Outstanding animal immunogenicity is a prerequisite for progression of novel vaccines to clinical trials. The measurement of vaccine immunogenicity is critically dependent on the specificity, accuracy, sensitivity, and precision of the employed assays. This has been greatly aided by the generation of isogenic mouse strains. Here, we identified three novel H-2(d) -restricted CD8+ T cell epitopes derived from the human immunodeficiency virus type 1 and demonstrated a fine evaluation of the vaccine-elicited T cell responses in an inbred mouse strain. However, unlike inbred mice, outbred mouse stock indicated preferential induction of CD4+ T cell responses by a heterologous DNA-prime-recombinant modified vaccinia virus Ankara boost regimen and induction of dominant responses to the env-derived vaccine component, i.e., observations reminiscent of human data. Thus, an outbred mouse stock may provide more rigorous and realistic tests for candidate vaccine evaluation in addition to sensitive assays in a selected, well-responding inbred strain.