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John R. La Montagne Memorial Symposium on Pandemic Influenza Research: Meeting Proceedings 3 MORNING PLENARY DISCUSSION, DAY 1 (APRIL 4, 2004) Moderator: Dr. Harvey Fineberg Panel Participants: Dr. Bruce Gellin, Dr. Julie Gerberding, Dr. Jesse Goodman, Dr. Klaus Stöhr, Dr. Anthony Fauci DR. FINEBERG: I would like to invite this morning’s speakers to join us here on stage for a half-hour of questions and comments. PARTICIPANT: I have two comments, one rather general and one very specific. First, in all the articles published on H5N1 and its potential, particularly its introduction into people, I have not seen any evidence of a rigorous study of the neuraminidase antibody concentration in a population that must have some N1 immunity. This is particularly important if we are facing inapparent infections and wondering about the sporadic occurrence of lethal or very severe diseases. I am wondering whether those cases have been cautiously and deliberately investigated with respect to their neuraminidase antibody response. Before that question is answered, I would like to make a comment about intradermal versus subcutaneous inoculation. In comparisons of intradermal and subcutaneous routes of inoculation, an important control is often omitted—namely, the comparison of equal doses of vaccine delivered by the two routes. We are beginning to create new studies for comparing small doses of flu vaccine and larger doses of flu vaccine as a second injection. In these studies we do not compare apples and oranges, we give the same amount of virus—namely one-tenth of an mL—by both subcutaneous and intradermal routes. Very few studies have been done using equal amounts of virus. We gave one-tenth mL intradermally, and we gave five-tenths mL intramuscularly, and the response is about the same. Perhaps this is because we are usually dealing with a primed population. DR. GERBERDING: We have not been able to do a comprehensive serologic assessment of any of the antigens in the H5N1 immune response because those studies have been difficult to start. They are obviously very important. We need field investigations that would allow us to do sampling on a population basis in several regions that are experiencing infection. DR. STOHR: Yes, I think it would be quite interesting—because it is so difficult to assess the significance of the immune response—to try to better understand the effectiveness, or at least the immunogenicity, of vaccines in non-human primates, which could be vaccinated with a vaccine with an N1 component irrespective of its HA component. We can then see if the vaccine provides any cross-protection against the H5N1, and the significance of that cross-protection.
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John R. La Montagne Memorial Symposium on Pandemic Influenza Research: Meeting Proceedings Many people have thought about doing that, but it’s a very costly exercise, and nobody has tried it. Such a study requires a considerable number of non-human primates as well as a better understanding of the infectious dose. DR. GERBERDING: It is not so much science as samples that are rate-limiting. DR. FINEBERG: The second question concerned intradermal immunization or route of administration more generally. DR. FAUCI: Yes, I agree with you completely. If we consider whether we could stretch out supply, and give a half a dose intradermally versus the full dose intramuscularly, we could prove the concept that we could get relatively equivalent protection. Another question is: what happens if you give an equivalent dose intradermally to intramuscularly in elderly individuals who generally have poorer antibody response? I would be interested, from an immunological standpoint, as to whether we can boost the relatively poor immunological response in people 65 years of age and older toward a relatively normal response by using intradermal dosing but relying on the dose that we would use intramuscularly. DR. FINEBERG: If I understood, your point was also that the immunologic memory might enhance responsiveness to an intradermal dose of lower intensity, and therefore could mask what might happen in a population that was immunologically naive. DR. GELLIN: Both those questions highlight the need for international collaboration. Dr. Stohr, I hope you hold the meeting you mentioned, because based on what we have seen here, I think there is going to be tremendous interest. If we continue to compare apples to oranges we are going to be in trouble, because we are going to have a range of data points that we don’t know how to put together. We need international collaboration to understand who is doing these studies and how they are advance the science in this area. PARTICIPANT: In response to the previous question about the apples and oranges of intradermal versus subcutaneous: In preparing for tomorrow’s workshop, I found a number of studies that used the same dose intradermally and subcutaneously. Back in 1949, Bruin et al. found that, using the same doses, geometric mean titers were higher intradermally than subcutaneously in both adults and children. Still, when the antigen mask was small, intradermal did better. When the antigen dose quantity was higher, subcutaneous did better. More recently, in 1969 in the Canadian Journal of Public Health, Davies found that giving the same dose intradermally or subcutaneously with jet injectors for both routes produced a higher response intradermally, but the result was not significant. PARTICIPANT: Our biotech company, founded less than two years ago under the National Biodefense Program, focuses on developing novel therapeutics and prophylaxis for influenza. I agree that a fundamentally new approach against influenza is greatly needed, because as Dr. Fauci pointed out, even cross-reactive vaccines are very difficult to generate because the natural infection doesn’t offer long-lasting cross-protection. In light of this, we have developed a new molecule that is sialidase based and is designed to tether to the human receptor epithelium. Our lead works by eliminating the sialic acid used as a receptor for all strains of influenza viruses. The strain works by making the host inaccessible to influenza viruses. With the help of NIAID, we have done some very successful in vitro studies, and now multiple animal studies, showing that this approach holds great promise, not only as a prophylaxis but as a
