The genetic variability of our species dictates that some individuals will develop strong humoral and cellular immune responses to vaccines whereas others do not. With aging, these differences in protective immunity become even more severe, reflected in the increased risk for death and morbidity from infections in older individuals. For example, the impact of seasonal influenza is particularly acute in the geriatric age group, with 90% of the 20 to 40 thousand annual deaths attributed to influenza occurring in individuals over the age of 65. However, the efficacy of the trivalent inactivated influenza vaccine is as low as 30%, and the frail subset of elderly individuals who are at risk for worsened disability, hospitalization, falls and death, represent a particularly vulnerable population. This project builds on our experience recruiting and evaluating influenza vaccine response in young and older individuals, and our access to unique cohorts-such as frail elderly individuals (including a recruited cohort of 860 nursing home elders participating in an NIH-funded trial of pneumonia prevention) and a group of 300 individuals under the age of 30 already subjected to genome wide genotyping. We will utilize the Multidimensional Flow Cytometry and Quantitative Gene Expression Cores, and the analytic methods of Project 3 to develop cellular and gene expression signatures of a successful innate and adaptive immune response to influenza vaccination, and will elucidate the impact of aging and impaired functional status (such as the geriatric syndrome of frailty) on these signatures in cohorts of young, non-frail older, and frail older individuals. Our access to genetic information on 300 genotyped individuals receiving influenza vaccine will also facilitate the integration of cellular and gene expression data with genetic correlates of vaccine response. Identifying the genes and their allelic variations in humans that underlie robust or weak responses, and how their expression patterns are affected by age or frailty is a necessity for a greater understanding of the function of our immune system. Moreover, understanding the genetic architecture of immune responses is likely to identify immune pathways that could be targets of therapies, drugs or other biological treatments to enhance or suppress immune responses as needed.

Public Health Relevance

The goal of this proposal is to identify patterns of gene expression or cell function in the human immune system that are signatures of a response to influenza vaccination that is associated with protection from infection. We will also evaluate how these signatures are altered in older or frail individuals, who usually do not generate protective responses to vaccination and are at increased risk for severe influenza infection.

Agency
National Institute of Health (NIH)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI089992-05
Application #
8699128
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Yale University
Department
Type
DUNS #
City
New Haven
State
CT
Country
United States
Zip Code
06510
Murray, Kristy O; Garcia, Melissa N; Rahbar, Mohammad H et al. (2014) Survival analysis, long-term outcomes, and percentage of recovery up to 8 years post-infection among the Houston West Nile virus cohort. PLoS One 9:e102953
Yao, Yi; Liu, Rebecca; Shin, Min Sun et al. (2014) CyTOF supports efficient detection of immune cell subsets from small samples. J Immunol Methods 415:1-5
Olivieri, Fabiola; Procopio, Antonio Domenico; Montgomery, Ruth R (2014) Effect of aging on microRNAs and regulation of pathogen recognition receptors. Curr Opin Immunol 29:29-37
Vander Heiden, Jason A; Yaari, Gur; Uduman, Mohamed et al. (2014) pRESTO: a toolkit for processing high-throughput sequencing raw reads of lymphocyte receptor repertoires. Bioinformatics 30:1930-2
Zapata, Heidi J; Shaw, Albert C (2014) Aging of the human innate immune system in HIV infection. Curr Opin Immunol 29:127-36
Qian, Feng; Thakar, Juilee; Yuan, Xiaoling et al. (2014) Immune markers associated with host susceptibility to infection with West Nile virus. Viral Immunol 27:39-47
Lee, Naeun; Shin, Min Sun; Kang, Ki Soo et al. (2014) Human monocytes have increased IFN-?-mediated IL-15 production with age alongside altered IFN-? receptor signaling. Clin Immunol 152:101-10
Chattopadhyay, Pratip K; Gierahn, Todd M; Roederer, Mario et al. (2014) Single-cell technologies for monitoring immune systems. Nat Immunol 15:128-35
Gierahn, Todd M; Loginov, Denis; Love, J Christopher (2014) Crossword: a fully automated algorithm for the segmentation and quality control of protein microarray images. J Proteome Res 13:362-71
Goel, Gautam; Conway, Kara L; Jaeger, Martin et al. (2014) Multivariate inference of pathway activity in host immunity and response to therapeutics. Nucleic Acids Res 42:10288-306

Showing the most recent 10 out of 24 publications