Pneumococcal surface protein A (PspA) is a cell-surface protein of Streptococcus pneumoniae that is present on a number of clinical isolates as well as on the nonencapsulated laboratory strain Rx1. PspA was originally identified by monoclonal antibodies that can protect mice against intravenous challenge with some pneumococcal strains. A gene, pspA, required for the production of PspA was inactivated with use of insertional inactivation. By immunizing CBA/N (Xid) mice with congenic PspA+ and PspA- pneumococci, it was possible to demonstrate that PspA can elicit protective antipneumococcal antibodies. This result may be significant to future vaccine research, since Xid mice, like children, are not responsive to the present pneumococcal vaccine. When pspA was inactivated in three virulent, encapsulated strains of pneumococci, all three strains showed a reduction in virulence and two became totally avirulent: the 50% lethal dose was less than 10 colony-forming units (cfu) for the parents and greater than 5 x 10(4) cfu for the PspA- mutants.