what they think was most important, but I also would like to invite those who had thoughts about what they took away as a most important lesson from the two days that they would like to share with the group, that this would be a good time to do it. So, the floor is now open for any discussion of lessons, take homes that you would like to offer to share with everyone here. PARTICIPANT: I would like to respond to the request for doing something now about something that might happen very soon. I do not know what the next pandemic strain is. I do not have the crystal ball that everybody else seems to have. Since 1969, I have been advocating that we make high yield reassortment viruses against all the existing known HA subtypes. It would not have to be put into storage, but certainly seed viruses can be made. They could be preliminarily tested and so forth. Every planning commission that has come up since has endorsed this recommendation. I do not know what really is going to have to be done to implement it, but I am making one final plea, that this very simple operation, if anything occurs in the next five years, it is going to be chick embryo derived inactivated vaccine in all probability. All the elegant work with reverse genetics, and the DNAs and so forth should proceed apace, and I hope very rapidly. But in practical terms, that is what is going to be available to us. So, I think that we can at least get a hold of H14 and H10 and so forth and so on, that thus far have not caused any trouble, and simply add those to a stockpile of seed vaccines ready to go. It would save us months when the trigger is pulled, and we know what actually the next pandemic virus is, if there ever is one. PARTICIPANT: We are starting a program to do this for developing live attenuated virus vaccines. We have been listening to you, but only part of what you are saying. We are very interested in developing live attenuated virus vaccines, because we think that they are going to be especially useful in the time of pandemic for the reasons that Dr. Fauci put up on the screen during his talk. The point I want to make is that I think that one of the problems that we have now, is that for the existing technology for making subunit vaccines—for inactivated or non-living vaccines—the results were terribly disappointing in terms of their immunogenicity. What we are doing now is we are disrupting a virus and finding out that for the H5 antigen, it is not terribly immunogenic unless we now put back in an adjuvant, which we do not have a lot of experience with, and then hopefully get it up to levels that are barely associated with resistance. I think one of the reasons that there has not been an awful lot of enthusiasm is that we really have not developed a coherent strategy for exactly what is the goal in this situation. And I think one of the real important things that we need to come out of this particular meeting is making a simple decision. Do we want a whole virus vaccine that we do not have to disrupt and then use an adjuvant, rather than a subunit vaccine? Because right now, most of the manufacturers I think are making the opposite, making the subunit type vaccine. And that is a simple decision. That would not be a bad decision to come up early on, because the other decision has complications. So, I just think we need to really decide on a strategy. And then I think Ed is absolutely right. We need to not just get the vaccines

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John R. La Montagne Memorial Symposium on Pandemic Influenza Research: Meeting Proceedings made, but make experimental lots of sets of experimental vaccines to find out whether H4s through H15s are indeed immunogenic in humans. How immunogenic are there? We need to find out what kind of generalities can you make by using these particular immunogens. That information does not exist right now. It is absolutely essential in order to say if a new virus comes, are we going to be able to successfully use a strategy which we think is going to work. Right now we are finding it is not very successful for the H5. So, I think there is a lot of very, very important stuff that needs to come out of this. And I would agree that we need to make vaccines, decide on strategies, get lots of experience with multiple HAs, both live, inactivated formats. There are even some vector strategies that need to be considered, and make progress along these lines. PARTICIPANT: Well, I think my favorite moment is where we start thinking about what is in pandemic preparedness for countries with limited resources. For example, why should a resource poor country be engaged in pandemic planning when it is unlikely they will ever get a slash of the vaccines or the antivirals? And I thought with Neil Ferguson's presentation for example, that the incredible importance in getting there early, partnering, and actually having something in terms of incentives to offer to those countries that are actually engaging and contributing, that is really, really important and key from this whole meeting. PARTICIPANT: I would like to pick up on some earlier comments about the reasons why we find ourselves here every few years. And I think we have a problem of a law of the commons. All of us here have private interests as well as public interests, and we share the same public interest about doing something for the global public good for public health measures for influenza. However, there are also commercial, academic and public agencies who are seeking also their own incentives, whether it is for funding or credit for the future, or other types of incentives. And it brings up an issue about in this country we have no national institute of public health in effect, that funds global collective goods. And getting the type of collaboration, whether it be for the magnitude that we are seeing ourselves dealing with, this is a magnitude of proportions that mankind sees perhaps a few times a century, but yet we all need to act together collaboratively. Dr. Gerberding pointed that out very succinctly in her slide. But again, the incentives of our individual provide settings do not necessarily allow that collaboration to take place. So, that is why I think we find ourselves here every 10 years, seeing the same problem. And we come back again when H5 resurfaces and have a few meetings. We had a meeting here in June, a similar meeting, but yet hopefully this perhaps will be different. I do not know how it could be different. We talked about data sharing. There are a number of new mechanisms that were created. The NIH has NLM, which has GenBank which puts out data in the public domain. We have a sequencing unit now that will sequence all data. I do not know if that will be successful, if people will share their strains. That's data that can be modeled, that can help to prevent and predict potential strain drift and shift. There are other types of IPR technologies which companies have, and I am not sure whether or not there are commercial incentives which will allow them to share it or not. Again, these are issues that are very valid, because everyone has their own private and public incentives.

