REPORT OF THE BLUE RIBBON PANEL

ON INFLUENZA RESEARCH

September 11-12, 2006
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Report of the Blue Ribbon Panel on Influenza Research 

CONTENTS 

I. Executive Summary 

II. Introduction 

A. Background 

B. Planning and Assessment Process 

III. Guiding Principles 

A. Promote innovative multidisciplinary research 

B. Integrate seasonal and pandemic influenza research activities 

C. Balance investigator-initiated basic research with targeted research 

activities 

D. Maximize broad applicability of influenza research results 

E. Enhance research coordination and collaboration 

IV. Research Recommendations 

A. Influenza at the Animal-Human Interface 

B. Influenza in Individuals 

C. Influenza in Human Populations 

D. Animal Models 

E. Vaccines 

F. Therapies 

G. Assay Technologies 

H. Resources 

V. Appendices 

A. Membership Roster of the Blue Ribbon Panel on Influenza Research 

B. NIAID Attendees of the Meeting of the Blue Ribbon Panel on Influenza 

Research 

C. Summary of Major NIAID Influenza Research Activities, by Division 

Posted June 2007 
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I. EXECUTIVE SUMMARY 

The National Institute of Allergy and Infectious Diseases (NIAID), a component of the 

National Institutes of Health (NIH) of the Department of Health and Human Services 

(DHHS), has primary responsibility within the Federal government for basic and applied 

influenza research. In early 2006, NIAID undertook a comprehensive examination of its 

influenza portfolio to improve its planning and coordination in this area, and to take full 

advantage of recent scientific and technological advances. NIAID then convened a Blue 

Ribbon Panel on Influenza Research to identify areas of influenza research in which 

progress is needed. 

The panel outlined several strategic principles that should guide the research and 

provided specific research recommendations in eight areas in which substantial progress 

is needed. Taken together, these principles and recommendations provide a framework to 

guide NIAID's influenza research activities in the years to come. 

Guiding Principles 

Five important principles regarding the conduct of influenza research emerged repeatedly 

during the panel’s deliberations. 

•	 Promote innovative multidisciplinary research. 

•	 Integrate seasonal and pandemic influenza research activities. 

•	 Balance investigator-initiated and targeted research. 

•	 Maximize applicability of influenza research results to other fields. 

•	 Enhance research coordination and collaboration within NIH, within DHHS 

(especially with the Centers for Disease Control and Prevention, CDC), across all 

Federal agencies, with private industry, and internationally. 

These overarching, strategic principles are critical to the successful implementation of the 

recommendations that follow. 

Research Recommendations 

The panel identified eight specific aspects of influenza research in which there are 

substantial gaps in knowledge and outlined several key recommendations within each 

area which are essential for progress to be made: 

Influenza at the Animal-Human Interface 

Scientific understanding of how animal and human influenza viruses interact, 

including how influenza viruses circulate among various reservoirs and the 

evolutionary pressures that lead to the emergence and spread of new viral sub-types, 

could be improved. 

•	 Elucidate patterns of influenza virus diversity and evolution. 
 

 

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•	 Define patterns of influenza virus transmission in and between human and 

animal populations. 

•	 Examine interactions of diverse influenza viruses with various hosts. 

Influenza in Individuals 

Many aspects of human clinical and immune responses to influenza infection, such 

as the role innate and adaptive responses play in pathogenesis and the host genetic 

factors that lead to severe influenza outcomes, have not been fully described. 

•	 Increase understanding of influenza pathology and pathogenesis in humans. 

•	 Fully describe human cellular immune responses to influenza infection. 

•	 Describe innate and mucosal immune mechanisms in influenza. 

•	 Map genomics and proteomics of human responses to influenza viruses. 

•	 Strengthen infrastructure for clinical influenza research. 

Influenza in Human Populations 

Many aspects of influenza epidemiology, including the relative importance of 

aerosol, droplet, and fomite transmission and the contribution of specific subpopulations such as schoolchildren to epidemic spread, are not adequately 

understood. 

• Expand understanding of influenza viruses in different human populations. 

Animal Models 

Animal models, which are essential tools for virtually all aspects of influenza 

research, could be improved. 

•	 Enhance the depth of understanding of commonly used models. 

•	 Increase the range of options for animal models. 

•	 Improve the availability of appropriate animals for use in influenza research. 

Vaccines 

Development of improved influenza vaccines is a key priority for the control of 

both seasonal and pandemic influenza. 

•	 Define all correlates of immune protection from influenza. 

•	 Facilitate studies that include challenge of human volunteers with live virus. 

•	 Improve adjuvants and other dose-optimization technologies for influenza 

vaccines. 

•	 Define evaluation criteria for vaccine efficacy testing. 

Therapies 

Expansion of the current repertoire of antiviral drugs and other therapies to reduce 

the severity of influenza outcomes would allow better control of both seasonal and 

pandemic influenza. 
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• Expand studies of currently licensed antiviral drugs. 

• Develop new drugs and new drug targets for influenza. 

• Investigate therapies for late-stage, severe influenza. 

Assay Technologies 

The advent of new technologies such as DNA microarrays has provided new 

opportunities to improve diagnostic and immunological assays relevant to 

influenza. 

• Develop new point-of-care diagnostic assays. 

• Improve and standardize assays for cellular immune responses to influenza. 

• Improve methods for assaying immune responses in the respiratory tract. 

Resources 

• Expand the range of materials available to the research community. 

• Increase services for researchers. 

• Improve mechanisms for the exchange of information among researchers. 
 

 

 

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II. INTRODUCTION 

A. Background 

Influenza is a familiar but dangerous infectious disease. Historical records indicate that 

influenza epidemics have occurred among human populations for hundreds if not 

thousands of years. The virus was first isolated in the 1930s, and by the 1940s an 

influenza vaccine had been shown to be capable of preventing infection among young, 

healthy adults. Since the 1960s, U.S. public health authorities have recommended annual 

influenza vaccination for the elderly and other people at high risk for severe influenza 

outcomes. 

Influenza, however, continues to impose a substantial annual burden of morbidity and 

mortality. An average of about 200,000 influenza-related hospitalizations and about 

36,000 influenza-related deaths occur in a typical winter-seasonal epidemic in the United 

States; the majority of these severe outcomes occur among seniors aged 65 years and 

older.1

 The cumulative burden is even more striking: approximately 900,000 influenzarelated deaths have occurred in the United States over the past 30 years,2

 making 

influenza one of the leading causes of death among vaccine-preventable infections. 

Beyond the seasonal toll, however, influenza viruses have an as yet unpredictable ability 

to cause devastating pandemics. Influenza pandemics occur when a virus arises that 

causes illness, is one with which the population has no prior immunological experience, 

and is easily transmitted between individuals. Three influenza pandemics occurred in the 

20th century. The pandemics of 1957 and 1968 were serious infectious disease events that 

killed approximately two million and 1 million people worldwide, respectively; the 1918 

pandemic, however, was catastrophic, and caused an estimated 40 million deaths 

worldwide.3 

The current global outbreak of H5N1 avian influenza among domestic and wild birds, as 

well as a growing awareness of the burden of seasonal influenza and the potential for 

another catastrophic pandemic, has refocused attention on the threat of influenza. As of 

June 6, 2007, 310 cases of human H5N1 influenza infection had been confirmed; of 

these, 189 had died as a consequence.4

 Although a few instances of human-to-human 

transmission have been documented, the virus has not acquired the ability to spread 

1

Thompson WW, Shay DK, Weintraub E Brammer L, Cox N, Anderson LJ, and Fukuda K.. Mortality
 

associated with influenza and respiratory syncytial virus in the United States. JAMA 289:179 (2003). 2

 Simonsen L, Reichert TA, Viboud C, Blackwelder WC, Taylor RJ, Miller MA. Impact of influenza 

vaccination on seasonal mortality in the U.S. elderly population. Arch Intern Med 165:265 (2005). 3

 WHO, Avian Influenza: Assessing the Pandemic Threat, January 2005. Available at 

http://www.who.int/csr/disease/influenza/H5N1-9reduit.pdf, accessed February 8, 2007. 4

 Cumulative Number of Confirmed Human Cases of Avian Influenza A/(H5N1) Reported to WHO,
 

available at http://www.who.int/csr/disease/avian_influenza/country/en/, accessed February 5, 2007. 
 

