Attenuated mannheimia haemolytica vaccines and methods of making and use
The present invention provides attenuated M. haemolitica strains that elicit an immune response in animal against M. haemolitica , compositions comprising said strains, methods of vaccination against M. haemolitica , 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. An intranasal 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.
2. The intranasal vaccine of claim 1 , 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.
3. The intranasal vaccine of claim 2 , consisting essentially of the attenuated strains.
4. The intranasal vaccine of claim 2 , further comprising an adjuvant.
5. The intranasal vaccine of claim 2 , 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 9.2×10 6 CFU of the attenuated A6 strain.
6. The intranasal vaccine of claim 2 , 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.
7. The intranasal vaccine of claim 5 , further comprising an adjuvant.
8. The intranasal vaccine of claim 7 , wherein the adjuvant is inactivated bacteria, inactivated virus, fractions of inactivated bacteria, bacterial lipopolysaccharides, bacterial toxins, or derivatives or combinations thereof.
9. The intranasal vaccine of claim 2 , 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.
10. The intranasal vaccine of claim 2 , further comprising at least one additional antigen associated with a bovine pathogen other than M. haemolytica.
11. A method of vaccinating an animal comprising administering at least one dose of the intranasal vaccine of claim 2 .
12. The method of claim 11 , wherein the animal is a bovine.
13. The method of claim 11 , wherein the bovine is a calf that is 28 days or older.
14. An immunological composition suitable for the prevention of bovine respiratory disease caused by M. haemolytica , comprising the vaccine of claim 2 , and further comprising an immunologically effective amount of attenuated Pasteurella multocida and Histophilus somni.
15. The composition of claim 14 , comprising 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.
16. The composition of claim 14 , further comprising an adjuvant.
17. The composition of claim 16 , wherein the adjuvant is selected from inactivated bacteria, inactivated virus, fractions of inactivated bacteria, bacterial lipopolysaccharides, bacterial toxins, chitosan, derivatives and combinations thereof.
18. The composition of claim 17 , wherein the adjuvant is a chitosan derivative.