Lakshmi Krishnan, Felicity C Stark, Valeria Alcon, Fanny Tzelepis, G. Dennis Sprott and Subash Sad
Scientific Tracks Abstracts: J Vaccines Vaccin
Induction of CD8 + T cells is oft en the goal for vaccines against intracellular pathogens and cancer. CD8 + T memory cells are heterogenous and are classifi ed into eff ector and central phenotypes. It is unclear how CD8 + T cell quantity and quality diff erentially aff ect vaccine effi cacy. We have developed a panel of vaccine delivery adjuvants that diff erentially impact the kinetics, quantity, quality of the CD8 + T cell response and immune memory. Archaeosomes adjuvant (made up of polar lipids derived from the archaea , Methanobrevibacter smithii ), generates a large number of antigen specifi c CD8 T cells and a balanced phenotype of eff ector and central memory cells to entrapped antigen (J. Immunol., 278:2396, 2007). Recombinant Listeria monocytogenes (LM) and Salmonella Typhimurium (ST)-based vaccine delivery vectors are also eff ective at targeting antigen for CD8 T cell response (Stark et al., Cancer Res., 69:4327, 2009). We have also constructed a novel Salmonella Typhimurium vector capable of translocating (ST-T) antigen to the cytosol for eff ective MHC class I presentation. We evaluated the infl uence of the adjuvant, antigen processing pathway and vaccination regimen on CD8 T cell response to the same antigen, Ovalbumin (OVA) utilizing these diff erent vaccine delivery approaches. A single dose of OVA-archaeosomes or Listeria monocytogenes -OVA (LM-OVA) primed low numbers of exclusively CD8 central memory T cells. Repetitive boosting with LM-OVA failed to expand the numbers of CD8 T cells further, probably due to rapid neutralization of the live vector during subsequent boosts. In contrast archaeosomes given repetitively stimulated large numbers of OVA-specifi c CD8 T cells, with each injection increasing the total numbers of antigen-specifi c CD8 T cells in the lymphoid organ, up to shortly aft er the third dose. Th ereaft er a quantitative maximum threshold appeared to have been reached. Furthermore, repetitive boosting resulted in predominately eff ector memory phenotype CD8 T cells. In contrast, ST-OVA induced low numbers of CD8 T cells with delayed kinetics but predominantly eff ector memory phenotype. However, ST-OVA-T induced a strong and rapid CD8 T cell response, nevertheless of an eff ector memory phenotype. Th e diff erential responses evoked by each antigen delivery system correlated to the mechanisms of antigen presentation and resulted in varied protection against murine melanoma, in a prophylactic and therapeutic setting. Protection against cancer benefi ted from a central memory response whereas for clearance of LM and ST infection, a rapid kinetics of CD8 T cell response appeared to be most essential. Th us, the adjuvant and vaccination regimen strategy selected needs to be considered in the context of target application for tailoring the induction of cell-mediated immunity.