The pneumococcal conjugate vaccine (CV), although highly immunogenic in infants and young children, does not consistently demonstrate an advantage over the pneumococcal polysaccharide vaccine (PPV) in older adults. To further elucidate the adult immune response to CV, we compared its response to PPV on a molecular level using a severe combined immunodeficient (SCID) mouse model. This model allowed us to analyze a single individual's response to two different forms of antigen and define differences in gene usage elicited by these vaccines. We reconstituted SCID mice with human lymphocytes derived from an unimmunized donor; the mice were divided into two groups and immunized with either the PPV or CV. Our results demonstrate significant differences in variable gene usage in SCID mice immunized with PPV versus CV and suggest that the nature of the immunizing agent has a significant impact on gene usage and therefore influences antibody function and vaccine efficacy.