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PLENARY SPEAKERS, DAY 1

OPENING REMARKS

The Honorable Michael Leavitt, Secretary of the Department of Health and Human Services

Thank you, Harvey, for that kind introduction (Harvey Fineberg, President of the Institute of Medicine).

This meeting is a tribute to a man who was a friend to many in this room, Dr. John La Montagne. You all know how his brilliant work helped save people from many diseases. While working on one of these projects, he told a colleague, “It’s good that we’re doing this. But if anything is going to get us, it will be the flu.”

I am also especially pleased to have the opportunity to share the podium with Dr. Fineberg this morning. Because, as he knows, I have learned many lessons from his excellent book: The Epidemic that Never Was: Policymaking and the Swine Flu Scare.

I know that many of you have dedicated your careers to this field. In the short time that I have been Secretary of Health and Human Services, I have become acutely aware of the disastrous public health impact that an influenza pandemic could have throughout the world. This is one of the most urgent health challenges we face, and I’ve made it a top HHS priority. Recently, I increased my briefing frequency on the flu to daily.

While much of our attention is focused on the H5N1 virus in Asia, I know very well that it is not the only flu threat we face. Many of the lessons that we learn from it will prepare us for annual influenza as well as for other potentially pandemic influenza viruses that may emerge in the future.

President Bush also understands the gravity of our situation. In fact, the United States government has made significant progress on pandemic influenza since he took office. We have increased spending on influenza tenfold over the past 5 years. We have added flu vaccine and flu drugs to the stockpile and made influenza part of regular public health discussions.

In order to increase our readiness against a pandemic strain of influenza, last Friday, on my recommendation, President Bush added pandemic influenza to the list of quarantinable events. This gives HHS the authority to take steps to prevent people with a new or reemerging influenza virus from infecting others by stopping them at our borders.

As we learned from CDC in last week’s Morbidity and Mortality Weekly Report, there was a silver lining in last season’s influenza vaccine situation. Despite the fact that we lost nearly half of our expected influenza vaccine supply, careful management of the available supply allowed this vaccine to be directed to the most vulnerable members of our population. We also sought out additional vaccine produced by foreign manufacturers and made arrangements to use



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John R. La Montagne Memorial Symposium on Pandemic Influenza Research: Meeting Proceedings 2 PLENARY SPEAKERS, DAY 1 OPENING REMARKS The Honorable Michael Leavitt, Secretary of the Department of Health and Human Services Thank you, Harvey, for that kind introduction (Harvey Fineberg, President of the Institute of Medicine). This meeting is a tribute to a man who was a friend to many in this room, Dr. John La Montagne. You all know how his brilliant work helped save people from many diseases. While working on one of these projects, he told a colleague, “It’s good that we’re doing this. But if anything is going to get us, it will be the flu.” I am also especially pleased to have the opportunity to share the podium with Dr. Fineberg this morning. Because, as he knows, I have learned many lessons from his excellent book: The Epidemic that Never Was: Policymaking and the Swine Flu Scare. I know that many of you have dedicated your careers to this field. In the short time that I have been Secretary of Health and Human Services, I have become acutely aware of the disastrous public health impact that an influenza pandemic could have throughout the world. This is one of the most urgent health challenges we face, and I’ve made it a top HHS priority. Recently, I increased my briefing frequency on the flu to daily. While much of our attention is focused on the H5N1 virus in Asia, I know very well that it is not the only flu threat we face. Many of the lessons that we learn from it will prepare us for annual influenza as well as for other potentially pandemic influenza viruses that may emerge in the future. President Bush also understands the gravity of our situation. In fact, the United States government has made significant progress on pandemic influenza since he took office. We have increased spending on influenza tenfold over the past 5 years. We have added flu vaccine and flu drugs to the stockpile and made influenza part of regular public health discussions. In order to increase our readiness against a pandemic strain of influenza, last Friday, on my recommendation, President Bush added pandemic influenza to the list of quarantinable events. This gives HHS the authority to take steps to prevent people with a new or reemerging influenza virus from infecting others by stopping them at our borders. As we learned from CDC in last week’s Morbidity and Mortality Weekly Report, there was a silver lining in last season’s influenza vaccine situation. Despite the fact that we lost nearly half of our expected influenza vaccine supply, careful management of the available supply allowed this vaccine to be directed to the most vulnerable members of our population. We also sought out additional vaccine produced by foreign manufacturers and made arrangements to use

