Influenza is responsible for significant morbidity and mortality worldwide every year and causes severe pandemics when new strains evolve that have not previously circulated in humans. The high viral mutation rate necessitates new vaccines be generated based on the prevalence of circulating strains every year. These reformulated versions of influenza vaccine are not always protective--the CDC estimates the influenza vaccine efficacy to be 70-90%, but only when it is well matched to the circulating virus. There is an urgent unmet need for influenza vaccines that induce greater strain cross-protective immunity. We hypothesize that vaccines capable of inducing T cell responses directed against conserved internal viral proteins could provide more broadly protective influenza immunity. Thus, we propose to harness the immunogenic potential of broadly reactive influenza-specific T cell epitopes to produce vaccines with universal significance. Completion of the following specific aims in this application will provide proof-of-concept that T cell-based vaccines designed to stimulate human T cell responses can induce broadly heterotypic protective immunity, as well as a strong basis for development of a T cell focused vaccine to complement existing B-cell focused vaccines.
Aim 1 : Immunoinformatic identification of highly conserved, HLA immunogenic consensus CD4 and CD8 epitopes in influenza NP and matrix proteins.
Aim 2 : Construction of new DNA and protein influenza vaccines containing "universally" relevant CD4 and CD8 T cell epitopes.
Aim 3 : Evaluation of immunogenicity and protection induced by new "universally" relevant T cell targeting influenza vaccines in HLA-DR1/A2 mice. The proposed work can provide important new products and direction for influenza vaccine development, focusing on a paradigm-shifting concept of inducing broadly protective T cell responses.

Public Health Relevance

Influenza causes significant morbidity and mortality every year worldwide, and the evolution of pandemic strains leads to periodic world health emergencies. The current influenza vaccines must be updated every year because they focus on inducing antibody responses directed against the hemagglutinin molecule, one of the least conserved genomic regions of the virus. We propose to develop novel influenza vaccines that focus on the induction T cells capable of recognizing highly conserved internal proteins which could provide universal protective immunity against all current and future influenza A viral strains--a paradigm-shifting approach to prophylactic influenza vaccination.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI105605-01
Application #
8490618
Study Section
Vaccines Against Microbial Diseases (VMD)
Program Officer
Salomon, Rachelle
Project Start
2013-04-15
Project End
2015-03-31
Budget Start
2013-04-15
Budget End
2014-03-31
Support Year
1
Fiscal Year
2013
Total Cost
$225,000
Indirect Cost
$75,000
Name
Saint Louis University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
050220722
City
Saint Louis
State
MO
Country
United States
Zip Code
63103