Dean's Newsletter

Archive of previous newsletters

The "Flu Grant"

April 11 , 2007

Seven million people died in the Great War
A bout of influenza quadrupled that score
Why pimp to posterity?
Why should they admire us? All the heroes of Valhalla
Weigh less than a virus
    Verse from Momus, "Morality is Vanity"
    In "Monsters Of Love" (1990)

Last week, NIH announced that it would fund six Centers nationally to study the flu. Under the leadership of Drs. John Treanor and David Topham, and with the expertise of a large number of faculty co-investigators, Rochester will be one of these Centers. Over the next seven years, we will receive $26 million (!) to conduct studies that will improve our understanding of the biology of the virus and of our immune response to influenza viruses and vaccines.

A key goal of this research is to learn enough about the virology and immunology of influenza to prevent the next pandemic. As referenced in the Momus song, the influenza epidemic of 1918 killed 20-30 million people by various accounts. But do we really have to worry about a pandemic these days? The "Spanish Flu" epidemic of 1918 was almost a century ago; don't we now have vaccines that are tailored each year to the predominant viral strain? Why the renewed interest in flu research in general, and the major increase in NIH funding? The answer lies in the emergence of bird flu as a potential basis for another devastating world pandemic. Indeed, as will be described below, there is now evidence that the 1918 influenza virus was a strain that originated in birds.

In this newsletter I will try to convey the excitement about this extraordinary grant coming to Rochester and to acquaint you with the faculty behind it. As a backdrop, however, it is probably useful to provide some background on flu and bird flu.

Background

Influenza is caused by a virus--chains of genetic material lumped inside a protein coat. Viruses are not plants, animals, or bacteria. Rather, they are quintessential parasites. Although they seem like living organisms because of their prodigious reproductive abilities, viruses are not living organisms in the sense that they cannot carry out life-sustaining functions or reproduce without a host cell. They cannot synthesize proteins, because they lack ribosomes and must use the ribosomes of host cells to translate viral messenger RNA into viral proteins. Viruses cannot generate or store energy, deriving their energy, and all other metabolic functions, from the host cell. They also parasitize the cell for basic building materials, such as amino acids, nucleotides, and lipids. Thus, host cells are innocent victims infiltrated by the virus to commandeer its machinery to make new viral particles.

Viruses are generally classified by the type of genetic material they contain (DNA or RNA) and by the organisms they infect--animals, plants, or bacteria. The influenza virus is an RNA virus that infects animals. Indeed, part of the reason that influenza virus is so difficult to control is that its infectivity is not limited to human populations. Various strains of the virus can infect pigs, horses, and birds (including chickens). Sometimes, a pig or chicken can even become infected with more than one strain of influenza. When that happens, the viruses may "share" genetic information, creating a whole new influenza strain. These new strains of influenza can be very dangerous, because the more different the new virus is from its "parents," the less likely it is that people will have immune defenses against it. Next stop--worldwide pandemic.

The reason that influenza epidemics and pandemics often begin in Asia is the close contact between human and animal populations in rural China. When people work on or near farms with pigs and chickens, influenza viruses can spread between species, thereby leading to a new form of influenza that may cause an epidemic or pandemic.

Imagine an international influenza epidemic that infected 20% to 40% of the world's population. More than 20 million people dead in 18 months--about 2.5-5% of the world's population--about 500,000 of them in the United States alone. This is what happened in 1918. Between September 1918 and April 1919, the Spanish Flu* devastated communities all around the world. It attacked young and old alike, sometimes with shocking speed. Victims were often said to wake up feeling perfectly healthy, and fall ill and die by the end of the day. Others might survive the initial illness, only to develop pneumonia and die days or weeks later. Doctors, nurses, and emergency workers were particularly hard-hit. Then, in the spring of 1919, the epidemic faded away and did not return.
[*It is interesting to note that the first cases of influenza in 1918 were discovered in Haskell County, Kansas, but the Allies of WW1 came to call it the "Spanish Flu" because the pandemic received greater press attention in Spain than in the rest of the world, as Spain was not involved in the war and had not imposed wartime censorship.]

The Spanish Flu was an unusually severe influenza pandemic, but it was not the first or last one. The Asian Flu epidemic of 1957-1958 and the epidemics of Hong Kong Flu that struck in 1968-1969 and again in 1970 and 1972 show how easy it is for influenza to spread among people who lack immunity to a new strain of virus. With frequent airline travel linking the global community ever more closely, a new strain of influenza could travel around the world in a very short time.

