The increased susceptibility to seasonal influenza coupled with decreased vaccine efficacy among older adults, who make up the fastest growing population in the United States, constitutes an emerging public health crisis. The Live Attenuated Influenza Vaccine (LAIV) is a nasally administered vaccine that has been shown to be more effective than the trivalent inactivated vaccine (TIV) in pediatric populations due to its ability to replicate and elicit a mucosal immune response at the site of natural infection - the nasal epithelium. Our preliminary data demonstrate that the LAIV exhibits significantly less replication in human nasal epithelial cell (hNEC) cultures from adults over 65 compared with younger subjects. Inadequate infection of the nasal epithelium limits the vaccine-activated immune response and we hypothesize that decreased LAIV infection and replication in the nasal epithelium of older adults contributes to the reduced vaccination efficacy. This proposal aims to characterize the defect in LAIV infection of nasal epithelial cells from older adults by comparing virus replication and nasal epithelial cell immune responses between adults over 65 and younger subjects between the ages of 5 and 17. The functional significance of any differences in the epithelial cell-derived immune responses between younger and older hosts will be assessed in order to identify potential mechanisms at the level of the epithelium, which modulate immune responses to the LAIV. Then we will study the effect of aging on the interaction between hNECs and dendritic cells in order to gain insight into how these age-specific changes in LAIV replication and nasal epithelial immune responses affect the dendritic cell-initiated adaptive immune response. The ultimate goal of this project is to identify age-specific epithelial cell factors that affect virus replication, which can then be used in the development of either novel vaccines with expanded immunoprotection or immune-modulatory adjuvants that can improve vaccine efficacy in older adults by enhancing vaccine replication.

Public Health Relevance

The increased susceptibility to seasonal influenza coupled with decreased vaccine efficacy among older adults constitutes an emerging public health crisis. The Live Attenuated Influenza Vaccine is the most effective vaccine in pediatric populations but is not protective in older adults. The reason the LAIV is believed to work so well in children but not in older adults is that it can replicate well in the nose of children and stimulate a protectiv immune response whereas in older adults the lack of adequate replication fails to elicit an effective immune response. The primary goal of this proposal is to further our understanding of how aging affects LAIV efficacy in older adults by identifying the epithelial cell specific factors that inhibit vaccine replication in older adults which will lead to the development of novel strategies designed to improve vaccine efficacy in older adults through enhanced vaccine replication.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Small Research Grants (R03)
Project #
1R03AG045088-01
Application #
8556553
Study Section
Special Emphasis Panel (ZAG1-ZIJ-9 (M1))
Program Officer
Salive, Marcel
Project Start
2013-08-15
Project End
2015-07-31
Budget Start
2013-08-15
Budget End
2014-07-31
Support Year
1
Fiscal Year
2013
Total Cost
$76,000
Indirect Cost
$26,000
Name
University of North Carolina Chapel Hill
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599