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John R. La Montagne Memorial Symposium on Pandemic Influenza Research: Meeting Proceedings it if needed. I applaud the remarkable effort that this took, and the close working relationship between our agencies, the vaccine companies, state and local health officials, and healthcare providers that made it possible. In spite of such challenges as that one, we’ve made great progress on influenza preparedness over the past few years. Flu preparation is an international responsibility, and I know many of you are involved in projects around the world. My study of this matter has been short in duration by intensive, and the best in the world. Flu virus is a networked enemy. We must fight it with a networked army. The United States will take precautions necessary to protect this country but we know our success is dependent on others protecting their own countries. When you fight a networked enemy, a mainframe response will not do. Let me just mention a few steps we’ve taken here in the United States: HHS is working to bring more influenza vaccine manufacturers into the domestic market through the joint efforts of CDC, FDA, NIH, our National Vaccine Program Office (NVPO), and the Office of Public Health Emergency Preparedness. We’re working to accelerate the development of new influenza vaccine formulation and production techniques that will allow us to have a flexible surge capacity to make the doses of vaccine that we would need in a pandemic. We’re devoting an unprecedented amount of resources to vaccine research, development, and procurement, and we want to increase the routine seasonal use of influenza vaccine for all who would benefit from it. On Friday, I was delighted to announce a contract with Sanofi Pasteur for the development of an influenza vaccine produced in cell culture rather than eggs. We’re doing all we can to ensure that Americans are healthy and protected against the flu. And everything we do to improve our approach to seasonal influenza prepares us to respond to an influenza pandemic. In the past century, the world experienced three global outbreaks, or pandemics, of influenza. The recent emergence and persistence of a new influenza virus in birds in Asia and its infection of a limited number of humans with a high mortality rate has raised concern among scientists and public health professionals about the possibility of another pandemic influenza. Dr. Julie Gerberding will talk more about this situation later this morning. I am sure that most of you have seen the HHS draft Pandemic Influenza Preparedness and Response Plan we released last August, and I know that many of you have submitted comments. We're grateful for all of your input. I expect we will have the next revision out in the next few months. I am hopeful that the discussions and deliberations at this important meeting will feed into this effort. And as part of our commitment to preparedness against the possibility of a pandemic, I am pleased to report that NIH has very recently begun clinical trials of a vaccine specifically designed against the H5N1 strain of avian influenza that is currently circulating in Asia. We have also gone ahead and produced 2 million doses of this vaccine in bulk. You will hear more about these efforts from Dr. Fauci later this morning.

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John R. La Montagne Memorial Symposium on Pandemic Influenza Research: Meeting Proceedings Since we don’t know where or when a pandemic may originate, we have enhanced our surveillance network across the globe, but especially in east and southeast Asia, where we at HHS have people on the ground who are working with local researchers, clinicians, and governments. We are also in daily contact with the World Health Organization Secretariat in Geneva and its regional offices in Manila and New Delhi. We at HHS have experts on short- and long-term assignments to W.H.O. headquarters and the W.H.O. Country Office in Vietnam. I've begun meeting with health ministers and ambassadors from affected countries, and soon I will begin to visit their countries. In May, I will also travel to the World Health Assembly, where pandemic influenza preparedness is on the agenda; I am convening a special meeting of health ministers from affected and donor countries to coordinate planning on influenza, followed by a technical meeting of experts the next day. Influenza will continue to be an important topic in all my discussions with my counterparts. Needless to say, I’ve gained a much greater appreciation for how important your work is. We have learned so much in recent years about how to assess and respond to flu outbreaks, but we also have much more work to do. I am glad that all of you are engaged in these research and public health activities, and glad that you’ve come together today to compare notes and help us reexamine and reset the direction of our collective efforts. While pandemics have happened several times in the past, never before have we had all of the tools of today. Never before have we possessed the wealth of knowledge on the problem and the ability to prepare. The challenge is immense, but so is our will to protect and preserve. The outcome of this conference will be extremely important and will help guide us all in our work toward improving our ability to prepare ourselves. I look forward to being able to present a brief report on this symposium to my fellow health ministers when we meet at the World Health assembly next month.

