Significant changes in anti-pneumococcal polysaccharide (PPS) variable gene usage occur with aging and may be influenced by changes in cytokine environment. Severe combined immunodeficient (SCID) mice were engrafted with B cells obtained from young and elderly donors, supplemented with human cytokines and immunized with the pneumococcal polysaccharide vaccine. B cells specific for PPS serotypes 4 and 14 were isolated from mice and immunized donors, and variable region sequences analyzed. Significant differences in variable heavy and light chain gene usage were observed between young and elderly adults despite a more constant cytokine environment. Due to the limitations of the hu-PBL-SCID model, the use of alternative systems would be beneficial in the elucidation of mechanisms underlying the reduced vaccine efficacy in the elderly.