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 elderty 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 genomewide 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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-QV-I)
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Yale University
New Haven
United States
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Murray, Kristy O; Nolan, Melissa S; Ronca, Shannon E et al. (2018) The Neurocognitive and MRI Outcomes of West Nile Virus Infection: Preliminary Analysis Using an External Control Group. Front Neurol 9:111
Molony, Ryan D; Malawista, Anna; Montgomery, Ruth R (2018) Reduced dynamic range of antiviral innate immune responses in aging. Exp Gerontol 107:130-135
Martin-Gayo, Enrique; Cole, Michael B; Kolb, Kellie E et al. (2018) A Reproducibility-Based Computational Framework Identifies an Inducible, Enhanced Antiviral State in Dendritic Cells from HIV-1 Elite Controllers. Genome Biol 19:10
Wang, Xiaomei; Malawista, Anna; Qian, Feng et al. (2018) Age-related changes in expression and signaling of TAM receptor inflammatory regulators in monocytes. Oncotarget 9:9572-9580
Cahill, Megan E; Conley, Samantha; DeWan, Andrew T et al. (2018) Identification of genetic variants associated with dengue or West Nile virus disease: a systematic review and meta-analysis. BMC Infect Dis 18:282
van Dijk, David; Sharma, Roshan; Nainys, Juozas et al. (2018) Recovering Gene Interactions from Single-Cell Data Using Data Diffusion. Cell 174:716-729.e27
Ordovas-Montanes, Jose; Dwyer, Daniel F; Nyquist, Sarah K et al. (2018) Allergic inflammatory memory in human respiratory epithelial progenitor cells. Nature 560:649-654
Mead, Benjamin E; Ordovas-Montanes, Jose; Braun, Alexandra P et al. (2018) Harnessing single-cell genomics to improve the physiological fidelity of organoid-derived cell types. BMC Biol 16:62
Avey, Stefan; Mohanty, Subhasis; Wilson, Jean et al. (2017) Multiple network-constrained regressions expand insights into influenza vaccination responses. Bioinformatics 33:i208-i216
Cahill, Megan E; Yao, Yi; Nock, David et al. (2017) West Nile Virus Seroprevalence, Connecticut, USA, 2000-2014. Emerg Infect Dis 23:708-710

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