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John R. La Montagne Memorial Symposium on Pandemic Influenza Research: Meeting Proceedings MEETING OBJECTIVES Dr. Bruce Gellin, Director, National Vaccine Program Office As you just heard from Secretary Leavitt, the Department of Health and Human Service is devoting unprecedented focus on pandemic influenza preparedness. In addition to our work and the many activities that you'll hear about during this meeting, other countries and international organizations are also stepping up to the plate. As individual nations and as a global public health community, we are now better prepared to detect and respond to an influenza pandemic, but we clearly have to do more. Secretary Leavitt also reminded us that the draft pandemic influenza plan issued last summer is now being revised to more clearly articulate the roles and responsibilities at each stage of an emerging pandemic and provide clearer guidance to state and local health departments, the healthcare sector and the public. In addition, the updated plan will conform to the new format proposed by the World Health Organization (WHO) which will facilitate international communication before and during a pandemic. Like the pandemic influenza plans of many countries, our plan has had a long incubation period. In 1995, under John La Montagne’s leadership, the National Institutes of Health convened an international meeting to examine available data, identify critical scientific issues, and frame research questions to address gaps in knowledge vital to controlling pandemic influenza. Many of you participated in that meeting in December 1995, and much has happened since, but it is worth reviewing a few of the nearly 20 recommendations as they appeared in the 1997 supplement to the Journal of Infectious Disease (JID): Improve or sustain international surveillance efforts, particularly in Asia and the Pacific Rim. Improve our understanding of the role of humeral, cellular and mucosal immunity in protection against exposure to influenza, especially in immunologically naive populations. Determine immunologic correlates of protection for live attenuated influenza virus vaccines. Improve our understanding of the molecular basis of pathogenesis of pandemic strains. Manufacture and clinically test new, inactivated vaccines made from selected novel influenza viruses that have pandemic potential. Evaluate the effectiveness of using less than 15 micrograms of the current inactivated vaccine. In addition to the specific research priorities was the overarching recommendation to establish a mechanism to facilitate collaboration among international laboratories—to share reagent strains and new technological advances and to enhance overall capacity and capability. Some of those ideas that helped us respond to severe acute respiratory syndrome (SARS). The international composition of this meeting acknowledges the need for a coordinated global response. By the time the proceedings of that 1995 NIH symposium were published in 1997, we were facing the outbreak of H5N1 in Hong Kong that was challenging some existing assumptions. We expect that the road ahead will include additional twists and turns.

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John R. La Montagne Memorial Symposium on Pandemic Influenza Research: Meeting Proceedings Before turning our attention to the task ahead over the next two days, I would like to offer one final quote from Dr. La Montagne that appeared in the 1997 JID supplement. “The ability to initiate the tasks outlined above is beyond the responsibility and resources of the NIH or any single government agency. This scope of action requires international organizations and the vaccine and pharmaceutical companies.” Acknowledging the need for a coordinated global response, HHS and WHO organized this meeting to refocus our collective efforts on the scientific underpinnings of preparedness. Within this venue of the National Academy of Sciences, and with Institute of Medicine (IOM) president Dr. Fineberg presiding, we have assembled the top scientific leaders to seek your individual and collective input on critical scientific and epidemiological questions. The goals of this meeting are to describe the state of the sciences relevant to pandemic influenza, identify and prioritize scientific and technical questions that will have the greatest impact on our ability to identify and respond to a pandemic, and develop an action plan for addressing those gaps. This meeting also provides an opportunity set a course that will strengthen our international collaborations. For this we will need your input, and have constructed the meeting with substantial time for breakout sessions that focus on specific scientific areas. Last fall, Dr. John La Montagne speculated to a small group of us that pandemics might not necessarily be the virologic equivalent of the Big Bang, wherein a spark instantly becomes a raging fire. Rather, he hypothesized, that our strengthened surveillance systems and new diagnostic tools allow us to watch pandemics slowly unfold. If that is the case, then now is the time to advance our preparedness, because the only thing that is more difficult than planning for an emergency is explaining why you didn’t. We have a large task ahead.

