Attenuated Mannheimia haemolytica Vaccines and Methods of Making and Use

Abstract

The present invention provides attenuated M. haemolytica strains that elicit an immune response in animals against M. haemolytica , compositions comprising said strains, methods of vaccination against M. haemolytica , and kits for use with such methods and compositions. The invention further provides multi-valent vaccines, which provide protective immunity when administered in an effective amount to animals susceptible to “shipping fever” or bovine respiratory disease.

1 . A vaccine comprising an attenuated Mannheimia haemolytica ( M. haemolytica ) A1 strain and an attenuated  M. haemolytica  A6 strain, which vaccine provides a safe and protective immune response in a bovine against both  M. haemolytica  strain A1 and  M. haemolytica  strain A6, or diseases caused by  M. haemolytica  strains A1 and A6; and wherein both the A1 and A6 strains contain nucleic acid deletions in their respective leukotoxin A (lktA) genes, which deletions have rendered the strains attenuated relative to the virulent parental strains A1 and A6 from which the attenuated strains A1 and A6 were produced. 
     
     
         2 . The vaccine of  claim 1 , consisting essentially of the attenuated strains. 
     
     
         3 . The vaccine of  claim 1 , further comprising an adjuvant. 
     
     
         4 . The vaccine of  claim 1 , wherein a safe and protective intranasal dose of the vaccine comprises from about 1.19×10 6  to 1.19×10 7  CFU of the attenuated A1 strain and from about 9.2×10 5  to 9.2x 10 6  CFU of the attenuated A6 strain. 
     
     
         5 . The vaccine of  claim 4 , further comprising a pharmaceutically or veterinary acceptable vehicle, diluent or excipient and from about 1.19×10 6  to 1.19×10 7  CFU of the attenuated A1 strain and from about 9.2×10 5  to 9.2×10 6  CFU of the attenuated A6 strain. 
     
     
         6 . The vaccine of  claim 5 , further comprising an adjuvant. 
     
     
         7 . The vaccine of  claim 6 , wherein the adjuvant is inactivated bacteria, inactivated virus, fractions of inactivated bacteria, bacterial lipopolysaccharides, bacterial toxins, or derivatives or combinations thereof. 
     
     
         8 . The vaccine of  claim 4 , which provides a protective immune response in a bovine against an experimental challenge of about 2.4×10 9  CFU of virulent  M. haemolytica  strain A1. 
     
     
         9 . The vaccine of  claim 1 , further comprising at least one additional antigen associated with a bovine pathogen other than  M. haemolytica.    
     
     
         10 . A method of vaccinating an animal comprising administering at least one dose of the vaccine of  claim 1 . 
     
     
         11 . The method of  claim 10 , wherein the animal is a bovine. 
     
     
         12 . The method of  claim 11 , wherein the bovine is a calf that is 28 days or older. 
     
     
         13 . An immunological composition suitable for the prevention of bovine respiratory disease caused by  M. haemolytica , comprising the vaccine of  claim 1 , and further comprising an immunologically effective amount of attenuated  Pasteurella multocida  and  Histophilus somni.    
     
     
         14 . The method of  claim 10 , wherein the vaccine is administered intranasally.