Actinobacillus pleuropneumoniae (A. pleuropneumoniae) is a highly contagious lethal causative agent of swine pleuropneumoniae. Vaccines for this disease are usually serotype specific. In order to identify immunogenic genes specific to serotypes, two differentially expressed gene cDNA libraries of A. pleuropneumoniae CCVC259 (serotype 1) and CCVC263 (serotype 5) had been constructed by using a cDNA representational difference analysis (cDNA-RDA). From the libraries, six potential vaccine candidate genes expressed only in serotype 1 and 13 genes in serotype 5 were identified by antibody screening after gene expression in vitro with a ribosome display system. Eight sequences out of these exhibited 77-100% identity to the corresponding genes in Propionibacterium acnes. The antisera raised against A. pleuropneumoniae serotypes 1 and 5 were reactive with P. acnes at a titer of 1:6400 and vice versa (ELISA titer, 1:3200). Mice immunized with P. acnes were protected against 10 x LD50 challenge with A. pleuropneumoniae serotypes 1 and 5, and the survival rates were 90% and 95%, respectively. Pigs vaccinated with the P. acnes strain could develop high level antibody cross-reacted with A. pleuropneumoniae and obtain noticeable protection from A. pleuropneumoniae infection. These data demonstrate that there were common antigens between A. pleuropneumoniae and P. acnes, and the cross protectivity highlights the possibility of using P. acnes vaccines for preventing infection by A. pleuropneumoniae.