This study was undertaken to evaluate and compare the efficacy of different multi-antigen vaccines, including heat-inactivated, whole lysate, and subunit (outer membrane proteins [OMPs]) vaccines along with the immunostimulant CpG ODN in controlling colonization in chickens. In the first trial, 125 μg of OMPs and 50 μg of CpG ODN were administered individually or in combination, either in ovo to chick embryos or subcutaneously (SC) to one-day-old chicks. In the second trial, different concentrations of antigens (heat-killed, whole lysate, and OMPs) were administered SC to one-day-old chicks. The results of the first trial revealed that SC immunization with the combination of CpG ODN and OMPs elevated interferon (IFN)-γ, interleukin (IL)-1β, and IL-13 gene expression in the spleen, significantly increased serum IgM and IgY antibody levels, and reduced cecal counts by approximately 1.2 log. In contrast, in ovo immunization did not elicit immune responses or confer protection against . The results of the second trial showed that SC immunization with whole lysate or 200 μg OMPs reduced counts by approximately 1.4 and 1.1 log, respectively. In conclusion, lysate and OMPs are promising vaccine antigens for reducing colonization in chickens.