Edwardsiella species cause major economic losses in the U.S. catfish industry. In 2023, E. ictaluri and E. piscicida represented 43.2% of disease diagnoses at the Aquatic Research and Diagnostic Laboratory in Stoneville, Mississippi. The experimental live-attenuated E. ictaluri vaccine (340X), distributed under veterinary prescription, has significantly reduced enteric septicemia of catfish (ESC) losses. Although 340X provides partial cross-protection against E. piscicida in channel and hybrid catfish (~60–70% RPS vs. 95–100% against E. ictaluri), researchers are exploring whether co-administration with an E. piscicida bacterin can enhance this protective effect. This study evaluated the efficacy of the orally delivered E. ictaluri LAV (340X) paired with a formalin-killed E. piscicida bacterin and β-glucan (0.1% of feed for 14 days) as an oral adjuvant. Fish were distributed into seven treatment groups plus controls (five replicates/treatment, 20 fish/tank) and challenged with wild-type E. ictaluri (immersion) or E. piscicida (injection) 36 days post-vaccination. Treatments included: 340X alone, 340X + β-glucan, 340X + bacterin, 340X + β-glucan + bacterin, β-glucan + bacterin, β-glucan alone, and bacterin alone. Results indicated that the 340X alone gives high protection against E. ictaluri (RPS=97%) and neither bacterin nor β-glucan improved or negatively interfered with 340X efficacy. After E. piscicida challenge, the most notable finding was 340X significantly improved survival, consistent with previous reports, however there were no substantial improvements attributed to the bacterin or β-glucan. Anti-E. piscicida antibody activity was not significantly improved in any treatment over controls. Comparably, while survival was not significantly improved over the 340X alone, anti-E. ictaluri antibody activity was significantly increased in fish receiving the LAV + β-glucan oral adjuvant, suggesting a more robust immune response to vaccination. Results indicate the efficacy of 340X is not impaired by the presence of the E. piscicida bacterin and may be enhanced by β-glucan supplementation. One limitation of this study is the reduced susceptibility of channel catfish to E. piscicida infection resulting in negligible mortality upon E. piscicida challenge, which may have masked any protective effects from the treatments. This study will be repeated in hybrid catfish to determine if co-administration of 340X with an E. piscicida bacterin can improve the cross-protective benefit of 340X against E. piscicida in hybrids.