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John R. La Montagne Memorial Symposium on Pandemic Influenza Research: Meeting Proceedings CURRENT STATUS OF AVIAN INFLUENZA AND PANDEMIC THREAT Dr. Julie Louise Gerberding, Director, Centers for Disease Control and Prevention Secretary Leavitt, in his opening remarks, used a metaphor—the network model—that is absolutely appropriate for this meeting. CDC is a highly connected hub in the network of disease preparedness and response, and we are here to exchange ideas and information with our colleagues from the Department of Health and Human Services, (DHHS), the Department of Defense, the Department of State, other federal agencies, state and local agencies, private sector organizations, academics, and our key global partner, the World Health Organization. We thank Dr. Fineberg and IOM because you are also a highly connected node in this network, and much of the scientific work we do would not happen without your facilitation. Every time I have been in this room in the last four years, it has been in the context of some horrifying public health threat—anthrax, smallpox, SARS, and now influenza. Anthrax, smallpox, and SARS are threatening situations where the risk calculation is relatively low yet the terror threat is high. In the case of influenza, the risk calculation suggests that we will certainly experience a pandemic sooner or later, yet most people perceive a very low threat. How do we prepare our society and the world for a likely threat amid growing complacency? The fact that we are here today speaks to growing scientific recognition that influenza is an urgent menace, and that the time for action is now. I'm going to talk about we know about avian influenza, highlight what we don't we know, and mention a few steps we are taking to do something about it. One thing we know for sure is that influenza epidemics and pandemics do happen—the three large pandemics in the last century attest to that. But as Mike Osterholm will tell you, many other influenza pandemics have also occurred throughout recorded history, some as large if not larger than the 1918–1919 epidemic. It doesn't take a scientist to appreciate that the clock is ticking, and that another pandemic is due. We also have some understanding of how antigenic shift occurs in influenza viruses, and why pandemics may emerge. There are at least two mechanisms. One is through reassortment of viruses—typically avian and human viruses in swine, which create a new strain which can infect people who lack immunity to the new antigens. The second mechanism, direct avian-to-human transmission, may also have accounted for some of the past pandemics. The picture becomes more complicated in the context of the current avian influenza outbreak, because we also have the possibility of an avian virus and a human virus reassorting in people and/or other host species. We need to know much more about influenza virus strain evolution before we can predict whether any of these mechanisms would allow this or any other avian strain to emerge and become more efficiently transmitted to people. We also know that pandemics are brutal on their impact on human mortality. The spike in mortality in 1918 and 1919 is a sober reminder of what happened when global connectivity was unusually high, given the movement of people that occurred at the end of the world war. But that situation was nothing compared with the connectivity and complex global networks in which we