6 

efficiently in the human population.5 The vast majority of human cases are strongly 

linked to exposure to infected domestic fowl. 

Within the Federal government, NIAID, a component of NIH and DHHS, has long held 

primary responsibility for both the conduct of scientific research in influenza and for 

carrying out applied research and clinical evaluation to foster development of drugs, 

vaccines, and diagnostic tools; this role was reconfirmed in the 2005 DHHS Pandemic 

Influenza Plan. Annual funding for influenza research at NIAID has increased from 

approximately $15 million in fiscal year 2001 to an estimated $212 million in fiscal year 

2007. 

Much has been learned, but many basic scientific topics must be more fully explored, and 

vaccines, drugs, and diagnostics for influenza need to be improved. Accomplishing these 

goals will help policy makers make the difficult choices involved in pandemic planning 

by arming them with better countermeasures and scientific information. Only continued 

basic and applied research can lay the foundation for development of new vaccines, 

therapies, and diagnostic tools that will allow society to cope effectively with the next 

influenza pandemic. 

B. Planning and Assessment Process 

To improve the planning and coordination of NIAID influenza research activities, to 

identify research gaps, and to ensure that these activities are structured to take full 

advantage of every avenue that recent scientific and technological advances have to offer, 

NIAID undertook a comprehensive examination of its influenza research portfolio. In 

February 2006, a one-day “NIAID Influenza Research Summit” of senior NIAID 

scientific staff was convened, at which the influenza research activities of the Institute 

were reviewed and specific gaps and opportunities identified. 

NIAID then convened a 35-member Blue Ribbon Panel on Influenza Research to build 

on the results of the February meeting. Panel members were chosen from among 

scientists affiliated with academic research institutions, various U.S. government and 

international agencies, vaccine and pharmaceutical manufacturers, and non-governmental 

organizations. NIAID deliberately sought to create a panel of experts with broad 

experience and a wide variety of viewpoints and expertise. 

The Blue Ribbon Panel met in Bethesda, MD, on September 11-12, 2006. The goal of the 

meeting was to provide guidance for NIAID’s influenza research activities in the coming 

years. On the first day, participants separated into three groups for discussions. All three 

breakout groups were given the charge to review, comment on, and suggest additions to 

the report from the NIAID Influenza Research Summit, and to recommend approaches 

that NIAID could use to develop an innovative research agenda to guide its future 

influenza research program. They were also asked to identify barriers that must be 

overcome, partnerships that must be forged, and resources that must be provided to speed 

5

WHO, Basic health information on Human Avian Influenza A/H5N1. 

http://www.wpro.who.int/information_sources/databases/regional_statistics/rstat__Human_Avian_influenz 

a.htm, accessed June 11, 2007. 
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research progress. Participants were urged to think broadly and for the long term, paying 

particular attention to how new technological advances in research could be applied for 

maximum effect. The entire panel reconvened on the second day for presentations from 

each breakout group, and for discussion of the issues raised. 

This report presents a summary of the Panel’s deliberations and recommendations. 

Section III, “Guiding Principles,” presents five overarching, strategic approaches to the 

conduct of influenza research that emerged during the Panel’s discussions. Section IV, 

“Research Recommendations,” presents specific recommendations in eight areas of 

influenza research in which substantial progress is both needed and, with sufficient effort, 

will likely occur. Taken together, these principles and recommendations provide a 

framework to guide NIAID's influenza research activities in the years to come. 
 

 

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III. GUIDING PRINCIPLES 

Throughout both the February NIAID Influenza Research Summit and the Blue Ribbon 

Panel meetings, several important themes regarding the conduct of influenza research 

emerged repeatedly and in multiple contexts. These themes are summarized here as five 

strategic principles to guide NIAID’s influenza research program. 

A. Promote innovative multidisciplinary research 

Increasingly, a multidisciplinary approach that integrates individuals from diverse 

fields—both within and beyond the life sciences—is required to translate biomedical 

research advances into improved patient care. Indeed, well-integrated teams of 

individuals with different perspectives, approaches and expertise are needed to solve 

basic and applied research problems related to influenza. Laboratory-based scientists with 

expertise in, for example, virology, immunology, genomics, ecology, evolutionary 

biology and epidemiology, should work with clinical researchers with expertise in, for 

example, infectious diseases and pulmonology, to conduct both laboratory and clinical 

research. It is equally important that research teams include individuals drawn from nonbiological disciplines as needed, such as physics, mathematics, engineering, and 

computer science. Integration of divergent fields, people and perspectives into a wellcoordinated influenza research program will be essential in order to make rapid progress. 

B. Integrate seasonal and pandemic influenza research activities 

Seasonal and pandemic influenza differ mostly in virulence and the degree of immunity 

present in the human population. Increased basic understanding of seasonal influenza 

helps the development of vaccines and other countermeasures that could be used against 

the next influenza pandemic; and increased development of new vaccines, treatments, 

and diagnostics for seasonal influenza will strengthen our ability to respond adequately 

when the next pandemic influenza virus emerges. There is one caveat to this principle, 

however. Because a pandemic virus is by definition one with which scientists and 

physicians have little experience, specific plans, infrastructure and protocols that allow 

laboratory and clinical study of a pandemic influenza virus to proceed rapidly need to be 

developed before a pandemic virus emerges. 

C. Balance investigator-initiated basic research with targeted research activities 

Much contemporary research requires large-scale or multi-site collaborative projects that 

are beyond the reach of any single investigator. At the same time, however, investigatorinitiated basic research projects, which have for decades been the foundation of NIHfunded research and the source of knowledge on which new medical interventions are 

based, will continue to be critically important. Thus, it is crucial that NIAID continue to 

support investigator-initiated studies in influenza. 

D. Maximize broad applicability of influenza research results 

Much of the knowledge gained as a result of the influenza research effort, as well as 

many of the product platforms developed, may be applicable to other infectious diseases. 

Influenza research activities should be structured to take full advantage of any 
 

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opportunities to collect data with broad uses and to create technology platforms and 

infrastructure applicable to other infectious diseases, and thereby capitalize on these 

opportunities to the greatest extent possible. 

E. Enhance Research Coordination and Collaboration 

Influenza research demands cooperation and collaboration across international and 

organizational boundaries, as well as across scientific disciplines and between public and 

private entities. At both the February and September meetings, however, a clear 

consensus emerged that collaboration and coordination in influenza research at all levels 

is at present imperfect and should be improved. The strong collaborative relationships 

that are necessary are found at many organizational levels, including: 

•	 Within NIH. Although NIAID plays the lead role in influenza research, other 

institutes and centers, including the National Institute of Child Health and Human 

Development (NICHD), the Clinical Center (CC), the National Institute of 

General Medical Sciences (NIGMS), and the National Heart Lung and Blood 

Institute (NHLBI), play important roles as well. 

•	 Within DHHS. DHHS is the parent agency of the CDC and the Food and Drug 

Administration (FDA) as well as the NIH. CDC is the lead U.S. agency for public 

health response and disease surveillance; CDC also carries out research in 

influenza epidemiology and molecular virology, and conducts development 

activities for vaccines and diagnostic tests. FDA regulates vaccines and therapies, 

and its Center for Biologics Evaluation and Research conducts influenza research. 

•	 Across Federal Agencies. Several agencies across the Federal government are 

involved in activities relevant to influenza research, including the U.S. 

Department of Agriculture (USDA), the Department of the Interior, the 

Department of Defense (DoD), the Department of State, and the U.S. Agency for 

International Development (USAID). 

