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Simple Summary: Determining effects of physiological stress and vaccination type on performance and immune responses in cattle can be a difficult task due to the many factors that contribute to the stress response. Nonetheless, defining alterations caused by the stress response after vaccination upon feedlot arrival is vital in improving vaccination practices in the feedlot industry. Utilizing a stress model with stressors induced by current industry practices to mimic a "high-risk" cattle situation, we found that vaccination with a killed or modified-live virus vaccine induces altered immune responses in cattle that underwent industry stressors when compared to a control group. In addition, performance variables were altered in stressed cattle and those that received modified-live vaccination. We propose the feedlot industry consider these results when implementing a vaccine protocol in "high risk", or chronically stressed, cattle during arrival processing. The study objective was to determine if a combined weaning and transportation stress model affected performance, antibody, endocrine, or hematological responses to modified-live virus (MLV) or killed virus (KV) respiratory vaccination in beef steers. In total, 48 calves (Day 0 BW = 226 ± 6.2 kg) from a single origin were used in a 2 × 2 factorial to evaluate main effects of stress model, vaccine type, and their interaction, resulting in four treatments (n = 12/treatment) including non-stress control (C) with KV (CKV), C with MLV (CMLV), stress model implementation (S) with KV (SKV), and S with MLV (SMLV). The C calves were weaned at the origin ranch on Day −37 and transported 472 km to the study site on Day −21 to allow acclimation. The S calves were weaned on Day −3, transported 460 km to a research facility on Day −2, held overnight, and transported 164 km to the study site on Day −1 to mimic the beef cattle marketing process. Vaccines were administered on Day 0 and KV was revaccinated on Day 14. The animal was the experimental unit and dependent variables were analyzed using PROC MIXED with repeated measures (day). A stress model effect (p = 0.01) existed for DMI from Day 0 to Day 7 with greater DMI for C (6.19 vs. 4.64 kg/day) when compared to S. The MLV groups had reduced (p = 0.05) ADG from Day 0 to Day 56, compared to KV. There was a vaccine type × day (p < 0.01) interaction with increased (p ≤ 0.01) PI3V- and IBRV-specific antibody titers for KV on Day 21; conversely, MLV had increased (p ≤ 0.01) BVDV titers on Days 14, 28, 35, 42, 49, and 56. Increased (p ≤ 0.05) BRSV titers were observed in a stress model × day (p < 0.01) interaction for S on Days 21, 28, 36, and 42; however, C exceeded S in BVDV-specific antibody concentration on Days 21, 28, and 49. A day effect (p < 0.01) was observed for serum haptoglobin with the greatest (p < 0.01) concentration on Day 3. Serum cortisol concentration was greater (p ≤ 0.04) for C vs. S on Days −2, 0, 1, 3, and 5. Total leukocytes were decreased for C vs. S on Days 0, 1, 3, 5, 7, 14, and 21 (p ≤ 0.02). A reduction (p ≤ 0.04) in total leukocytes was observed for MLV on Days 5, 7, and 14 vs. KV. Neutrophils and neutrophil:lymphocyte were markedly increased (p ≤ 0.01) for S on Day −2, whereas neutrophils were decreased (p ≤ 0.01) on Days 1 and 21 for S. Monocytes were decreased on Days 1, 5 and 7 for MLV (p ≤ 0.04) and Days −2 to 14 for S (p ≤ 0.03). Eosinophils were reduced (p = 0.007) for S vs. C on Day −2, yet a distinct rebound response (p = 0.03) was noted for S on Day 0. The results indicate that S and MLV vaccination more profoundly induced immunomodulation in beef calves. [ABSTRACT FROM AUTHOR]