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John R. La Montagne Memorial Symposium on Pandemic Influenza Research: Meeting Proceedings live and move today, and the increasing connectivity between humans and animal reservoirs of influenza viruses. We have only to think about SARS, as it moved from “Hotel M” in Hong Kong to global distribution in just a few short weeks, to be sobered by how quickly a problem in one corner of the world can reach other backyards literally overnight. So while we can be optimistic about advances in medical care and vaccine development, the potential for a pandemic with high mortality in this very small world is great. We know of avian influenza have been identified in people living in Thailand, Vietnam, and Cambodia. Why haven’t we seen human cases in other countries? Is this surveillance bias? Is it virologically determined? Is it host determined? What exactly is the explanation for the relative paucity of infections among people, given that the virus is much more prevalent in avian species than these human cases would suggest? What is the full spectrum of illness? We must do more research to understand the relationships among the virus, its virulence factors, the host’s immune response, and the clinical outcomes of infection. We know that the people with H5N1 influenza reported to the WHO in the current outbreak have a high mortality rate. To date, 74 cases and 49 deaths in Asia have been reported to the WHO, yielding case fatality rate of 66 percent. We don’t know if this fatality rate is accurate. Does it represent detection bias—in that sicker people are being diagnosed? Is the reported number of cases the tip of the iceberg, in that many less severe or asymptomatic cases have gone unrecognized? We do not know why so many young people died from influenza in 1918–1919. Certainly the stereotypical explanation has cited complications—particularly bacterial complications, although a 1976 review in the New England Journal of Medicine suggests that they might not have been the reason for so many deaths. Case reports, a review of the pathology literature, and recent experiments with influenza virus constructs containing genes from that pandemic strain suggest other potential explanations for the high incidence of shock and death associated with that pandemic. Most of the affected individuals in the current epidemic have been young and healthy. Why young and healthy people? Does this reflect exposure bias or a susceptibility in young people that perhaps reflects lack of prior exposure? Does age, ethnicity, nutrition status, or viral strain affect the case mortality rate? We need to address these very important questions about the clinical presentation and outcome of avian influenza through careful epidemiologic, laboratory, and clinical investigations. We also lack information on the relationship between treatment and the outcome of these infections. We know that the avian viruses currently causing human infections are resistant to amantadines and susceptible to neuraminadase inhibitors, and that some of the patients who succumbed had been treated. But whether treatment, alone or in combination of antivirals, offers any virologic or outcome advantage is unknown. We know that exposure to infected birds is a major source of infection among people, but what are the specific modes of transmission? Recent case reports suggest exposure to contaminated water and eating uncooked chicken could be risks as well. If we look back at the H5N1 influenza virus outbreak in Hong Kong in 1997, some information could direct us to the studies that we need to do today. We learned from case-control studies that the primary risk factor in the last outbreak was exposure to live poultry, and that the prevalence of the virus in chickens was very high. The prevalence of antibody to H5 in a cohort of the exposed population

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John R. La Montagne Memorial Symposium on Pandemic Influenza Research: Meeting Proceedings was about 10 percent, and those who butchered high risk birds were at higher risk for seropositivity. Targeted research—designed to understand the relationship between exposure, transmission modes, immunity, and disease outcome, as well as opportunities for intervention in environmental, occupational, household, and healthcare settings—is critical in affected countries. We must conduct these studies and many others in people, birds, swine, other mammals, as well as water and other potential environmental reservoirs to develop a comprehensive understanding of the epidemiology of this infection. Although we know that avian H5N1 influenza virus is widespread in Asia today, some places are not represented in the surveillance network or have very weak connectivity, and those weak links create vulnerability. Research needs to address how to strengthen the network and obtain information from these missing nodes on the network. Other critical questions include: Are all virus isolates among the poultry strains alike, and are they evolving? If so, what selection pressures are encouraging that evolution? Where are the carriers of these viruses from one country to another or one population to another or one species to another? How does the ecology of avian influenza virus affect its mobility to other parts of the world through migratory bird vectors or other movements of people, animals, birds, or fish? Unlike the 2003 isolates, which were homogeneous, these H5N1 influenza viruses now circulating in Asia are expressing some degree of heterogeneity. We don’t know how immunogenic these viruses are. We also don’t know what implications heterogeneity will have for vaccine development. We need a much more comprehensive understanding of the differences between the human and the avian isolates and their geographic distribution. Given the relative paucity of what we know compared with what we need to know, what are we doing about it? At DHHS, Secretary Leavitt received a comprehensive briefing on influenza even before his Senate confirmation, and CDC has since had several face-to-face briefings with the DHHS team as well as a daily update. We could not have better departmental leadership and commitment. Besides our support for WHO as the lead for international preparedness, we are also investing resources in specific Asian countries to improve their ability to detect emerging influenza strains and transport them to laboratories for reliable evaluation. Our other regional activities include our International Emerging Infections Program in Thailand and our collaboration with the US Naval Medical Research Unit laboratories of the U.S. Department of Defense (DOD) in Jakarta and Cairo. Our laboratory and epidemiologic scientists are hard at work to study the genetic determinants of pathogenicity and transmissibility, the genomic bases of drug resistance and binding properties, tracking and monitoring the antigenic evolution of virus isolates in time and place, and understanding the epidemiology of the current epizootic in more detail. This meeting will undoubtedly incubate other scientific questions. We are taking steps to enhance communication between public health and veterinary agencies. Dr. Lonnie King, former dean of the College of Veterinary Medicine at Michigan State University, is heading CDC’s Office of Strategy and Innovation. Dr. King is forging better connectivity between CDC and the veterinary community—both domestically and internationally—and the academic animal health community. Through investments in influenza preparedness as well as global detection of emerging threats, CDC is building a comprehensive international health protection network to connect all