•	 With Private Industry. Both established pharmaceutical corporations and new 

start-up companies play a vital role in the development of new products and 

strategies for control of influenza. Efficient development of improved vaccines, 

therapeutics, and diagnostics therefore requires close collaboration with the 

private sector. 

•	 Internationally. The World Health Organization (WHO) is responsible for 

coordinating global influenza surveillance and the global response to an emerging 

influenza pandemic. DHHS is the official point of contact between WHO and the 

U.S. government; CDC is a designated WHO Influenza Reference Center and 

thus has the most extensive relationship with the WHO influenza program. 

Building these various collaborative relationships is not an easy task. Approaches that 

might help improve collaborations within NIH and with other Federal agencies include 

holding joint conferences to foster the exchange of information and to increase awareness 

of other agencies’ activities, increased sharing of data such as genomic sequences, and 

providing funding and incentives for scientists and staff to establish collaborative 

relationships between agencies and organizations. 
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Improving international coordination and collaborations is more complex. Many U.S. 

government organizations are involved, especially in coordinating the response to an 

emerging influenza pandemic, and National governments are subject to a variety of 

conflicting pressures and incentives concerning the free movement of information, 

materials, and people involved in influenza research and pandemic response. The trend in 

international health research generally is to complement strategies that establish 

centralized clearinghouses for samples or information regarding a particular international 

health problem by increasing support for resource-poor countries’ as they strive to 

improve their indigenous scientific, laboratory, and public health capacities. It is 

therefore important that NIAID and CDC collaborate closely as NIAID continues to build 

its international research portfolio in influenza and integrate its activities and resources 

more completely into international influenza research coordinated by WHO. 
 

 

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IV. RESEARCH RECOMMENDATIONS 

The NIAID Influenza Research Summit report identified eight major aspects of influenza 

research in which there are substantial gaps in knowledge, and that therefore present 

opportunities for further research. The Blue Ribbon Panel reviewed this list, provided 

additional items, and discussed ways to answer the key questions. A summary of the 

findings and recommendations is presented here; unless specifically noted, these 

recommendations are intended to apply to both seasonal and pandemic influenza 

research. Each sub-section below begins with a brief statement of the research area 

identified, followed by specific recommendations for action. 

A. Influenza at the Animal-Human Interface 

Animal reservoirs play a central role in the emergence of new seasonal influenza viruses 

as well as of viruses with pandemic potential. However, it is not yet clear how the 

interactions of various animal influenza reservoirs with each other and with the human 

population affect the evolution of influenza viruses and their adaptation to humans. 

Highly-pathogenic H5N1 avian influenza (AI), for example, has been shown to infect at 

least 105 avian species as well as several mammalian species6. Although most human 

H5N1 infections have resulted from contact with infected chickens, other wild and 

domestic species could participate in the propagation of H5N1 AI to regions currently 

unaffected and cause new cases of human infection. Learning more about how influenza 

viruses circulate between animal reservoirs and about the evolutionary pressures that lead 

to the emergence and spread of new viral sub-types—especially the factors that favor 

transmission from animals to humans—are urgent research priorities. 

Elucidate patterns of influenza virus diversity and evolution. Increased collection and 

sequencing of influenza viruses currently circulating in animal and human populations, as 

well as sequencing of viruses currently held in collections, would allow more complete 

comparative genomic studies to reveal patterns of viral diversity and evolution in various 

animal reservoirs. Although the number of influenza virus genome sequences available to 

the entire research community has grown substantially in the past two years, much more 

remains to be accomplished. Human and animal influenza virus sequences, combined 

with clinical data on the disease course and outcome, should be made available to the 

research community in an integrated database. Moreover, clinical samples from human 

hosts and samples of the virus should be made available to researchers when feasible. 

Define patterns of influenza virus transmission in and between human and animal 

populations. Improved sero-surveillance studies in various influenza virus reservoirs, 

including humans, would help to define past patterns of influenza transmission in animal 

and human populations. For example, mapping the number and distribution of people in 

different regions whose sera indicate a past exposure to H5N1 influenza could reveal the 

degree to which the virus has been transmitted to humans in the recent past, which would 

6

 Olsen B, Munster VJ, Wallensten A, Waldenström J Osterhaus ADME and Fouchier RAM. Global 

Patterns of Influenza A Virus in Wild Birds, Science 312:384 (2006). 
 

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in turn provide more direct evidence for the significance of the infections and deaths in 

the human populations affected thus far. 

Examine interactions of diverse influenza viruses with various hosts. Expansion of 

comparative studies of the interaction of animal and human influenza viruses with their 

hosts, including studies of the interactions between viral proteins and host receptors, 

would help to elucidate the factors controlling viral emergence and evolution, and 

provide data that would complement genomic analyses. 

B. Influenza in Individuals 

Many fundamental aspects of human clinical and immune responses to infection by both 

seasonal and pandemic influenza viruses have not yet been fully described—for example, 

the role innate and adaptive responses play in pathogenesis, host genetic factors that may 

affect susceptibility to severe influenza outcomes, and how innate immune mechanisms 

prevent or slow infection or, conversely, exacerbate illness. 

Increase understanding of influenza pathology and pathogenesis in humans. Expanded 

clinical study of seasonal influenza patients could provide insights into influenza disease 

pathology and pathogenesis, human immune responses to influenza infection (especially 

cytokine responses), and the effectiveness of treatments. These insights would in turn 

improve vaccines and therapeutics for seasonal and pandemic influenza alike. 

Fully describe human cellular immune responses to influenza infection. Antibodies 

against hemagglutinin and neuraminidase have long been known to play a role in 

protective immunity. However, studies of protection elicited by live-attenuated influenza 

vaccines indicate that humoral antibody responses are not the only important correlates of 

immunity, and that cellular responses also play an important role in immune protection. 

There is thus a need to understand these cellular response more completely, such as by 

fully describing all CD4+ T-cell, CD8+ T-cell, and cytokine responses to influenza, and 

determining the factors that lead to robust generation and maintenance of T- and B-cell 

memory. 

Describe innate and mucosal immune mechanisms in influenza. Innate immune 

responses are important in limiting progression in the early stages of influenza infection, 

and conversely, may contribute to the dysregulation of immune signaling that often 

accompanies severe outcomes. Moreover, a better understanding of innate immune 

responses to influenza may lead to new vaccine adjuvants, immune modulators, or other 

means of preventing infection. Mucosal immune mechanisms are important for 

preventing infection, both in the acute response to the virus and in long term protective 

immunity; for example, mucosal mechanisms are particularly important in protection 

provided by cold-adapted, live-attenuated influenza vaccines. A greater understanding of 

the important roles played by innate and mucosal immune responses in protecting against 

influenza is critical to efforts to develop new preventive measures. 

Map genomics and proteomics of human responses to influenza viruses. 

Comprehensive understanding of the host genes that activate in response to influenza 
 

 

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infection is lacking. Such clinical genomics studies could examine multiple sites within 

individuals—both the upper and lower respiratory tract as well as the blood, for 

example—to uncover host genetic factors associated with susceptibility to severe 

outcomes, and could facilitate early diagnosis and clinical management of influenza 

infection. 

Strengthen infrastructure for clinical influenza research. Increasing the number of 

centers at which clinical influenza research is routinely conducted would help to fill 

current gaps concerning how influenza viruses interact with human patients to cause 

disease, and would speed the study of pandemic influenza patients when they soon after a 

pandemic is declared. Moreover, the establishment of uniform case criteria, definitions, 

case report forms, and standardized databases would improve the ability to compare data 

from different studies, speed communication of results, and facilitate collaborations 

between clinical and basic researchers. 

C. Influenza in Human Populations 

Many issues relevant to influenza epidemiology are not adequately understood. Examples 

include the relative importance of aerosol, droplet, and fomite transmission; the 

contribution of specific sub-populations such as schoolchildren to epidemic spread; and 

how growth in the immunosuppressed and elderly populations in recent decades might 

affect influenza transmission. 

