The 2009 influenza pandemic reiterates the urgency in developing improved influenza vaccines. This pandemic is caused by the influenza A/H1N1 variant strain (HINIv), to which much ofthe human population has little pre-existing immunity. H1N1v vaccines have recently been approved for distribution in the fall. This very uncommon circumstance with the advent of a new pandemic influenza strain provides the opportunity to address several critical questions regarding the B cell immunity against influenza, a key determinant of protection against influenza infection. Traditional evaluation for B cell responses against influenza infection or vaccination has relied heavily on convalescent serum antibody assays, which may not represent the entire antibody response, especially mucosal antibody responses that are frequently of great importance for protecting against respiratory pathogens. Antibody responses are first mediated by activated B cells, or plasmablasts, which migrate through circulation to different target sites and become effector B cells, or plasma cells. Recently we have developed a comprehensive flow cytometric assay to define the patterns of multiple trafficking receptor expression on blood plasmablasts, including those with trafficking signals for the respiratory tree. We have also developed sensitive methods to collect and analyze the polyclonal antibodies secreted by the plasmablast population or its specific subsets. Taking advantage of these new assays, and the rare opportunity provided by the HINIv pandemic, we will address the following specific aims to: 1. Analyze the trafficking receptor profiles imprinted on plasmablasts after natural infection with those induced by immunization with two different influenza vaccines;2. define the quantitative and qualitative differences in plasmablast-derived polyclonal antibody (PPAb) responses to acute infection vs. mucosal or systemic vaccination in different age groups; 3. qualitatively and quantitatively compare the homotypic and heterosubtypic PPAb reactivity induced by wild type HINIv infection vs. the PPAb reactivity induced by the two types of HINIv influenza vaccine, as well as by seasonal influenza vaccines. Together these aims will define new immune indicators and provide new insights to the mechanisms of B cell response to influenza infection and vaccination.

Public Health Relevance

This study will provide important insight to the mechanism of protective B cell response against influenza virus, which is critical for developing improved vaccine strategies that are more effective against the range of variant influenza viruses, as well as other antigenically variable viruses such as HIV and HCV.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI090019-05
Application #
8705361
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Stanford University
Department
Type
DUNS #
City
Stanford
State
CA
Country
United States
Zip Code
94304
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