Current vaccination strategies against influenza A viruses are primarily based upon elicitation of neutralizing antibodies directed at virion surface expressed hemagglutinin (HA) and neuraminidase (NA) proteins. Given antigenic drifts during seasonal influenza A infection or large shifts associated with influenza A pandemics, elicitation of antibody-based immunoprotection through vaccination requires continual immunogen modification. Such alterations adversely impact public health preparedness. The current swine flu H1N1 pandemic 2009 strain is a case in point. Here we will use recent advances in bioinformatics and proteomics to explore the potential to elicit protective CDS T cell responses against 153 conserved epitopes derived from 5,315 sets of influenza A taxonomy data covering all internal and surface viral proteins and predicted to bind to common HLA alleles such as HLA-A*0201. These HLA restricted epitopes are capable of affording broad population protection coverage as determined through recently developed bioinformatics methodologies. Since tissue-resident peripheral memory effector CD8 T lymphocytes can mediate cytokine release and other terminally differentiated functions within hours of T cell receptor triggering, they have the potential to target rapidly the infected lung epithelium where productive infection is ongoing. Subsequently, these T effectors can terminate further viral replication in a time-efficient manner. To this end, we will pursue four alms. First, we shall develop bionformatic tools to determine global variability of influenza A, an Infrastructure for analysis of sequence diversity and potential T cell epitopes and a database for vaccine development. Implementation of a cDNA microarray for rapid HLA profiling will assess the impact of alleles on immune responses. Second, our novel ultrasensitive MS^ method will be used to assess the peptidome of H1N1, H2N2 and H3N2 influenza A infected human epithelial cells, defining the kinetics and hierarchy of peptide arrays. It is our hypothesis that viral chicanery, limited representation of relevant epitope crosspresentation and/or a detrimental impact of immunodominance during the course of natural infection precludes T cell response to those potentially protective conserved epitopes. Third, recognition of conserved Influenza A epitopes by human memory T cells from naturally exposed adults or T cells from LAIV-vaccinated children and adults during the trial period will test this notion. Fourth, we shall employ an HLA-A*0201 transgenic mouse model (HLA-A2.1 tg) to gauge immunoprotection against PR8 challenge using nanoparticles laden with conserved epitopes in influenza naive mice and determine how previous infection impacts immunity.

Public Health Relevance

This information has the potential to provide the basis, in the near-term, for development of a universal influenza A vaccine, affording protection against seasonal variants as well as pandemic strains of influenza A viruses. It has general application to other highly mutable viral pathogens affecting mankind.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI090043-03
Application #
8288788
Study Section
Special Emphasis Panel (ZAI1-QV-I (M1))
Program Officer
Esch, Thomas R
Project Start
2010-07-12
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
3
Fiscal Year
2012
Total Cost
$1,136,663
Indirect Cost
$478,247
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
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