Expand understanding of influenza viruses in human populations. Expanded studies 

of influenza in human populations would help to elucidate the modes of viral 

transmission; population sub-groups that affect transmission (e.g., age, occupation, 

residential setting, heath status, immunodeficiency); risk factors for severe outcomes 

(e.g., age, specific genetic characteristics, co-morbidities); and dynamics of viral spread 

across geographic regions. Moreover, such studies would improve the evidence base for 

modeling studies of the potential effects of public health interventions and thereby help to 

guide pandemic influenza preparedness. 

To accomplish this, one or more prospective, comprehensive cohort studies of people 

(including children and the elderly) with influenza could be undertaken; other respiratory 

illnesses might be covered by the study as well. Many of the available data about the 

epidemiology of influenza in U.S. communities were derived from prospective cohort 

studies conducted decades ago. These studies, such as the Cleveland Family Study, the , Tecumseh Study of Respiratory Illness and others,7,8 9 followed enrolled individuals and 

families over multiple years; illnesses were noted, and specimens taken for laboratory 

analysis. The goal was to increase understanding of the epidemiology, etiology, clinical 

7

 Jordan WS Jr, Badger GF, Dingle JH. A study of illness in a group of Cleveland families. XVI. The 

epidemiology of influenza, 1948-1953. Am J Hyg. 68:169 (1958). 

8

 Monto AS and Kioumehr F. The Tecumseh Study of Respiratory Illness. IX. Occurrence of influenza in
 

the community, 1966—1971. Am J Epidemiol. 102:553 (1978). 

9 Glezen WP, Couch RB. Interpandemic influenza in the Houston area, 1974-76. N Engl J Med. 298:587 

(1978). 
 

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manifestations and best treatments of influenza and other respiratory infections. New 

studies could be similar in structure but use newer scientific tools, including 

•	 genomic analysis of both viruses and human hosts 

•	 comprehensive, standardized assays of cellular, humoral, and innate immune 

responses. 

•	 rapid identification of infected patients with the best available diagnostic 

technology 

•	 storage of accessible specimens for later analysis in laboratory studies 

•	 collection of clinical and virologic data in integrated databases 

•	 less-invasive methods for obtaining information from the lower respiratory tract 

Such cohort studies would help to illuminate the mechanisms and patterns of viral 

transmission in a modern setting; these may have changed from a generation ago, when 

child day care was less pervasive and people commuted to work over shorter distances. 

Such studies could also help to reveal the factors related to severe outcomes, including 

viral genomics, host HLA type, age, co-morbidities, and use of various treatment 

strategies. They could also shed light on the effectiveness of possible pandemic-control 

measures such as antiviral prophylaxis of close contacts, school closings, and other steps 

to limit transmission within a population, and would provide an opportunity to field-test 

and compare new point-of-care diagnostic assays. 

In addition, existing cohorts assembled for the study of other diseases could be adapted 

for influenza research. This could be done retrospectively, by analysis of banked clinical 

samples and relevant data, or prospectively, by adding influenza data and sample 

collection to ongoing or planned protocols. For example, NIAID’s Multi-Center AIDS 

Cohort Study (MACS), which has been following thousands of individuals since 1984, 

could be adapted to also collect information relevant to influenza; other NIAIDsponsored cohorts in the United States and overseas could similarly be adapted to answer 

questions in influenza research. 

D. Animal Models 

Animal models are essential tools for virtually all aspects of influenza research, from 

basic immunology and pathogenesis studies to testing and development of vaccines, 

antiviral drugs, and other countermeasures. Influenza researchers use a variety of inbred 

and outbred animal models—e.g., pigs, chickens, ducks, ferrets, non-human primates—to 

serve distinct research needs in areas such as transmission, pathogenesis, immunity, and 

vaccine development. 

Enhance the depth of understanding of commonly-used models. Animal models such as 

mice and ferrets have been used widely in influenza research for many years. 

Enhancements would include adding further detail about the immunology, pathogenic 

mechanisms, and other aspects of the model’s responses to influenza, and increasing 

knowledge of how those responses correlate to human immune responses. In addition, 

better standardization of assays and reagents used in animal studies would allow 

improved comparisons of results from different laboratories. Full genome sequencing of 
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animals used in influenza research such as ferrets would also be useful, as would the 

development of additional reagents to study host immune responses in other animals. 

Increase the range of options for animal models. Some animal models that have been 

used only rarely or not at all for influenza could be further characterized and developed 

for influenza research. For example, the miniature pig, which has been used in a 

relatively small number of influenza studies, might be more widely used if more were 

known about its responses to infection and if standardized reagents were made available 

to researchers. A wider repertoire of avian species for influenza models would be helpful, 

and humanized mice for use in influenza research should be developed and made 

available. And while non-human primates can be infected with influenza, they are rarely 

used as experimental models because they have not been reported to reliably develop 

influenza symptoms; it would be useful to systematically re-evaluate selected non-human 

primates as models for influenza. 

Improve the availability of appropriate animals for use in influenza research. Because 

they are convenient and inexpensive to use, mice are used for most animal studies of 

influenza. However, mice do not always mimic human immune responses. Steps to 

increase the availability of ferrets, humanized mice, and perhaps other models would 

speed research. 

E. Vaccines 

Development of improved influenza vaccines and related manufacturing technology is an 

important priority. Influenza vaccines currently used in the United States must be cultured 

in fertilized chicken eggs, which would make it difficult to rapidly scale up production in 

response to the surge in demand for vaccine that would accompany a pandemic. Current 

vaccines must also be reformulated every year on the basis of predictions about the strains 

most likely to circulate in the coming season; live-attenuated vaccines may offer a greater 

degree of heterosubtypic protection but are not as yet used in a large proportion of the 

population. Inactivated virus vaccines effectively prevent infection in adults and children; 

however, while these vaccines are recommended for use by people over age 65, this 

population does not in general respond as vigorously as young adults. Promising new 

technologies for new influenza vaccine platforms and production methods, some of which 

are currently used in licensed vaccines for other diseases, are now under development. 

Define all correlates of immune protection from influenza. High titers of 

hemagglutination inhibiting antibodies against well-matched strains are correlated with 

both protection and also with neutralizing antibody titers. Other (non–HA) protective 

immune responses have not been as thoroughly described. For example, cell-mediated 

responses to influenza antigens other than hemagglutinin and neuraminidase could be 

important to protection, especially against divergent viral subtypes (heterosubtypic 

protection). Similarly, innate immune responses to influenza, which keep the virus in 

check until adaptive immune responses become active, are not thoroughly understood. 

Passive immunization to protect individuals, either by itself or in combination with an 

active vaccination strategy, must also be evaluated. Comprehensive description of all 

protective mechanisms and the interdependent roles they play in immune protection 
16 

might better inform decisions on which vaccine candidates should proceed to large scale 

efficacy trials. 

Facilitate studies that include challenge of human volunteers with live virus. In order 

to assess potential efficacy more completely than with surrogate measures alone, 

protocols for studies in which human volunteers are challenged with live influenza virus 

under controlled conditions must be developed, and regulatory issues must be resolved. 

Such studies could involve either wild-type virus or live-attenuated strains, and would 

also be useful for increasing knowledge of the entire set of human immune responses to 

influenza. In addition, these studies would be facilitated by the provision of wellcharacterized strains of influenza virus, including live-attenuated strains of H5N1 AI, for 

use in challenge studies. 

Improve adjuvants and other dose-optimization technologies for influenza vaccines. 

Currently, influenza vaccines administered in the US do not contain adjuvants. 

Evaluation of seasonal vaccine preparations containing adjuvants is a priority, especially 

for use in populations in which vaccine response may be reduced. Development of new 

adjuvants and other dose-optimization techniques for use in a pandemic, when vaccine 

will be in short supply, is also needed and is best addressed now. 

