Modeling and optimization of the Mannheimia haemolytica vaccine production process
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[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] Leukotoxin (Lkt) from Mannheimia haemolytica has been discovered as the primary pathogenic factor for bovine respiratory disease (BRD), causing huge economic losses annually to feedlot industry. To reduce overuse of antibiotics, vaccination has been a preferred alternative. The production of Lkt vaccine, however, is challenged by issues of low and varied potency, and conventional statistical studies have proven ineffective in identifying the problems. In this research, a mathematical model was developed to characterize the relationship among major process state variables with Lkt concentration as the process output. A kinetic model structure was formulated based on the major reactions involved in the process. Experimental data were collected with a 200-L pilot-scale reactor to verify the model structure and to estimate the model coefficients. The modeling process revealed that Lkt has a significant denaturation rate at the process temperature and the Mannheimia haemolytica proliferation activities could impede the production of Lkt. Based on the model, a process optimization strategy is devised to maximize Lkt concentration by raising Mannhaimia haemolytica to maximum density in the shortest possible time and harvesting Lkt at its peak time. Additionally, during model development, a new method, referred to as partial-space least squares method, was developed to improve the accuracy and the efficiency of parameter estimation. Keywords: BRD, Mannheimia haemolytica, Leukotoxin, vaccine, process optimization, model, parameter estimation.