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John R. La Montagne Memorial Symposium on Pandemic Influenza Research: Meeting Proceedings relevant capabilities and assets. The private sector is a key partner that we have engaged through our global roundtable of senior business leaders to understand how the international business community can benefit from our preparedness efforts and provide relevant information as another hub in our preparedness and response network. Secretary Leavitt mentioned that President Bush has authorized us to use our quarantine powers, if needed, for a novel or re-emergent strain of influenza with the potential to cause a pandemic. We are also moving domestically to expand our capacity from 8 quarantine stations to 30. Those are important steps, but they also highlight the fact that preparedness takes time – and time is of the essence if we hope to optimize quarantine and isolation capacity on a global scale. We had some practice with SARS. That experience taught us that with the right framework, people can do the seemingly impossible. But SARS was a relatively easy problem compared with the global challenges that an influenza virus strain with a high reproductive number (Ro) would create. We need to investigate the human aspects of isolation and quarantine, and what we need to do to prepare people and engage our leaders and our population in appropriate isolation and quarantine responsibilities. Anthrax and SARS taught us that we need solid communication science if we are going to have any hope of managing a major influenza outbreak. That science needs to address the content and credibility of communication to diverse populations. That effort isn’t just about translating science into messages that ordinary people can understand. It’s about translating ordinary messages into hopeful and helpful information that people of multiple cultural and linguistic backgrounds can use, and about transmitting information through a variety of channels on which we do not usually rely in the Western Hemisphere. I would urge this meeting not to lose sight of the human side of the research agenda, and to grapple with the communication sciences that are essential to our ability to prepare for and respond to an influenza outbreak or pandemic. The biggest lesson we have learned from other public health threats is that the most important enemy is complacency. I do not know how to develop a research agenda around preventing complacency, but I would submit that doing so is urgent. My fear is that although the lens may be shining on avian influenza right now, if the H5N1 strain does not become more transmissible to people, we will falsely assume that the threat is over. Worse, we could be accused of inappropriately revving up our preparedness efforts without a scientific basis. I do not believe we have done that, but it reminds us about the importance of credible communication so that the public understands the need to prepare and what is at stake if we don’t. We must strike the right balance between action and reassurance. The stimulus to effective research that this conference promises to foster is an essential step toward evidence-based policy decisions, effective public health action, and credible communication in the context of this global threat.

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John R. La Montagne Memorial Symposium on Pandemic Influenza Research: Meeting Proceedings Plenary Presentation Slides-Dr. Julie Louise Gerberding

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John R. La Montagne Memorial Symposium on Pandemic Influenza Research: Meeting Proceedings