Define evaluation criteria for vaccine efficacy testing. Many vaccine candidates—both 

new seasonal vaccines and vaccines against H5N1 AI—are now undergoing preclinical 

studies and, in some cases, Phase I clinical trials, but not all of these candidates can be 

tested in large efficacy trials. It is therefore important to carefully define the criteria that 

will be used to identify the most promising candidates to evaluate for efficacy. To allow 

comparison of assay results from different laboratories, it is imperative to standardize 

assays and reagents not only for well characterized correlates of protection such as virus 

neutralization, but for less well-defined correlates such as cellular and innate immune 

responses. 

F. Therapies 

Antiviral drugs and other therapies to reduce the severity of influenza outcomes have the 

potential to be important tools for controlling both seasonal and pandemic influenza 

epidemics. 

Expand studies of currently licensed antiviral drugs. Currently licensed influenza 

antivirals have been shown to modestly speed recovery from disease if given shortly after 

symptoms first appear. However, further study is required to clarify whether these drugs 

can be effective when administered to patients hospitalized with severe influenza, 

including patients with H5N1 AI; if so, dosing regimens would have to be optimized. 

Moreover, the mechanisms that result in resistance to these drugs should be explored 

further. 

Develop new drugs and new drug targets for influenza. Preclinical research, such as 

identifying new protein targets for antiviral therapy, should be pursued vigorously. 

Candidate compounds that do not directly block a viral protein but act indirectly, such as 
 

17 

by preventing the virus from disabling innate immune responses or by preventing 

aberrant cytokine signaling, should also be investigated. Clinical activities, including 

determining the optimal timing and dosing of antiviral candidates should follow as soon 

as feasible. Protocols and preparations for testing of candidate therapeutic interventions 

for pandemic influenza should occur in advance of need. 

Investigate therapies for late-stage, severe influenza. In many patients with severe 

influenza, disruptions of cytokine signaling occur days after viral titer has reached its 

peak. Such dysregulation is thought to be linked to severe influenza outcomes, but very 

little is known about how it occurs. Immunomodulatory and other therapies for use in 

patients with severe influenza or secondary infections should be explored. 

G. Assay Technologies 

New technologies for detecting and quantifying biomolecules such as DNA 

microarrays—chip-based arrays that can detect the presence of small concentrations of 

specific nucleotide sequences—are in the process of being converted from research tools 

into clinically useful products. Activities to speed development of new assay technologies 

for influenza should therefore be pursued. 

Develop new point-of-care diagnostic assays. During the Severe Acute Respiratory 

Syndrome (SARS) crisis, the lack of diagnostic assays capable of quickly and accurately 

identifying infected individuals soon after infection was keenly felt by public health 

authorities. Tools to rapidly and definitively identify people infected with a pandemic 

influenza virus would help to both slow the spread of the virus and maximize the 

effectiveness of stockpiled antivirals. Use of improved diagnostics during seasonal 

epidemics, especially those capable of diagnosing other common respiratory infections, 

would allow physicians to prescribe influenza drugs only for people who are actually 

infected, and would permit rapid identification of potential participants for clinical 

studies of influenza. 

Improve and standardize assays for cellular immune responses to influenza. Assays of 

specific T-cell responses, innate immune responses, and cytokine responses to influenza 

infection or vaccination are not as widely conducted or standardized as are antibody 

assays; indeed, many of the important cellular responses to influenza have yet to be fully 

described. But in order to facilitate measurement of these responses in a large number of 

influenza patients, the technology of the immune-function assays themselves must be 

improved. Improvements would include standardization to allow more valid comparison 

of results from different studies, decreased sample size requirements, automation, and 

improved access to necessary reagents. Currently available assays are too expensive for 

large-scale applications. Thus, it is important to develop technologies based on 

nanotechnology and microfluidics, which would use smaller volumes and could reduce 

costs. Moreover, if possible these assays should be adapted to allow physicians to predict 

more accurately which patients diagnosed with influenza are at highest risk for severe 

outcomes. 
 

18 

Improve methods for assaying immune responses in the respiratory tract. Current 

methods for obtaining samples from deep within the lungs, either to look for the evidence 

of infection or to assay specific immune responses for research purposes are highly 

invasive and not suitable for routine use. Other technologies, such as exhaled-breath 

analysis or advanced imaging, should be developed that would allow researchers to take 

samples or otherwise probe deep in the lungs of patients with influenza infection. 

Involvement of individuals with expertise in pulmonology would likely prove to be 

useful in this area. 

H. Resources 

NIAID currently provides many resources to the global influenza research community. 

Influenza research would benefit significantly from an expansion of resources provided 

by NIAID and other organizations. 

Expand the range of materials available to the research community. The range of 

materials pertinent to influenza which NIAID currently makes available to the research 

community could be expanded to include different virus strains (including strains suitable 

for use in human challenge studies), cDNAs, peptide arrays, monoclonal and polyclonal 

antibodies, purified proteins, and clinical specimens; if necessary, a scientific advisory 

committee could be established to determine priorities for access to limited materials in 

this reagent repository. 

Increase services for researchers. NIAID supports sequencing of influenza viral 

genomes in order to expand the availability of these sequences in publicly available 

databases, and provides in vitro and in vivo screening of compounds for antiviral activity. 

The establishment of a central laboratory at which samples relevant to clinical studies 

could be analyzed for a variety of immunologic responses would be a valuable addition to 

those services currently available. 

Improve mechanisms for the exchange of information among researchers. Mechanisms 

for the exchange of information and data among influenza researchers should be 

improved. Establishing accessible, integrated databases that combine clinical and 

genomic data from influenza patients, and encouraging adoption of standardized database 

architectures to permit appropriate data comparisons would be useful in this regard. In 

addition, NIAID could facilitate researchers’ access to the resources and services by 

consolidating information about all that it offers to influenza researchers at a single portal 

on the NIAID Web site. 
 

19 

V. APPENDICES 

A. Membership Roster of the Blue Ribbon Panel on Influenza Research 

Alan A. Aderem, Ph.D. 

Director 

Institute for Systems Biology 

Ann M. Arvin, M.D. 

Lucile Packard Professor of Pediatrics and 

Professor of Microbiology & Immunology 

Stanford University School of Medicine 

Jacques F. Banchereau, Ph.D. 

Director, Baylor Institute for Immunology Research 

Baylor University 

Robert B. Belshe, M.D. 

Professor and Director 

Division of Infectious Diseases and Immunology 

Saint Louis University School of Medicine 

Thomas J. Braciale, M.D., Ph.D. 

Director, Beirne Carter Center for Immunology Research 

University Of Virginia 

Carol A. Dahl, Ph.D. 

Director, Global Health Technologies 

Bill and Melinda Gates Foundation 

Mildred Donlon, Ph.D. 

Program Manager, Defense Sciences Office 

Defense Advanced Research Projects Agency 

Francis A. Ennis, M.D. 

Director, Center for Infectious Disease and Vaccine Research 

University of Massachusetts Medical School 

Claire Fraser-Liggett, Ph.D. 

President and Director 

The Institute for Genomic Research 

Keiji Fukuda, M.D., M.P.H. 

Coordinator, Global Influenza Program 

World Health Organization 
20 

Bruce Gellin, M.D., M.P.H. 

Director, National Vaccine Program Office 

Department of Health and Human Services 

Jesse Goodman, M.D., M.P.H. 

Director, Center for Biologics Evaluation and Research 

Food and Drug Administration 

Larry Granger, D.V.M. 

Associate Deputy Administrator 

Animal and Plant Health Inspection Service 

United States Department of Agriculture 

Harry B. Greenberg, M.D. 

Senior Associate Dean of Research and Training 

Acting Co-Chairman, Department of Medicine 

Stanford University School of Medicine 

Michael G. Katze, Ph.D. 

Associate Director for Molecular Sciences Washington National Primate Research Center 

University of Washington 

Yoshihiro Kawaoka, Ph.D., D.V.M. 