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John R. La Montagne Memorial Symposium on Pandemic Influenza Research: Meeting Proceedings That is the way society is set up. But once again, are we dealing with an issue of significant magnitude that will invite a collaborative spirit that we have not seen before? PARTICIPANT: I want to just support what others have said about this being a serious problem. I would like to harken back to something I mentioned when I talked, and that I have thought a lot about, which is sort of like whether this particular avian flu is Chicken Little, and we said the sky is falling, and it does not fall, or it is Chicken Big. The issue really is that pandemic preparedness has to be addressed for the short- and long-term. This perspective ties in with this preparedness portfolio. As we move new technologies further along, and understand better what interventions we make, we also have to be focused on public health preparedness. I want to return to the comment that I made earlier. There are studies of immunogenicity of novel strains. Further, the studies that have just begun that were described here by some of the funders and participants will be informative. If we do see substantive immunogenicity in any of the regimens, one could consider: Can we incorporate immunologic preparedness for pandemic strains into influenza preparedness in general? And we will then have some vaccine, and a way to give it. And one could conceivably make more. I am not saying it is just building immunologic memory in the population. It is evaluating this whole portfolio critically. But that is something that I think we do not have to wait forever, and can help build the kind of capacity we need. PARTICIPANT: I would like to thank the organizers for supporting me to come here from Thailand. I feel badly for other countries like Vietnam or Cambodia that did not have the chance to come here. In Thailand we have had a few meetings to discuss similar issues that are being discussed here. So, we appreciate that you recognize the problem in our area. When I heard the modeling of a pandemic presentation, and it was said that it could take about two to four months for the pandemic to spread around the world. I thought that in reality, if we had a pandemic, we would have no chance in my country. To have access to tamiflu at the time of outbreak is difficult, it was difficult in the past with the two outbreaks that have occurred. In Thailand we believe that other countries will have their own stockpile of drugs or vaccine for their people. But how many people or countries will think about getting vaccine to the hot spot where the outbreak occurs. We would like to plan to be self sufficient—to stand by our own. But we do not we have the factory to produce vaccines, why? The technology is difficult for us acquire. We would like the WHO or other international organizations to help support vaccine production in our countries. Similar support is given to us for work on HIV research. We have a NIS laboratory to support us with the reagent, the serum, and the peptides. I would like to see something like this for pandemic flu. It is difficult to send materials out of the country. You need a special channel for transporting infectious material out and to communicate to with the international organizations, it takes time. If an international organization can help us get access to materials—reagents so we can take care of ourselves from the beginning. We can then give you preliminary data at the time that the material is being shipped to your lab. PARTICIPANT: My comment follows-up on an earlier comment, what was missing was social science research linked to all the research that was presented and discussed here—the more basic infectious disease immunology and virology research. When a plan or strategies for the implementation phase is developed, you need to know the recipients of these strategies very well. There could be some near-term research that would look at how you reach different kinds