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John R. La Montagne Memorial Symposium on Pandemic Influenza Research: Meeting Proceedings therapeutic as well. Even 48 to 72 days after the viral challenge, we still get very significant therapeutic effects. A novel approach like ours would not be possible without the support of the national biodefense effort and NIAID. We are several months from filing an investigational new drug application, and we are hoping to go to clinical trials quickly. Our scientists are working day and night, but the limiting factor is still funding. I'm here to urge continued public-sector funding because private-sector funding is hard to come by. When we talk about pandemics, the market is not there. Companies like ours can do such research with many fewer resources. With less than $14 million, we believe we can take the drug all the way through phase III clinical trials. So, important progress is being made with public funding. PARTICIPANT: Dr Gerberding alluded to the fact that we are exploring an expanded surveillance effort in Southeast Asia, with partnering between DOD and CDC. DOD has a fairly significant global surveillance system for emerging infections, with laboratories in Cairo and Jakarta, Peru, Thailand, and elsewhere around the world. Our folks in Jakarta commented on the opportunity after the tsunami to greatly enhance surveillance efforts in Vietnam and Cambodia with modest funding. Specific suggestions for the types of studies that need to be done would be very helpful. We are certainly willing to partner with others, including with WHO and Dr. Stohr, to expand this effort. We have some funding that we could apply right away, but we need to know what we need to do. PARTICIPANT: Several speakers touched on the stockpiling of antivirals. It is very difficult to know when we should pull items out of the stockpile and start shipping them for use in the field. Tamiflu is under patent from Roche. It costs about $3 a pail to buy the drug in bulk. Under the World Trade Organization’s TRIPS agreement [trade-related aspects of intellectual property rights], a country can issue a compulsory license during a public health emergency to allow other companies to manufacture the drug. I am interested at what point the panelists think the United States should evoke the TRIPS agreement to start producing its own Tamiflu. And at what point should we deploy non-vaccine interventions? DR. GELLIN: I think all countries are grappling with that issue. As you said, a single manufacturer now has a patent, and it is the only feasible player in a pandemic setting. Unlike the H5 vaccine, which is still being evaluated, anyone can purchase that product today. The question is how nations handle that on a public health basis. Nobody knows how much of the drug to buy and exactly when to pull the TRIPS trigger. I hope this workshop will shed light on how to refine the models so we can understand some of these trigger points more precisely. I don't have the answer, but clearly how much of the drug we buy and how we deploy it are issues of great importance, given that there will not be enough vaccine to go around. DR. STOHR: The international trigger point for WHO would be the emergence of a virus with effective human-to-human transmission. In the next couple of days WHO will publish a new pandemic preparedness plan that will not only recommend what countries should do during different phases of a pandemic but also clearly outline what countries can expect from WHO during those phases. The plan will include trigger points for national use of antivirals from a
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John R. La Montagne Memorial Symposium on Pandemic Influenza Research: Meeting Proceedings national stockpile, but, as Bruce said, the modeling data are just not available at this stage for use with an international stockpile. The TRIPS agreement is a powerful tool that can be used when a global health emergency would require increased access to a certain drug. That powerful tool is accessible to every nation in the world. Hopefully, nations will think twice before they use that tool, as doing so would encourage others to use the same tool for other drugs and circumstances. A country has to balance the advantage of gaining access to one drug against what might happen if other countries use the agreement to gain access to patented drugs made in the first country. DR. GERBERDING: One of the early triggers for the use of antivirals would clearly be the need to initiate prophylaxis to continue the initial rounds of replication and outbreak. Another important other aspect is the scalability of our use of these countermeasures. And at least with antivirals, the stockpile exists, and we have conceptualized the idea that we will deploy it under certain circumstances to obtain the biggest public health benefit for the amount of drug we have. But we haven’t effectively researched the deployment step. The U.S. public health system is working to deliver countermeasures to a population within a short timeframe, but research does not tell us the best strategy. How do you mobilize effectively? What models of distribution actually work? We did learn some lessons from distributing flu vaccine this year. But we can also consider provocative ideas such as pre-event deployment and home storage of countermeasures. We need to be open to all possibilities and then do the studies to figure out the best models for specific circumstances. DR. GOODMAN: I think it is very important to obtain more knowledge of antivirals and their impact, particularly in treatment and containment. They are likely to be effective prophylactically, but the amount of drug needed on any scale beyond a very small population would be daunting. On the treatment end, perhaps the working group on antivirals will consider studies that—relying on the NIH and WHO clinical trial networks—would tell us rather quickly about the safety and effectiveness of antivirals in a pandemic threat. Assumptions should not go unquestioned. As with vaccines, the time to assess production needs and build a manufacturing infrastructure is before the pandemic. Making a high-quality, complex pharmaceutical that is safe and effective in a crisis situation would be difficult. We need to understand better how we to use these drugs and prepare for those uses. PARTICIPANT: One issue raised in recent biodefense discussions is what would happen with a limited supply of countermeasures given an international outbreak of disease. Everyone hoped to deal with that question later. Well, this may be later. Domestic versus international law poses a particular problem, in that U.S. officials have a congressional mandate to protect the American people with whatever measures are necessary. Given the fact that Tamiflu supplies are limited and no vaccine is available, how will we decide which countermeasures to retain for domestic purposes and which to make available for international use, given an outbreak in another country? That question is especially important given that the use of countermeasures internationally is often the best way to protect a domestic population. On the other hand, if a disease were not contained, a country would be obligated to use the countermeasure to the maximum possible extent domestically. I can see borders all over the world closing to the transfer of countermeasures.