Professor, Department of Pathobiological Sciences 

School of Veterinary Medicine 

University of Wisconsin-Madison 

Paul S. Keim, Ph.D. 

Director of Pathogen Genomics, The Translational Genomics Research Institute 

The Cowden Endowed Chair in Microbiology 

Northern Arizona University 

Arthur M. Krieg, M.D. 

President and Chief Executive Officer 

Coley Pharmaceuticals 

Robert M. Krug, Ph.D. 

Professor of Molecular Genetics and Microbiology 

Institute for Cellular and Molecular Biology 

University of Texas at Austin 

Robert A. Lamb, Ph.D., Sc.D. 

John Evans Professor of Molecular and Cellular Biology 

Northwestern University 
21 

James W. Le Duc, Ph.D. 

Influenza Coordinator 

Centers for Disease Control and Prevention 

David Lipman, M.D. 

Director, National Center of Biotechnology Information 

National Library of Medicine, NIH 

Richard M. Locksley, M.D. 

Sandler Distinguished Professor of Medicine and Microbiology/Immunology 

Director, Sandler Asthma Basic Research Center 

University of California, San Francisco 

Philippa C. Marrack, Ph.D. 

Professor, Integrated Department of Immunology 

National Jewish Medical and Research Center and University of Colorado at Denver 

Health Sciences Center 

Peter M. Palese, Ph.D. 

Professor and Chair 

Department of Microbiology 

Mount Sinai School of Medicine 

Ellis L. Reinherz, M.D. 

Professor of Medicine 

Harvard Medical School 

Chief, Laboratory of Immunobiology 

Dana Farber Cancer Institute 

Martin Rosenberg, Ph.D. 

Chief Scientific Officer 

Promega Corporation 

Kathy L. Rowlen, Ph.D. 

Professor of Chemistry 

University of Colorado, Boulder 

Chief Science Officer 

InDevR, LLC 

Alessandro D. Sette, Dr. Sc. Biol. 

Head, Division of Vaccine Discovery 

Director, Center for Emerging Diseases and Biodefense 

La Jolla Institute for Allergy and Immunology 
22 

Derek R. Smith, M.D. 

Clinical Assistant Professor 

Harvard Medical School 

Director, MS Care of Connecticut 

John Treanor, M.D. 

Professor of Medicine, and of Microbiology and Immunology 

University of Rochester School of Medicine and Dentistry 

Rajeev Venkayya, M.D. 

Special Assistant to the President for Biodefense 

White House Homeland Security Council 

Bruce D. Walker, M.D. 

Professor of Medicine 

Harvard Medical School 

Director, Partners AIDS Research Center at Massachusetts General Hospital 

Robert Webster, Ph.D. 

Rose Marie Thomas Chair 

Department of Infectious Diseases 

St. Jude Children’s Research Hospital 

Richard Whitley, M.D. 

Director, Division of Pediatric Infectious Diseases 

The University of Alabama at Birmingham 
 

23 

B. NIAID Attendees of the Meeting of the Blue Ribbon Panel on Influenza Research 

Office of the Director 

Anthony Fauci, M.D. 

Director 

Hugh Auchincloss, M.D. 

Principal Deputy Director 

H. Clifford Lane, M.D. 

Deputy Director for Clinical Research 

and Special Projects 

John McGowan, Ph.D. 

Deputy Director for Science Management 

Hillery Harvey, Ph.D. 

Special Assistant to the Director 

Carole Hudgings, Ph.D. 

Senior Advisor to the Deputy Director 

Robert J. Taylor, Ph.D.* 

Analyst∗

Division of Clinical Research 

John Beigel, M.D. 

Staff Clinician 

Critical Care Medicine Department 

Elizabeth Higgs, M.D., DTMH, MIA 

Deputy, Collaborative Clinical Research Branch 

Office of Strategic Planning and Financial Management 

Ralph Tate 

Acting Chief, Mission Planning and Integration 

Branch 

Karin Lohman, Ph.D. 

Acting Chief, Strategic Planning and Evaluation 

Branch 

∗

 Contractor 
 

24 

Michele Aleibar 

Program Specialist 

Cheryl Silver* 

Health Policy Analyst 

Division of Acquired Immunodeficiency Syndrome 

Ed Tramont, M.D. 

Director 

Rodney Hoff, D.Sc., M.P.H. 

Chief, International Research Branch 

Sandra Lehrman, M.D., Ph.D. 

Director, Therapeutics Research Program 

Gerald Sharp, Dr.P.H. 

Epidemiologist 

Division of Allergy, Immunology, and Transplantation 

Daniel Rotrosen, M.D. 

Director 

Chuck Hackett, Ph.D. 

Deputy Director 

Lynda Chiodetti, Ph.D. 

Chief, Molecular and Structural Immunology 

Section 

Richard Hatchett, M.D. 

Associate Director for Radiation Countermeasures 

 Research and Emergency Preparedness 

Helen Quill, Ph.D. 

Director of Therapeutics Research Program 

*

 Contractor 
 

25 

Division of Microbiology and Infectious Diseases 

Carole Heilman, Ph.D. 

Director 

Linda Engel* 

Special Assistant to the Director 

Irene Glowinski, Ph.D. 

Director, Office of Scientific Coordination and 

 Program Operations (OSCPO) 

Catherine Laughlin, Ph.D. 

Chief, Virology Branch 

Barbara Mulach, Ph.D. 

Acting Chief, Policy, Legislation and 

 Communications Section, OSCPO 

Linda C. Lambert, Ph.D. 

Chief, Respiratory Diseases Branch (RDB) 

Maria Y. Giovanni, Ph.D. 

Assistant Director for Microbial Genomics and 

Advanced Technology 

Diane Hulse-Post, Ph.D. 

Influenza Program Officer, RDB 

Sonnie Kim, M.S. 

Program Officer, Influenza Clinical Trials, RDB 

Karen Lacourciere, Ph.D. 

Program Officer, Basic Influenza Research, 

RDB 

Roland Levendowski, M.D. 

Chief, Influenza, SARS, and Other Viral 

 Respiratory Diseases Section, RDB 

*

 Contractor 
26 

Division of Intramural Research 

Kathy Zoon, Ph.D. 

Director 

Kanta Subbarao, M.D., M.P.H. 

Senior Investigator 

Laboratory of Infectious Diseases 

Jeff Taubenberger, M.D., Ph.D., 

Senior Investigator 

Laboratory of Infectious Diseases 

Lone Simonsen, Ph.D. 

Senior Epidemiologist 

Vaccine Research Center 

Gary Nabel, M.D., Ph.D. 

Director 

Barney Graham, M.D., Ph.D. 

Chief, Viral Pathogenesis Laboratory 

Office of Global Research 

Karl Western, M.D. 

Acting Director 
27 

C. Summary of Major NIAID Influenza Research Activities, by Division 

EXTRAMURAL RESEARCH ACTIVITIES 

Division of Microbiology and Infectious Diseases (DMID) 

DMID is the lead NIAID Division for influenza research, and supports a large portfolio 

of influenza research projects that will lead to more effective approaches to control 

influenza virus infections. These projects include 

•	 Basic research on virus structure and function, viral pathogenesis, and host 

responses to infection 

•	 Epidemiologic studies on the natural history and ecology of influenza viruses 

among birds and other animals 

•	 Vaccine development and evaluation 

•	 Improved vaccine delivery 

•	 Drug discovery and evaluation 

•	 Development of diagnostic technologies 

Taken together, DMID activities constitute the major portion of the overall NIAID 

influenza research effort. 

Biology of the Virus and Host Response. DMID-funded basic research projects in 

influenza cover a comprehensive array of studies of the biology of influenza virus and the 

host response to it, including topics in virology, pathogenesis, immunology, and 

genomics. The DMID portfolio of basic research grants in influenza has expanded 

substantially in recent years to more than 100 grants. This expansion has been due in 

large measure to specific requests for applications and other solicitations DMID has 

issued, and the resurgence of interest in influenza since the first human cases of H5N1 AI 

in 1997. 

