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GOALS/OBJECTIVES Intensive livestock production and management systems are associated with increased fecal-oral pathogen transmission and a resultant high prevalence of multiple salmonellae in large dairy farms and feedlots, posing a significant increase in public health risks and industry-associated losses. The long-range objective of this proposal is to develop livestock vaccines that elicit cross-protective immunity against multiple salmonellae. Immunization with Salmonella Typhimurium vaccines, which lack the DNA adenine methylase (Dam), confer cross-protection against heterologous Salmonella in murine, avian, and bovine models of salmonellosis. Significantly improved cross-protection was achieved by immunization of mice with a bivalent vaccine consisting of dam- and Dam overproducing (DamOP) S. Typhimurium. <P>(AIM 1). We propose to test whether this Salmonella bivalent vaccine can confer robust cross-protective immunity against multiple salmonellae in calves.<P> (AIM 2). Vaccine commercial success is dependent on their efficacy relative to safety. Here we propose to evaluate whether the introduction of attenuating mutations (e.g., aroA) into Salmonella dam mutant vaccine strains improves vaccine safety without compromising efficacy. <P>(AIM 3). Oral vaccination of pre-ruminant calves with dam mutant Salmonella attenuates the severity of clinical disease, reduces fecal shedding, and promotes clearance of salmonellae following virulent challenge. We propose to evaluate oral (via drinking water) versus parenteral delivery of Salmonella dam mutant vaccines in adult ruminants with the objective of developing a cost effective delivery system to prevent livestock salmonellosis. Reducing pre-harvest pathogen load to multiple salmonellae through vaccination will promote the health and productivity of livestock, reduce Salmonella contamination of livestock-derived food products, and enhance overall food safety. <P>TIMETABLE AND MILESTONES <BR>First Year: Initiate multivalent dam mutant cross-protection experiments in calves. Initiate construction of additional attenuating mutations in Salmonella dam mutant vaccines. Initiate vaccination of adult ruminant. <BR>Second Year: Complete multivalent dam mutant cross-protection experiments in calves. Initiate safety and efficacy studies in mice and calves with vaccines carrying additional attenuating mutations. Continue evaluation of dam mutant vaccination of adult ruminants. <BR>Third Year: Complete safety and efficacy studies of Salmonella dam mutant vaccines in mice and calves with vaccines carrying additional attenuating mutations. Complete evaluation of dam mutant vaccination of adult ruminants.
NON-TECHNICAL SUMMARY: Intensive livestock production and management systems are associated with increased fecal-oral pathogen transmission and a resultant high prevalence of multiple salmonellae in large dairy farms and feedlots, posing a significant increase in public health risks and industry-associated losses. Salmonella is the most commonly isolated infectious enteric bacterial pathogen of dairy cattle and the most common zoonotic disease associated with human consumption of beef and dairy products. In recent years there has been a rise in the incidence and severity of human cases of salmonellosis, and emergence of multidrug resistant strains of Salmonella. Prevalence studies indicate 16 to 73% of U.S. dairy farms are infected with Salmonella and up to 50% of cull dairy cows are contaminated with Salmonella at slaughter. On-farm Salmonella control is important to reduce production losses and human food borne disease. Additionally, on large commercial dairy farms it is very common for cattle to be exposed to multiple Salmonella serotypes and for calves to become infected shortly after. Thus, it is imperative to develop livestock vaccines that are capable of eliciting potent states of cross-protective immunity against a diversity of serovars of a given species. The long-range objective of this proposal is to develop livestock vaccines that elicit cross-protective immunity against multiple salmonellae. We propose to test whether a modified live Salmonella vaccine can confer robust cross-protective immunity against multiple salmonellae in calves. Since vaccine commercial success is dependent on their efficacy relative to safety, we further propose whether vaccine safety can be improved by further attenuating the virulence of the Salmonella vaccine strain. Last, we propose to evaluate oral (via drinking water) versus parenteral delivery of modified live Salmonella in adult ruminants with the objective of developing a cost effective delivery system to prevent livestock salmonellosis. Reducing pre-harvest pathogen load to multiple salmonellae through vaccination will promote the health and productivity of livestock, reduce Salmonella contamination of livestock-derived food products, and enhance overall food safety.
<P>APPROACH: We propose to determine whether immunization of calves with a dam mutant Typhimurium vaccine (serogroup B) has the capacity to elicit cross-protection against a virulent challenge with an emerging, clinically relevant, and multi-drug resistant strains of Salmonella that have been associated with clinical disease in recent salmonellosis outbreaks in calves. Since vaccine commercial success is dependent on their efficacy relative to safety, we further propose whether vaccine safety can be improved by introducing additional attenuating mutations into the the Salmonella dam mutant vaccine strains. The experimental outcome of the safety and efficacy studies will be evaluated by challenging vaccinated animals, and quantifying whether they exhibit a significant attenuation of clinical disease (improved attitude scores, increased daily weight gains and reduced fever and diarrhea) and a concomitant reduction in Salmonella fecal shedding and colonization of mesenteric lymph nodes and lungs compared to non-vaccinated control animals. The capacity to elicit cross-protective immunity in calves would have commercial application in commercial livestock production systems wherein livestock are exposed to a diversity of Salmonella serovars.