Now for some terminology that will lead us to bird flu and the flu grant. Influenza A viruses are classified by their "HA" and "NA" strands, which code for Hemagglutinin and Neuraminidase proteins, respectively. Hemagglutinin is an antigenic glycoprotein found on the surface the virus that is responsible for binding the virus to the cell being infected. Neuraminidase is an antigenic enzyme, also found on the surface of the virus, that facilitates the release of progeny viruses from infected cells. The HA and NA RNA strands specify the structure of proteins that are most medically relevant as targets for antiviral drugs and antibodies. HA and NA are also used as the basis for the naming of the different subtypes of influenza A viruses. The Avian or Bird Flu virus is an H5N1 virus. H1N1 caused "Spanish flu," H2N2 caused "Asian flu," and H3N2 caused "Hong Kong flu.

Bird Flu H5N1 normally does not infect humans. But the current human infections have caused worry as the virus has changed or shifted so that man can be infected. So far, the virus is hard to contract in humans unless they have close contact with infected poultry, droppings, or dead birds. But this can change as the virus mutates, a worry accentuated by the recent finding that the1918 virus shares genetic mutations with the Bird Flu H5N1 virus. Thus far, once infected with the H5N1 virus, the human mortality rate is about 50%.

The Flu Grant--The New York Influenza Center of Excellence

John J. Treanor, MD

John J. Treanor, MD, Professor of Medicine, and of Microbiology & Immunology, is Principal Investigator on Rochester's NIH flu grant, which establishes the New York Influenza Center of Excellence. Dr. Treanor is a home-grown physician-scientist, graduating from medical school here in 1979. After residency in Internal Medicine at the University of Vermont, John returned for his fellowship in Infectious Disease. Dr. Treanor was then awarded an NIH K23 career development grant, and completed a Senior Staff fellowship at the NIAID Laboratory of Infectious Diseases, where he worked with Dr. Brian Murphy on projects to assess the molecular mechanisms of avian influenza virus host range and the potential use of avian influenza viruses as human vaccines. He returned to UR as a faculty member in 1989, and became director of the Vaccines and Treatments Evaluation Unit (VTEU) in 1994. Dr. Treanor has now established himself internationally as one of the foremost experts in the clinical evaluation of vaccines and antiviral agents for a variety of respiratory pathogens.

In 2005, John expected that an RFP on influenza would be issued at some point from NIH, with a focus on Bird Flu. Until that point, NIH had supported one avian surveillance center at St. Jude's in Memphis, and rumor had it that NIH would add one more Center that would focus on pathogenesis. But when the RFP was issued in November, 2005, it indicated that several Centers would be funded. John was not optimistic that we would have much of a chance, but an immunologist and collaborator, David Topham, PhD, convinced him that we were underselling ourselves and that Rochester's broad array of expertise--in clinical vaccine research, immunology, virology, vaccine biology, and mathematical modeling of immune processes--would make us uniquely competitive for the grant.

David Topham, PhD

Dr. Topham is Associate Professor of Microbiology & Immunology in the David H. Smith Center for Vaccine Biology and Immunology. He received his Ph.D, in Cell & Molecular Biology from the University of Vermont in 1994 and was trained subsequently in the laboratory of Dr. Peter Doherty, a Nobel Laureate in Medicine for his work on cytotoxic T cells. David has now accumulated over 10 years of experience in viral immunology, with NIH funding and numerous publications on the CD4 and CD8 T cell responses to influenza and parainfluenza virus infections. Highly relevant to the flu grant, David is also a member of the UR Center for Biodefense Immune Modeling, an NIH grant to develop mathematical models of the immune responses to influenza virus infection in animal models and humans. (Hulin Wu, PhD, is PI on the immune modeling grant, and is co-investigator on the flu grant, providing statistical expertise.) Dr. Topham was truly the galvanizing force that brought Rochester faculty together and convinced them that a team from Rochester would indeed bring a unique set of skills to the flu consortium.

The Rochester team describe their conceptualization of the problem as follows: "The central problem in developing more effective control of influenza is that antigenic variation in influenza viruses has prevented our ability to provide durable, broadly cross-protective immunity with a single vaccine. Instead, we rely on a strategy of yearly vaccination with vaccines carefully crafted to match the particular antigenic variant predicted to be the predominant viruses in the coming epidemic season. The very short time between identification of new variants and the need for a fully manufactured vaccine, and the requirement to essentially make a new product every year, puts enormous strain on our ability to provide adequate amounts of vaccine in a timely fashion, and the result is frequent delays in vaccine availability, shortages, and antigenic mismatches. In addition, this situation prevents effective stockpiling of vaccines ahead of a pandemic, creating logistic problems that are conceded to mean that vaccines will not be able to contain the first wave of any pandemic effectively."