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John R. La Montagne Memorial Symposium on Pandemic Influenza Research: Meeting Proceedings and easy-to-grow strain. This approach has been used to develop the seed virus for the H5N1 vaccine, which has just recently entered clinical trials. Multiple HHS agencies, including CDC, as well as some of our grantees and pharmaceutical and biotechnology companies are also doing research to develop a sound, consistent, cell-culture–based capability. The goal is to take some of the uncertainty out of egg-based culture and to give us greater surge capacity so we can have the year-round capability to produce vaccine. These cell-culture–based strains are also important because if we confront a virulent influenza strain that might prove lethal to chicken embryos, we can use reverse genetics to splice out the virulence factor. Also, a vaccine that is not grown in eggs is important to individuals who have allergies to egg proteins. Another important project that NIAID supports is the influenza genome project in collaboration with CDC, the New York State Department of Health, the National Center for Biotechnology Information, St. Jude’s Hospital in Memphis, and others. This project collects the full genomic sequences of a large number of isolates of influenza from humans and, in some cases, animals. The goal is to make these sequences available for basic as well as applied researchers, so that they may be helpful in the development of drugs, vaccines, and diagnostics. As of a couple of days ago, we have released the sequences of about 93 human isolates—an important research resource for our grantees and collaborators. What about antiviral therapies? Four separate anti-influenza antivirals are available. Among these, only Oseltamivir (Tamiflu) is adequate for treatment of H5N1 influenza. We are putting about 2.3 million treatment courses of Tamiflu into the national stockpile, NIAID and NIH research projects are developing and testing long-acting, next-generation neuraminidase inhibitors. We need targeted antiviral efforts like those for other disease such as HIV/AIDS, for which we have made remarkable advances, with more than 20 separate antiviral drugs now available. Animal studies are examining the effectiveness of combination therapies—a new approach for influenza. Other non-traditional pharmacological approaches include inhaled polyclonal IgG as an immunoprophylactic and the evaluation of new targets—not just the M protein and the neuraminidase, but also viral entry, replication and maturation. Protocols for the use of oseltamivir in infants are evolving. Oseltamivir is licensed for individuals older than 1 year, but we do not have enough information on people 1–2 years of age or younger to feel totally confident in the use of this drug in these subjects. That is why we are developing protocols to try to identify the optimal use of oseltamivir, particularly in children. Our main weapon in the armamentarium against influenza is a vaccine. As we have done in developing other countermeasures, particularly in the arena of biodefense, we are collaborating with at least two companies to develop a new vaccine for H5N1. Last spring we signed contracts with Sanofi Pasteur and Chiron to develop an H5N1 vaccine, as well as with Chiron for an H9N2 vaccine. Progress has been quite good. In fact, for H5N1, we contracted to produce pilot lots of 18,000 doses—10,000 from Chiron and 8,000 from Sanofi Pasteur—for a phase I-II clinical trial. The trial of the Sanofi product, which has accrued about 450 individuals thus far, will examine safety and immunogenicity first in healthy adults, then in the elderly population, and ultimately in the pediatric population.

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John R. La Montagne Memorial Symposium on Pandemic Influenza Research: Meeting Proceedings We are also contracting for 2 million doses of the H5N1 vaccine from Sanofi Pasteur for the strategic national stockpile. We also have an H9N2 vaccine, and one might ask why we would want that. Although it is not now as important as the H5N1 virus in Asia, particularly in Vietnam and Thailand, we need to learn more about the body’s immune response and the safety of the vaccines that are derived avian viruses. The H9N2 has also started its clinical trial. The live attenuated version of both vaccines is very important. Studies on that version are taking place in the NIAID intramural laboratory of Brian Murphy and Kanta Subbarao, but other individuals in the outside community are also looking at this. We all know from experience with live attenuated vaccines that this approach induces a broader range of serum and local mucosal antibodies. It induces cellular immune responses as well as humeral, and immunity develops rapidly, usually with a single dose. This is important because there is a question of whether we will have to use multiple doses of the killed H5N1 vaccine. The attenuated vaccine has a wider breadth of cross-reactivity, as do most live attenuated vaccines. This becomes critical when dealing with H5N1. If it mutates to become much more efficient in its transmissibility from human to human, will that mutation affect the ability of the vaccine to protect against it? Not necessarily, but broader cross-reactivity would be very helpful. The other advantage is that such a vaccine does not require needle injection, and it is more effective in infants and children than are inactivated virus vaccines. Vaccine clinical trials traditionally occur in our vaccine and treatment evaluation units. The three involved in the H5N1 vaccine are located in Los Angeles, Baltimore, and Rochester, New York, but other units will also be involved in the second and third components of the clinical trial. I want to finish by commenting on the fragility of the vaccine enterprise in general, but particularly the influenza vaccine enterprise, and the role of the research enterprise in addressing this fragility. We all were faced with a rude awakening when we discovered the contamination of half of the U.S. supply of influenza vaccine last year. However, other nations that rely on influenza vaccine have also experienced delays. For example, Australia found that one of the influenza strains in a vaccine was not present in as great a concentration as required, which created somewhat of an analogous situation to the one that we experienced last fall. How can we strengthen the fragile vaccine enterprise? One approach is by targeting research resources. I have already mentioned several research efforts, such as the use of reverse genetics to add consistency and reproducibility to our ability to obtain a seed virus. We can also gradually transition to cell-based vaccines and the use of recombinant-DNA technologies to express hemagglutinin and neuraminidase and other proteins. Developing a perennial vaccine based on conserved epitopes is particularly problematic with influenza, because humans are continually infected each year, yet we do not seem to have adequate cross-protection against small changes in connection with the yearly antigenic drifts. We also lack dose-sparing strategies. Toward that end NIH is looking at using intradermal vaccines, and comparing intradermal with intramuscular vaccines. A clinical protocol to compare intramuscular to intradermal approaches in H5N1 vaccination is in preparation. We are also discussing production of an adjuvant-aided H5N1 vaccine with manufacturers, although the trial that has just started is not adjuvant-aided.