Much of this research is funded through grants to individual investigators at academic 

institutions and in industry; such grant applications are evaluated by a variety of study 

sections. Topics include 

•	 Structure/function studies, including binding of inhibitors, role of M1 motifs in 

viral budding, viral fusion 

•	 Viral replication, including factors that allow viral entry into host cells, viral RNA 

synthesis and virus particle assembly 

•	 Viral evolution, including molecular modeling to predict antigenic drift, 

emergence 

•	 Identification of virulence factors 

•	 Evaluation of role of immunomodulators (e.g., TGFβ) in virulence 

•	 Factors leading to interspecies adaptation and drug resistance 

•	 Characterization of strain-specific binding properties and host range 

•	 Genomic and proteomic analysis of host genes following infection 

•	 Innate immune responses 

•	 Monocyte and dendritic cell processing of influenza antigens 
28 

•	 Cellular immune responses, including CD8+ and CD4+ response and regulation, 

T-cell epitopes of core proteins, generation of memory CD8+ cells 

•	 Humoral immune responses, including induction, generation, and maintenance of 

influenza-specific B cell subsets 

NIAID funds a center on “Influenza Immunity: Protective Mechanisms against a 

Pandemic Respiratory Virus” under the Cooperative Centers for Translational Research 

on Human Immunology and Biodefense program. This center studies both vaccineinduced and naturally acquired immune responses to influenza A in children and adults. 

Specific topics studied at this center encompass innate, natural killer cell responses to 

influenza and the acquisition of adaptive immunity. 

In addition to grant support, some DMID research is conducted under contract. For 

example, DMID has a long-standing “Pandemic Preparedness in Asia” contract with St. 

Jude Children’s Research Hospital (Robert Webster, PI) not only to conduct surveillance 

for viruses with pandemic potential in China and other countries in Southeast Asia, but 

also to carry out research on the viral, host, and other factors that affect the evolution of 

influenza viruses in animal and human populations, to supply reagents for influenza 

research to the broader research community, and to conduct training to build research 

capacity abroad. 

DMID has expanded the number of contract influenza research centers from one to six. 

These new “Centers of Excellence for Influenza Research and Surveillance” will conduct 

surveillance in animals for influenza viruses with pandemic potential and carry out 

research into the factors that influence the properties of influenza viruses and host 

immune responses. 

DMID also supports the “Influenza Genome Sequencing Project” in collaboration with 

the National Center for Biotechnology Information and The Institute for Genomic 

Research (TIGR). The project is intended to increase the number of influenza genomic 

sequences in the public domain by supporting determination of complete genome 

sequences of influenza viruses submitted by domestic and international researchers. All 

sequence data generated by this initiative are released immediately to the public domain, 

so that they can be independently analyzed by researchers throughout the world. 

Targeted Development of New Products. DMID supports many efforts intended to 

accelerate the development of influenza vaccines, antiviral drugs, and diagnostics. These 

activities are funded by grants, cooperative agreements, and contracts. They are directed 

toward all stages of the development process, from the earliest proof-of-concept studies 

for a new influenza vaccine strategy to the purchase of doses for clinical trials of 

candidate vaccines and vaccine adjuvants for use against H5N1 and other influenza 

strains with pandemic potential. 

Representative examples of DMID research support intended to accelerate development 

of new influenza vaccines, therapeutics, and diagnostics include 
29 

•	 Vaccines 

- An inactivated nasal powder vaccine (Delsite Biotechnologies) 

- Novel cell-culture derived split influenza vaccine (ID Biomedical) 

- Replication-Defective Adenovirus-Vectored Pandemic Influenza (Vaxin) 

- M2 peptide-based “universal” vaccines against influenza (Washington 

University) 

•	 Therapeutics 

- Ion Channel Assay for Identifying Influenza Therapeutics (Integral 

Molecular) 

- Development of siRNAs to Prevent and Treat Influenza Infection 

(Galenea) 

- Identifying Broad-Spectrum Influenza Virus Inhibitors (Nexbio) 

- Inhalable IgG Synthesis For Influenza Immuno-prophylaxis (Aktiv-Dry) 

•	 Diagnostics 

- DNA/RNA Multiplex Platform for Detection and Sub-typing (U. 

Colorado) 

- Multiplex Immunoassay Platform for Respiratory Viruses (Lawrence 

Livermore) 

- New DNA genotyping chip-based technology (TIGR) 

Clinical Testing. DMID also supports clinical testing of new and currently-licensed 

influenza vaccines and antivirals through its clinical networks. Examples of these studies 

include 

•	 Safety and immunogenicity trials of inactivated H5N1 vaccines with and without 

adjuvants and alternate routes of administration 

•	 Safety and immunogenicity trial of inactivated H9N2 vaccine with adjuvant 

•	 Efficacy of combination oseltamivir and rimantadine for seasonal influenza 

•	 Oseltamivir in infants 

Influenza Research Resources. DMID supports three programs that provide resources 

and services relevant to influenza research. 

•	 Antimicrobial Acquisition and Coordinating Facility (AACF). This facility 

screens compounds for activity against a variety of viruses, including influenza. 

After a simple application process, compounds are first screened in vitro; to date, 

more than 3500 compounds submitted by more than 80 different organizations 

have been screened in vitro for activity against influenza viruses. If results 

warrant, compounds can also be tested in mice by AACF, and in ferrets through a 

separate DMID contract mechanism. 

•	 Vaccine and Treatment Evaluation Units (VTEUs). DMID supports a network of 

sites at university research hospitals across the United States to conduct Phase I 

and II clinical trials of candidate vaccines and treatments for infectious diseases, 

including influenza. Candidate H5N1 AI inactivated vaccines have already been 

tested through the VTEUs, and trials of other H5N1 candidates, including 

adjuvanted formulations, are under way or planned. 
30 

•	 Biodefense & Emerging Infections Research Resources Repository. This 

repository provides many reagents relevant to influenza research, including 

purified influenza proteins; monoclonal antibodies (including antibodies that bind 

H5 antigens), human sera, viral isolates (including influenza vaccine strains), and 

peptides for epitope mapping. 

Division of Allergy, Immunology, and Transplantation (DAIT) 

DAIT research focuses on the role of the immune system in health and disease. In that 

role, DAIT supports some research specific to influenza, as well as many other basic 

studies that are relevant to understanding influenza pathogenesis and immunology, and to 

the development of new vaccines, vaccine adjuvants, and immune-based therapies. 

Biology of the Host Immune Response. DAIT-funded basic research projects cover a 

comprehensive array of studies of the host immune response to influenza. Much of this 

research is funded through grants to individual investigators at academic institutions and 

in industry; such grant applications are evaluated by a variety of study sections. Topics 

include 

•	 Studies of B-cell and T-cell responses to influenza infection 

•	 B-cell and T-cell immune memory following influenza infection or vaccination 

•	 The role of the influenza NS1 protein in evasion of the immune response 

•	 Processing and presentation of influenza antigens to immune cells 

•	 Innate immune responses to influenza 

In addition to unsolicited research projects, solicited programs that encompass influenza 

research include 

•	 Cooperative Centers for Translational Research on Human Immunology and 

Biodefense, some of which study H5N1 adaptive immunity 

•	 Innate Immune Receptors and Adjuvant Discovery, with studies on new adjuvants 

for influenza vaccines 

•	 Immunity and Biodefense in Children, Elderly, and Immunocompromised 

Populations, with studies of immune responses to influenza vaccination in 

children, pregnant women, the elderly, and patients on immunosuppressive 

therapies for autoimmune disease or organ or tissue transplant 

•	 Modeling Immunity for Biodefense, including the mathematical modeling of 

innate and adaptive immune responses to influenza infection, validated through 

direct laboratory experimentation in animal systems and vaccinated humans 

•	 Epitope Discovery Program, to map CD4 and CD8 T-cell epitopes for influenza 

•	 Asthma and Allergy Centers, with studies on influenza-induced airway 

inflammation 

•	 Population Genetics Analysis Program: Immunity to Vaccines/Infections, 

including a study on immune response gene variations associated with outcomes 

of influenza infection 
31 

Influenza Research Resources. DAIT also supports programs that provide resources 

and reagents to the research community, including influenza researchers. These programs 

include 

•	 The Immune Epitope Database and Analysis Program, which maintains a 

comprehensive database of antibody and T-cell epitopes and provides tools for the 

analysis of antibody and T-cell epitopes from many pathogens, including 

numerous strains of influenza 

•	 The NIH Tetramer Facility, which produces MHC-peptide tetramers from many 

pathogens, including 5 pre-made MHC class II-influenza peptide tetramers and 

custom-made MHC class I and class II tetramers for detection of influenzaspecific T-cells 