To address these problems, the New York Influenza Center of Excellence (NYICE) will work to overcome two major problems: that current vaccines do not provide durable and broadly cross protective immunity, precluding effective stockpiling and requiring yearly vaccination; and that the exact features of avian influenza viruses that control species specificity are poorly understood. "Our goal," as they state in the grant, "is to provide a truly transforming approach to influenza research."

The grant consists of 5 research projects supported by 3 cores: bioinformatics (Jingming Ma, PhD), Statistics (Hulin Wu, PhD) and Quality Assurance (Sally Quataert, PhD).

Project 1 (PI: David Topham, PhD) will focus on an analysis of cross-reactive cell-mediated immunity (CMI) against influenza in humans, on the development of markers of tissue-memory human T cells, and on the creation of an improved animal model for studying CD4 T cell mediated influenza immunity in mice. Project 2 (PI: Andrea Sant, PhD) will examine the antigen specificity of CD4 T cell that are elicited and that persist in humans responding to natural influenza infection or live vaccine. Transgenic mice will then be used to identify the immunodominance patterns and fine specificity of influenza specific CD4 T cells and to characterize the B cell responses elicited in response to vaccines or influenza challenge. These data in mice will be correlated with the results seen in humans. Using these transgenic mouse models, we will gain an understanding of the factors governing the effectiveness of CD4 T cells in potentiating antibody responses.

These studies on CD4 T cell protection and memory (project 1) and immunodominance (project 2) will be further complemented by experiments in Project 3 (PI: Tim Mosmann, PhD), which will address the difficult choices and compromises made by the immune system regarding which types of effector mechanism to deploy: immune responses must be strong enough to destroy pathogens, but not so strong that host tissues are irreparably damaged. In some infections, possibly including influenza, much of the damage to host tissues may be caused by the immune system rather than directly by the pathogen. Project 3 will thus focus on the regulation of the balance between attack on pathogens and protection of host tissue, by examining T helper effector cytokine profiles in response to different forms of immunization or infection. Ultimately, the data from these three projects will inform the design of the next generation of influenza vaccines for both conventional and pandemic influenza.

At the same time, NYICE will aggressively pursue a series of studies to understand fully the role of critically important mutations in adaptation of avian influenza A viruses to mammals. Project 4 (PI, Dr. Gary Whittaker, Cornell) targets the changes in HA that are necessary for emergence of viruses from avian to mammalian species, with a focus on the events controlling fusion activation. Project 5 (Investigators: Steve Dewhurst, PhD, Beak Kim, PhD and Toru Takimoto, PhD) will focus on the residues in the viral polymerase associated with changes in catalytic activity, and on the interaction with cell cofactors and pathogenicity in mice, to reveal the molecular mechanism of mammalian host adaptation and virus mutability. These studies are expected to contribute to the identification of avian viruses in the field that may be associated with pandemic potential, as well as potentially leading to new strategies to develop antivirals and other control measures.

In his remarks at the Press Conference announcing the Flu Grant, Dr. Treanor emphasized that the culture we have created at the medical school is one of collaboration. He stated that the team of investigators in the NYICE at Rochester--which extends across many Departments and Centers--will create a research enterprise that will be greater than the sum of its individual parts. It is easy for a Dean to talk about collaboration, but a grant of this magnitude drives the point home and brings real meaning to the words.

On that note, I will end by quoting Dr. Mosmann, who when asked about his role in the grant (without any reference to collaboration), responded as follows: "Over the last several years, our lab has moved from basic mouse immunology towards research in human immunology, particularly in respiratory virus infections. This has been greatly assisted by the collaborative environment at URMC, particularly with clinical researchers in the divisions of Infectious Diseases, and Allergy, Immunology and Rheumatology. These interactions are fruitful for progress towards understanding disease, and also fit very well with the NIH Roadmap and the URMC emphasis on translational research. The RFP for research on potentially pandemic influenza offered a welcome opportunity to extend our previous studies on influenza and RSV, and analyze the types of effector functions induced by influenza infections and vaccines. This was a particularly good fit with the interests of several other research groups with complementary interests in the immunology, virology and vaccinology of influenza infection. Together with Dave Topham's energy in initiating and continuing the discussions around the application, and John Treanor's wealth of experience in influenza vaccines, this complementarity of interests made the writing of the application a pleasure."

Meliora,

David S. Guzick, MD, PhD
Dean, School of Medicine and Dentistry