Pneumococcal surface protein A (PspA) is a protection eliciting protein of Streptococcus pneumoniae. We observed that immunization of BALB/c mice with a plasmid lethal challenge with S. pneumoniae when compared to expressing PspA significantly protected the mice from lethal challenge with S. pneumoniae when compared to control mice that received injections of the plasmid vector alone. The plasmid construct expressing PspA has been designated pKSD2601. Mice immunized intramuscularly with pKSD2601 had a mean log of colony-forming units of 2.97 ± 8.25 pneumococci circulating in their blood at 24 h after challenge as compared with control mice that had a mean log of colony-forming units of 4.95 ± 0.59. Those mice with lower numbers of pneumococci subsequently survived the challenge. Given the quantitative nature and ultimate end point (ie live versus dead) our mouse model should be useful in working out optimum expression of bacterial genes for DNA immunization.