The overall goal of this project is to define the human T cell responses to influenza infection and to trivalent inactivated influenza vaccines (TIV) in younger and older adults. We hypothesize that (1) human T cell responses in younger adults will be greater than those in older adults to vaccination and to infection, (2) human CD4+ and CD8+ T cell responses will be lower to vaccine than to infection and (3) the TlV-induced T cell responses will correlate with the amount of internal proteins in the individual licensed vaccines. Influenza A virus hemagglutinin (HA) is a target of protective neutralizing antibodies, which are subtypespecific and vulnerable to antigenic drift. CD4+ and CD8+ T cell responses are thought to be more subtype cross-reactive. It is clear from studies in mouse models of influenza A virus infections that T cells can provide a second important line of defense, especially in the face of marked antigenic drift or shift due to emergence of viruses with changes in HA antibody combining sites, and there are also limited clinical studies which suggest the importance of T cells for protection, especially in a high-risk elderly population. There is, however, only a limited amount of data available on human T cell responses to influenza infection or vaccination. Importantly there appears to be more subtype cross-reactivity among influenza A virus T cell epitopes than to the antibody epitopes on HA. At present limited data suggest that current TIVs induce low to moderate CD4+ and CD8+ T cell responses. However, we found some individuals with high T cell responses to TIV. Recently, we and the other group also found the amount of influenza internal proteins in the TIVs differs. Despite the recommendation and use of about 100 million vaccine doses per year in the US alone, very little is known about TIVs induction of T cell responses and nothing is known about their contribution to vaccine associated protection.
In Aim 1 we propose to analyze CD4+ and CD8+ T cell responses to TIV vaccination in younger and older adults. In these studies, we will also compare the three US-licensed TIVs for their ability to stimulate CD4+ and CD8+ T cell responses and for protection (in older adults).
In Aim 2 we propose to characterize CD4+ and CD8+ T cell responses to natural influenza infections in younger and older adults and compare them to the CD4+ and CD8+ T cell responses induced by TIV. These analyses may lead to approaches towards improved influenza vaccines, which can protect against new and emerging influenza virus infections including H5N1 and other non-human strains.
For efficient protection against influenza A virus infection, influenza vaccines need to induce cellular immune responses as well as neutralizing antibody responses, especially in older adults. Despite the recommendation and use of about 100 million vaccine doses per year in the US alone, very little is known about cellular immune responses induced by the vaccines and nothing is known about their contribution to protection, which we propose to study in younger and older adults to help design better influenza vaccines.
|Townsley, E; O'Connor, G; Cosgrove, C et al. (2016) Interaction of a dengue virus NS1-derived peptide with the inhibitory receptor KIR3DL1 on natural killer cells. Clin Exp Immunol 183:419-30|
|Woda, Marcia; Friberg, Heather; Currier, Jeffrey R et al. (2016) Dynamics of Dengue Virus (DENV)-Specific B Cells in the Response to DENV Serotype 1 Infections, Using Flow Cytometry With Labeled Virions. J Infect Dis 214:1001-9|
|Ramirez, Alejandro; Co, Mary; Mathew, Anuja (2016) CpG Improves Influenza Vaccine Efficacy in Young Adult but Not Aged Mice. PLoS One 11:e0150425|
|Becerra-Artiles, Aniuska; Dominguez-Amorocho, Omar; Stern, Lawrence J et al. (2015) A Simple Proteomics-Based Approach to Identification of Immunodominant Antigens from a Complex Pathogen: Application to the CD4 T Cell Response against Human Herpesvirus 6B. PLoS One 10:e0142871|
|Woda, Marcia; Mathew, Anuja (2015) Fluorescently labeled dengue viruses as probes to identify antigen-specific memory B cells by multiparametric flow cytometry. J Immunol Methods 416:167-77|
|Jaiswal, Smita; Smith, Kenneth; Ramirez, Alejandro et al. (2015) Dengue virus infection induces broadly cross-reactive human IgM antibodies that recognize intact virions in humanized BLT-NSG mice. Exp Biol Med (Maywood) 240:67-78|
|Tervo, Laura; MÃ¤kelÃ¤, Satu; SyrjÃ¤nen, Jaana et al. (2015) Smoking is associated with aggravated kidney injury in Puumala hantavirus-induced haemorrhagic fever with renal syndrome. Nephrol Dial Transplant 30:1693-8|
|Thompson, Mikayla R; Sharma, Shruti; Atianand, Maninjay et al. (2014) Interferon Î³-inducible protein (IFI) 16 transcriptionally regulates type i interferons and other interferon-stimulated genes and controls the interferon response to both DNA and RNA viruses. J Biol Chem 289:23568-81|
|Mathew, Anuja; Townsley, Elizabeth; Ennis, Francis A (2014) Elucidating the role of T cells in protection against and pathogenesis of dengue virus infections. Future Microbiol 9:411-25|
|Yin, Liusong; Stern, Lawrence J (2014) A novel method to measure HLA-DM-susceptibility of peptides bound to MHC class II molecules based on peptide binding competition assay and differential IC(50) determination. J Immunol Methods 406:21-33|
Showing the most recent 10 out of 105 publications