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John R. La Montagne Memorial Symposium on Pandemic Influenza Research: Meeting Proceedings DR. FINEBERG: This and the previous question raise important ethical aspects of research as well as preparedness strategy. DR. GELLIN: While I cannot give you a comprehensive and definitive answer regarding what would be done in a given situation, the comment highlights the importance of on-the-ground surveillance. If we look only under the street lamp, we may miss important developments. DR. GOODMAN: We could well argue that the appropriate use of interventions on a global level will benefit both U.S. citizens and residents of other countries. We need to consider global response plans rather than pitting one country versus another. Maybe we can help our policymakers to come to the same conclusion. DR. GERBERDING: We need to emphasize economic as well as international health motives. Multinational corporate interests are likely to be more involved in addressing these problems than in the past. DR. STOHR: The question has a political as well as a technical component. The political component must be addressed at a relatively high level: we are talking about multinational treaties and agreements between heads of states. We should continue raising the issues at that level. At the same time, we need to continue to invest in technical solutions like antigen-sparing strategies that will give countries without production capacity access to vaccines and antivirals as well as knowledge when they are most needed. We should not put all our eggs in one basket. DR. FAUCI: If ever there were a need for international agreements on what countries will do if and when a crisis occurs, this is certainly one such situation, because if individual countries make conflicting policy decisions, we will have chaos. We need an international agreement before we get into a crisis. PARTICIPANT: We are talking about the availability of new technologies and new approaches. While on the science side that makes a great deal of sense, we are overlooking the supply side. Can we actually provide the new technologies, and what is the surge capacity per item? Given all the orders for antivirals, it’s going to be years before they are actually going to be filled. Today two companies own 80 percent of the market for N95 masks and have no surge capacity. The United States also lacks surge capacity for mechanical ventilators. The country has 105,000 ventilators, and in any one day 70,000 are in use; during flu season 100,000 are in use. Unless we are prepared to spend money to create capacity that will not be used except during a crisis, we can develop all the technologies we want, but our actual ability to bring a stockpile to market is going to be limited. During the anthrax situation, the biggest problem many of us in the states faced concerned reagents for testing for bacillus anthracis—they just did not exist. We couldn’t make them fast enough. Even though scientists might come up with wonderful diagnostics for influenza, I question how many will be available during a crisis. Wonderful new technology tools may have little applicability if they are not available. DR. GERBERDING: I agree but this also speaks to the need for communication, because we have to make hard decisions about how to spend our dollars. Business figured out a long time ago that just-in-time delivery was the most cost-effective approach. We are moving in the opposite direction by stockpiling and investing large quantities of resources in items we might never use. But that’s the role of leadership and the federal government.
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John R. La Montagne Memorial Symposium on Pandemic Influenza Research: Meeting Proceedings People must understand that readiness will be expensive, that funding might never be used, and that capacities are in reserve. That’s a tough message to communicate, and a tough position for politicians to be in, given so many competing priorities. We are lucky to have leaders who are willing to take those steps, but we need to do more, and we need to do it faster. DR. GOODMAN: We may have rare opportunities for win-win approaches. For example, progress in the inter-pandemic use of flu vaccine with current technologies will increase the capacity and ability to respond during a pandemic. DR. STOHR: Perhaps we need dress rehearsals for the delivery of vaccines and antivirals, which would enable us to see what is missing and what is needed. We have not mentioned syringes or the whole downstream need for vaccine packaging, such as multi-dose containers. If one link is missing in the chain, all our preparatory work may be in vain. DR. FINEBERG: As we begin to discuss research priorities in detail, we clearly have to consider the total preparedness strategy, including communication among scientists, across cultures and political boundaries, with the public at large, and with policymakers. All of that will affect the success of a flu preparedness strategy
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