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John R. La Montagne Memorial Symposium on Pandemic Influenza Research: Meeting Proceedings of people in different settings; this research would be helpful for any public health emergency, not just this one. We have had experience here, for example, the African American community in our country, which is not represented here, had a really hard time accepted preventive measures for HIV infection. It took a long time, because the public health community really did not understand what the concerns were, what their beliefs were, and how to reach people who had credibility in that community. So, whatever strategies are developed, be they for prevention, for prophylaxis, for management, for dealing with an emergency, maybe there is already research out there that I do not know about, but the linking of the social science research that would help in the implementation of whatever these other areas come up with I think would be helpful. PARTICIPANT: I spent a lot of time trying to make the case for investments in diseases that are very far away and neglected. And I am struck by the disparity and the reality, and how we are looking at it. And I do not know if that is social science, anthropology, or what the field that is required here. We have a disease here creates 36,000 excess deaths every year. And it is really different than malaria, where it is very far away, and it happens to children, and it is unseen, and there is not an advocacy group. So, I think we have in the context of a number of anthrax cases that caused sheer panic in this country; we have the basis for thinking that this is an important disease every year. And yet, we are unable to communicate that beyond the in community that works on influenza and works on vaccines and thinks that this is important. This abject failure to translate what are real, countable deaths and then the fear of the next pandemic when it strikes is really astonishing, and one that deserves some analysis that goes beyond the tools that we probably have at this table. PARTICIPANT: I just wanted to follow-up on the very good point about the social research agenda and what is going on here. I think this is a very important point. One of the areas that public health today is really short strapped in attempting to try and prepared for this kind of issue, and they obviously have been boosted to some degree by the recent funding that has come out relative to post-9/11. But what very few people realize is that while those dollars were coming from the federal government, state governments were cutting that amount or more in many states because of state budget issues. Many of the state health departments are not really much better prepared today in terms of infrastructure, planning, and so forth. You need look no further than what happened last fall when we had the vaccine shortage. Nobody was prepared in the public health or health care delivery system to figure out how to allocate vaccine in this drop of a dime when there was suddenly a shortage. And the fact that we did not even have that worked out I think goes to the point that was being made about we have a lot of work to do here. So, I think that agenda should be there very, very definitely, and that that is part of the research. It is as horrible to consider, but being prepared is as straightforward as how do we deal with bodies? We had one experience in this country in 1995 in Chicago when we had the heat wave, where they could not process bodies fast enough and had to put them in refrigerated semi-trucks, which created a psychological situation in itself, which was there. We have done the calculations. Even a mild pandemic today in this “just in time” delivery model of even funeral services and burial could not handle a slight increase in the number of bodies that would need to be processed. So, I think that is again, a social science issue as much as it is actually a technology issue. So, I think many of us would urge that that be part of the research agenda.

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John R. La Montagne Memorial Symposium on Pandemic Influenza Research: Meeting Proceedings PARTICIPANT: If you go on to the Department of Health in London's Web site, there is a public information leaflet that tells you and your family what you need to know about pandemic flu. The point about this is that this has been researched. And just as it is important to be doing the research on all of the things we have heard about in the last two days, this simple piece of writing and leaflet has been researched with the public. It is been redrafted and re-researched. This is part of the operational research and the infrastructure research that is every bit as important as the rest of the science. If you cannot communicate the issues, there is not much point to actually doing the science. So, we already have this communication piece. It is in place, and it is available. But this type of research is a part of the research agenda that we have not talked about in the last two days. It is every bit as important. DR. FINEBERG: Thank you for that reinforcement. This has been a remarkably hardworking group. I must say, the fact that you have been willing to attend so faithfully not only the plenary sessions, but to throw yourselves into the workshops to work so creatively, I would say so abundantly with the ideas that will give us a lot to work with in trying to craft the proceedings of this discussion that does justice not only to the ideas, but to the convictions and the drive that is behind so much of this discussion. I think that it is inevitable that a research strategy must begin from a vantage point of asking why we are starting on this research. And if we do that, and if we start from a vantage point of protecting the public, if we start from a vantage point of protecting the individual patient, if we start from a vantage point of solving mysteries of biology that apply to flu and to others, if we ask ourselves the question of what is important in one country, and what is important from another country's vantage point. If we are willing to take multiple perspectives, I think we are going to be able to define a convergent research strategy that is going to depend upon many actors working in a way, at a degree of coherence, and a degree of collaboration, and a degree of coordination that is unprecedented in the flu field, and maybe unprecedented in preparation in advance for any natural disaster. I am hopeful that this deliberation, this set of discussions can contribute materially to the ability of ourselves, our nation, our world to accomplish that kind of increased coherence for research. I want to ask each of you who are here if you have thoughts afterward that are result of further reflection, or perhaps you have not felt moved to come to a microphone, and would like to share some additional ideas bearing on these questions that we have discussed over the two days, we welcome them. We urge you to share them. I want to say personally how much of a thrill it is been for me to be able to be part of the discussions, to be with so many who have done so much over such a long time for public health, for influenza, for research, for the care of patients, for the advancement of science as it bears on all of these concerns. I am truly grateful to all of you for your participation. I want to thank the presenters, the briefers, the chairs, the rapporteurs, and all those who have contributed so much through the course of these discussions, and helping to plan it, and helping to carry it through. I look forward very much to our continued work together toward the goals that we have outlined. I want to thank all of you for being part of the program. And please join me in also thanking especially the staff, Dr. Rose Marie Martinez and others who have been so valuable through the course of these days in making our discussions come to life.

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