•	 The Systems Approach to Innate Immunity Program, which provides tools to 

characterize innate immune responses to influenza infection, such as antibodies, 

protein expression vectors, data analysis tools, and genetically-engineered mice 

Animal resources that could be used more extensively for influenza research include the 

National Swine Research and Resource Center, specific-pathogen-free (SPF) Macaque 

Breeding Colonies, and the Nonhuman Primate Reagent Resource Development program. 

Division of Acquired Immune Deficiency Syndrome (DAIDS) 

Because DAIDS focuses on HIV/AIDS, it has not supported a great deal of influenza 

research. However, DAIDS is currently expanding its activities relevant to influenza: 

•	 DAIDS is adapting long-running cohorts studies, including the Women’s 

Interagency Cohort Study (WIHS) and the Multi-center Aids Cohort Study 

(MACS), to study the effects of influenza in HIV-positive populations; protocols 

being prepared to make use of these cohorts will help to elucidate the 

consequences of both seasonal and pandemic influenza in people with HIV 

infection, as well as provide information relevant to influenza epidemiology in the 

population as a whole. 

•	 DAIDS is preparing its research infrastructure in China and elsewhere in South 

East Asia to help monitor for the emergence of influenza strains with pandemic 

potential. Similar efforts could be undertaken at DAIDS-supported research 

facilities in Africa as well. 

•	 A DAIDS master contract with Chiron was adapted to fund the manufacture of 

adjuvanted inactivated H5N1 influenza vaccines. 
 

32 

INTRAMURAL RESEARCH ACTIVITIES 

Division of Intramural Research (DIR) 

DIR researchers are studying the basic biology of influenza, including its pathogenesis, 

immunogenicity and genetic variability; investigating host immune responses to the virus 

in animal models and in humans; and developing vaccines to prevent influenza, 

especially strains with pandemic potential. 

Influenza is a primary research focus of four DIR laboratories: 

•	 The Respiratory Viruses Section of the Laboratory of Infectious Diseases (LID) is 

focused on pandemic influenza vaccine development. This section conducted the 

fundamental research that led to the development of the live-attenuated influenza 

vaccine manufactured by MedImmune. Currently, under a Cooperative Research 

and Development Agreement (CRADA), LID and MedImmune scientists are 

generating candidate, live-attenuated vaccines for a broad range of influenza 

subtypes with pandemic potential and evaluating them in preclinical studies and 

clinical trials. Analysis of data from a phase I trial of a live-attenuated H9N2 

vaccine is nearing completion, and a trial of a similar H5N1 vaccine began in 

June, 2006. The LID Respiratory Viruses Section also conducts studies of the 

basic biology of influenza virus, including the factors that influence virulence, 

immunogenicity, transmissibility, and susceptibility of various host species. 

•	 The Molecular Pathogenesis and Epidemiology of Influenza Section in LID was 

established in June 2006 when Jeffery Taubenberger, formerly of the Department 

of Molecular Pathology at the Armed Forces Institute of Pathology (AFIP) in 

Rockville, MD joined LID. This section will study the pathogenesis of influenza 

in diverse host species; influenza virus evolution and adaptation, especially the 

factors that lead to the emergence of pandemic strains; and the molecular basis for 

virulence of highly pathogenic influenza viruses, including the 1918 pandemic 

strain and H5N1 viruses. 

•	 The Cellular Biology and Viral Immunology Sections of the Laboratory of Viral 

Diseases (LVD) investigate basic aspects of the interaction of influenza A viruses 

with the host immune system to enable rational design of vaccines capable of 

eliciting optimal immunity. Specific topics include the cell biology of viral 

peptide generation and presentation to T-cells, the induction and regulation of Tcell anti-viral responses, the mechanism of antigenic drift in viral glycoproteins 

and the contribution of the accessory protein PB1-F2 to viral pathogenesis. 

•	 The Epidemiology Unit of the Office of Global Affairs joined the Epidemiology 

Section of the Laboratory of Infectious Diseases in June 2006. This group has 

studied historic patterns of pandemic and seasonal influenza mortality worldwide; 

the epidemiology of influenza vaccines, including efficacy in the elderly and the 

generation of herd immunity; and population-level trends in circulating influenza 

viruses such as the emergence and spread of antiviral resistance. 

Division of Clinical Research (DCR) 

The Division of Clinical Research (DCR) conducts clinical studies within NIAID’s 

Division of Intramural Research (DIR) and collaborates with clinical trial networks 
33 

worldwide to develop vaccines, therapeutics and diagnostics. DCR influenza research 

activities center on two international networks: 

•	 DCR recently initiated a multilateral collaborative program with the Wellcome 

Trust, Oxford University, WHO and researchers in Thailand, Vietnam, and 

Indonesia to establish the South East Asia (SEA) Influenza Clinical Research 

Network. The initial focus of the network is influenza, with a strong emphasis on 

building independent clinical research capacity in the region. A clinical trial to 

evaluate high-dose oseltamivir compared to standard dose against severe 

influenza is under way, and pharmacokinetic studies of intravenous Zanamivir, 

with and without Oseltamivir, are being planned. 

•	 The Department of Defense (DoD) maintains a large network of domestic and 

international sites for the clinical study of emerging infectious diseases. In 

September 2005 NIAID signed an Inter-agency Agreement (IAA) with 

Uniformed Services University of the Health Sciences (USUHS) to establish a 

NIAID/DOD Emerging Infectious Disease clinical research program. DCR is 

currently collaborating with DoD to develop an influenza research agenda that 

uses the DoD network. 

Vaccine Research Center (VRC) 

The primary focus of activities at the VRC remains the development of an effective 

HIV/AIDS vaccine. Over the last several years the VRC research program has also 

expanded its programs to include vaccine development for Ebola, SARS, West Nile Virus 

and Influenza. VRC scientific approaches and technology platforms have a time horizon of 

1 to 5 years, and include development of novel vaccine platforms as well as basic research 

questions related to the breadth of neutralizing antibodies, heterosubtypic immunity, the 

strengths of different vaccine platforms, and the relative contributions to protection of 

cellular and humoral immunity. This work builds on VRC capabilities in immunology, 

structural biology, and vaccine production. VRC contributions to the NIAID influenza 

program include 

•	 Development of novel gene-based and recombinant protein-based 

platforms 

•	 Identification of shared epitopes/serotypes 

•	 Generation of antiviral compounds and monoclonal antibodies 

•	 Evaluation of breadth and structural diversity of neutralizing antibodies, and 

assessment of the role of cellular immunity in cross-strain immunity 

Three new vaccines have been developed at the VRC, each composed of a single plasmid 

DNA encoding hemagglutinin (HA) protein from H1N1, H3N2 and H5N1 subtypes 

isolated from recent human outbreaks of influenza. In future, the list of targeted genes 

may increase to include all common variants of hemagglutinin, neuraminidase, and ion 

channel genes (HA, NA, and M2). AVRC H5 subtype DNA vaccine candidate entered 

Phase I clinical trials in December 2006.