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John R. La Montagne Memorial Symposium on Pandemic Influenza Research: Meeting Proceedings Because this is the John La Montagne symposium, I want to mention that one of his last scientific efforts was to co-author with me an invited commentary in the New England Journal of Medicine, which was published on November 3, 2004, the day after his death. He was hired as one of our first influenza program officers, and his last scientific publication was on influenza. The fragility of the influenza enterprise is real, and we must address it with incentives to industry as well as with basic research that improves the process of vaccine development. Potential incentives are now being discussed at HHS. NIAID is also trying to help industry make products that might supplement our normal supply of influenza vaccine—that is, to obtain the necessary information for as rapid FDA approval as possible. Such efforts are occurring with GlaxoSmithKline’s inter-pandemic Fluarix vaccine. One of the most rapidly accrued trials that we have ever experienced—it enrolled almost 1,000 people in 5 days—began in December 2004. People were interested in getting into the trial given the shortage of influenza vaccine. We are expecting the results shortly. I want to close by mentioning that when we deal with emerging diseases, we see the extraordinary capability of pathogens to persist, emerge, and reemerge. None does it better than influenza. To address this threat, we must balance public health measures, biomedical research, and technological advances. Staying on top of what could be an extraordinary public health problem is extraordinarily important. John was co-author of a review of the last such meeting in 1995, published in the Journal of Infectious Diseases, called “Pandemic Influenza: Confronting a Re-emerging Threat.” What he said then holds true today. Success in controlling a pandemic will benefit from new advances by the scientific community, which provides the pool of solutions to combating emerging threats.

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John R. La Montagne Memorial Symposium on Pandemic Influenza Research: Meeting Proceedings Plenary Presentation Slides-Dr. Anthony S. Fauci

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John R. La Montagne Memorial Symposium on Pandemic Influenza Research: Meeting Proceedings

OCR for page 7
John R. La Montagne Memorial Symposium on Pandemic Influenza Research: Meeting Proceedings

OCR for page 7
John R. La Montagne Memorial Symposium on Pandemic Influenza Research: Meeting Proceedings

OCR for page 7
John R. La Montagne Memorial Symposium on Pandemic Influenza Research: Meeting Proceedings

OCR for page 7
John R. La Montagne Memorial Symposium on Pandemic Influenza Research: Meeting Proceedings

OCR for page 7
John R. La Montagne Memorial Symposium on Pandemic Influenza Research: Meeting Proceedings

OCR for page 7
John R. La Montagne Memorial Symposium on Pandemic Influenza Research: Meeting Proceedings (Slides available on accompanying CD)