Losses due to respiratory infection (BRD) in newly received feedlot calves are a primary concern for the North American beef industry. Management of bovine respiratory disease relies primarily on antimicrobials but recent detection of integrative conjugative elements carrying multi-drug resistance in strains of Mannheimia haemolytica (MH), Pasteurella multocida and Histophilus somni has highlighted the need to shift to less drug dependent strategies to mitigate BRD. Advancements in high-throughput "omics" technologies have revolutionized the screening of proteins as vaccine candidates. Using MH, we screened whole genome sequences for conserved antigen candidates containing <4 transmembrane helices and signal peptides indicative of secreted, extracellular or periplasmic proteins. As an alternative to cloning, proteins tagged at both the N and C-termini were expressed using a high-throughput, coupled cell-free transcription/translation system. Using ELISA, translated proteins were evaluated for immunogenicity against sera generated from calves infected with MH 1 (S1), 2 (S2) and 6 (S6) serotypes. A total of 240 candidate proteins were identified; 78 periplasmic, 52 outer membrane, 15 extracellular and 95 unknown. Over two-thirds of the candidates were successfully translated, captured and screened. Multiple candidates were immunogenic, some explicitly to sera derived from both S1 and S6 infected calves. Screening of purified proteins in cell mediated immunity assays can also be used to further characterize innate immune responses. The methodology used drastically reduced the time required to screen hundreds of antigen candidates as compared to traditional cloning and expression techniques. The system provides a platform applicable to vaccine design against other bacterial pathogens of importance like P. multocida and H. somni.