The feasibility of expression library immunization against the pathogenic bacterium Neisseria meningitidis was studied. A genomic library of N. meningitidis serogroup B strain CU385, containing 6000 individual clones, was constructed and divided into 10 sublibraries. Immunization of BALB/c mice with plasmid DNA from six sublibraries induced a humoral response, with recognition of several meningococcal proteins by Western blot. Three of these sublibraries elicited bactericidal antibodies against the homologous strain, and sera from mice immunized with one of these sublibraries reduced significantly the number of viable bacteria in blood of infant rats challenged with N. meningitidis. In addition, after DNA immunization, mice were boosted intraperitoneally with 5 x 10(2) colony forming units of strain CU385. Mice immunized with nine of the 10 libraries developed bactericidal antibodies 1 week after the boost and controls did not, demonstrating the priming capacity and specificity of our immunization strategy. Our study demonstrates, for the first time, that genomic immunization offers a novel approach for screening possible vaccine candidates against N. meningitidis.