New York Influenza Center of Excellence

Welcome

NYICE PROGRAM OVERVIEW

NYICE is Directed by Drs. John Treanor and David Topham.

The overall structure of NYICE is shown in the figure below:

Scope of the influenza problem

Influenza virus was first identified as the cause of the syndrome of influenza in 1933 [1] and in the intervening 70 years much has been learned regarding the biology of these viruses, their epidemiology, and the immune mechanisms that are responsible for protection. In spite of this, influenza continues to represent an important, poorly controlled public health problem in the United States and elsewhere. Estimates are that each year, influenza is responsible for 40,000 deaths in the United States and up to 150,000 hospitalizations, making influenza the most common cause of vaccine-preventable morbidity and mortality [12, 13] .

The world currently faces an unprecedented threat of a new pandemic, as avian viruses of the H5N1 subtype continue to spread throughout the world along the flyways of migratory waterfowl, with ever increasing risk of transmission to humans and of the development of as yet unidentified mutations that might result in effective person to person transmission. The available vaccines for H5N1 influenza appear to be very poorly immunogenic in man [14, 15] , and the continued antigenic variation in H5 viruses precludes the ability to stockpile an optimally effective vaccine in advance of a pandemic. These developments suggest that our ability to control pandemic influenza may not be very much different today than it was in 1957, despite the incredible explosion of basic science information available.

NYICE and the influenza problem

Two major roadblocks can be identified that have hindered efforts to be better prepared for the next pandemic of influenza. First, current vaccines do not provide durable and broadly cross protective immunity, precluding effective stockpiling and requiring yearly vaccination. Second, although the role of avian influenza viruses in the generation of new pandemics has been clearly described, the exact features that control species specificity are poorly understood, significantly hampering our ability to predict pandemics. The New York Influenza Center of Excellence (NYICE) is a collaborative, multi-institutional, interdisciplinary approach involving investigators in the fields of immunology, virology, biochemistry, medicine, pediatrics, statistics and bioinformatics that will address directly the issues of cross-protective immunity and species specificity. Our goal is to provide a truly transforming approach to influenza research.

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 logistical problems that make it difficult to have sufficient vaccine available to effectively contain the first wave of any pandemic.

A major objective of the NYICE is to be better prepared for both seasonal and pandemic influenza. NYICE represents and integrated team of investigators and interrelated projects, and can achieve much more than would be possible with an uncoordinated effort of individual investigator grants. NYICE immunology projects as a group target cross-reactive, heterosubtypic immune responses to influenza from the following complementary perspectives: T cell specificity and cross-reactivity, antigen processing and immunodominance, and acquisition of effector functions. Similarly, the viral pathogenesis projects of NYICE together target molecular mechanisms that cooperate in the infection of cells and synergistically contribute to host range. Studies of the fidelity of the polymerase are central to understanding antigenic variation, which is in turn a critical component of heterosubtypic immunity. We believe that these synergistic efforts will create a research enterprise that will truly be greater than the sum of its individual parts.

Research Projects of the NYICE

Human Immunity to Influenza

Project 1: (David Topham) Will perform a detailed analysis of cross-reactive cell-mediated immunity (CMI) against influenza in humans, develop markers of tissue-memory human T cells, and create an improved animal model for studying CD4 T cell mediated influenza immunity in mice. Comprehensive assay systems will be established to target human CD4 and CD8 T cells, and B cells responding to influenza virus, viral hemagglutinin, or influenza vaccines.

Project 2: (Andrea Sant) 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, and identify their HLA-DR and HLA-DQ restricted peptide specificities. We will then use HLA-DR and HLA-DQ transgenic mice 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, correlating these results with the results seen in HLA-typed humans. Using these transgenic mouse models, we will evaluate whether effectiveness of CD4 T cells in potentiating antibody responses depends on the source protein from which the CD4 T cell epitopes are derived.

Project 3: (Tim Mosmann) Will further complemented the studies on CD4 T cell protection and memory by examining the T helper effector cytokine profiles in response to different forms of immunization or infection. Ultimately these data will inform the design of the next generation of influenza vaccines for both conventional and pandemic influenza.

Adaptation of influenza virus from birds to mammals

NYICE will aggressively pursue a series of studies to fully understand the role of critically important mutations in adaptation of avian influenza A viruses to mammals such as humans.

Project 4: (Gary Whittaker) Studies the changes in influenza hemagglutinin (HA) that are necessary for emergence of viruses from avian to mammalian species, with a focus on the events controlling fusion activation. We will determine those changes in HA that control the ability of HA to survive in the avian GI tract, to determine the role of an exposed basic path on the surface of H1 HA in fusion activation and to determine the molecular and structural basis of adaptation of a mammalian H7 influenza virus that is a prototype of a highly pathogenic avian influenza virus that successfully adapted to infect and transmit in mammalian hosts.

Project 5 : (Toru Takimoto) Will identify the residues in the viral polymerase associated with changes in catalytic activity, interaction with cell cofactors and pathogenicity to reveal the molecular mechanism of mammalian host adaptation and virus mutability. These studies are expected to contribute to the identification of avian viruses that may be associated with pandemic potential, as well as potentially leading to new strategies to develop antivirals and other control measures.

Personnel

NYICE has assembled a multidisciplinary team with expertise in virology, biochemistry, immunology, bioinformatics and statistics, medicine, and pediatrics to carry out this vision. In the table below, the key individuals involved in NYICE, and their roles in the overall mission of the Center, are outlined. Many of the individuals in the center will play a role in multiple projects, evidence of the highly interactive nature of our proposal.

John Treanor (Director)

David Topham (Co-director, PI Project 1)

Andrea Sant (PI Project 2)

Tim Mosmann (PI Project 3)

Gary Whittaker (PI Project 4, Cornell University)

Toru Takimoto (PI Project 5)

Stephen Dewhurst (investigator project 5)

Baek Kim (investigator project 5)

Alexandra Livingstone (investigator project 3)

Mark Sangster (investigator Projects 1 & 2, University of Tennessee, Knoxville)

Brian Crane (investigator project 4, Cornell University)

Sally Quaetert (core director, Quality Control)