Here we propose to characterize the responses of CD4[+], CD8[+] and gamma-delta T cells to the pandemic influenza H1N1v vaccination or infection in human volunteers. We will use both systems biology approaches as well as analyzing a variety of antigen specific responses with combinatorial peptide-MHC tetramers combined with single cell cytokine analysis, in which we can screen for hundreds of different epitopes and dozens of cytokines.
In Aim 1. we will ask whether particular epitope or cytokine expression patterns correlate with a robust vaccine response, as measured by a microneutralization assay, and/or a granzyme B T cell assay, or in the case of infected individuals, disease severity. With the twin studies we will ask how closely does dominant epitope choice follow genetic identity and does that change with increasing age and exposure to infectious diseases. This will be complementary to the results obtained with the complete HLA genotyping being done by the Genomics Core, as we expect that HLA haplotypes will have a major influence on epitope selection and dominance.
In Aim 2. we will characterize activation markers and cytokine expression in gamma-delta T cells, which recent evidence suggests influence antibody responses and help shape the responses of CD4[+] and CD8[+] T cells and other immune system components through the early production of IL-17.
In Aim 3 we will continue our now three year old longitudinal study of seasonal flu vaccination in young adults (20-30 yrs.) versus older cohorts (60-96 yrs), taking a systems biology approach with the help ofthe Human Immune Monitoring Core and the Biostatistics Core in which we correlate gene expression, cytokine stimulation and serum cytokines with parameters such as immune senescence to uncover new markers and mechanisms behind the failure of proper immune function in many older people. We have already identified a number of new markers of immune deficiency, including a decrease in AID expression in B cells and deficient responses to cytokines in many older people using phosphoflow analysis. Support by this mechanism will allow us to look extensively at year-on-year variations and early markers of immune senescence. Lastly, this same systems approach will be taken to compare H1N1v vaccination responses to actual infections, which should help us to understand the similarities and differences between the two and aid in the design of vaccines that are more protective.

Public Health Relevance

The outbreak of a novel swine flu or H1N1v pandemic earlier this year and the threat of H5N1 which might become transmissible between humans at any time, highlights the urgency of learning much more about how influenza vaccines work and confer protection, particularly in groups at great risk, such as the elderly. We also wish to use this information to help define immunological health in general and develop a systems biology approach to understanding immune function and its pathologies.

National Institute of Health (NIH)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1)
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Stanford University
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