Attenuated mannheimia haemolytica vaccines and methods of making and use
Inventors
Bey, Russell F. • Lawrence, Paulraj Kirubakaran • Simonson, Randy R.
Assignees
US Department of Agriculture USDA • Boehringer Ingelheim Animal Health USA Inc
Publication Number
US-9370561-B2
Publication Date
2016-06-21
Expiration Date
2033-11-08
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Abstract
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.
Core Innovation
The invention provides attenuated Mannheimia haemolytica (M. haemolytica) strains that induce an immune response in animals, particularly bovines, against M. haemolytica infections. These attenuated strains contain genomic modifications, including deletions in the leukotoxin CA (lktCA) genomic locus, resulting in secretion of a truncated, noncytotoxic form of the LktA protein. Compositions comprising these strains can be formulated as vaccines, which may be administered intranasally or by other routes, either alone or in combination with other bacteria such as Pasteurella multocida and Histophilus somni.
The problem addressed by the invention is the limited efficacy of existing vaccines against M. haemolytica, especially for preventing bovine respiratory disease complex (BRDC) and 'shipping fever' caused mainly by serotypes A1 and A6. Current commercial vaccines provide only moderate protection against shipping fever in beef cattle and are generally ineffective against neonatal dairy calf pneumonia. Cross-protection against different serotypes like A6 or A2 using conventional vaccines has been difficult to achieve. Thus, there is a need for an efficacious vaccine that effectively protects against serotypes A1 and A6 of M. haemolytica.
The invention further provides multi-valent vaccines comprising the attenuated M. haemolytica strains in combination with other bacteria, offering broad, safe, and effective protection against BRDC pathogens. The vaccines can be formulated with adjuvants, including mucosal adjuvants like chitosan derivatives, to augment the immune response. Additionally, methods for producing the attenuated strains, for vaccinating susceptible animals, and for diagnosing or differentiating M. haemolytica serotypes A1 and A6 using PCR techniques are provided.
Claims Coverage
The patent claims encompass multiple inventive features related to attenuated Mannheimia haemolytica vaccines, their compositions, methods of vaccination, and methods for providing protection against bovine respiratory disease. The independent claims focus on the composition of the vaccine, its dosage and administration, adjuvant inclusion, and multivalent formulations.
Vaccine comprising attenuated M. haemolytica A1 and A6 strains
A vaccine including both attenuated Mannheimia haemolytica serotype A1 and A6 strains that provide a safe and protective immune response in bovines against these strains or diseases caused by them, wherein both attenuated strains possess nucleic acid deletions in their leukotoxin A (lktA) genes rendering the strains attenuated relative to their virulent parental strains.
Vaccine dosage and administration
A safe and protective intranasal dose of the vaccine comprises approximately from 1.19×10^6 to 1.19×10^7 colony forming units (CFU) of the attenuated A1 strain and from about 9.2×10^5 to 9.2×10^6 CFU of the attenuated A6 strain, administered in a pharmaceutically or veterinarily acceptable vehicle.
Adjuvant inclusion in vaccine compositions
The vaccine may further comprise an adjuvant, which can be inactivated bacteria, inactivated virus, fractions of inactivated bacteria, bacterial lipopolysaccharides, bacterial toxins, or derivatives or combinations thereof, to enhance immune response.
Multivalent vaccine formulations
Vaccines can include additional antigens from other bovine pathogens aside from M. haemolytica, such as Pasteurella multocida and Histophilus somni, thus forming a multivalent immunological composition to prevent bovine respiratory disease.
Method of vaccinating animals
A method of vaccinating animals comprising administering at least one dose of the vaccine containing the attenuated M. haemolytica strains, preferably via intranasal route, particularly targeting bovines including calves aged 28 days or older.
The patent claims collectively cover vaccines comprising attenuated M. haemolytica strains A1 and A6 with leukotoxin gene deletions that confer attenuation, vaccine formulations including adjuvants and multivalent antigens, dosage and administration methods specifically for bovines, and the resulting protective immune response against M. haemolytica infections and bovine respiratory disease.
Stated Advantages
The vaccines provide safe, effective, and broad protective immunity against M. haemolytica serotypes A1 and A6, which are primary causes of bovine respiratory disease.
Multi-valent vaccine formulations confer protection against multiple pathogens involved in shipping fever and bovine respiratory disease complex.
Intranasal administration of the attenuated live vaccines effectively reduces nasopharyngeal colonization with wild-type M. haemolytica and induces protective immunity.
PCR methods developed enable rapid, reliable differentiation and monitoring of M. haemolytica serotypes A1 and A6, facilitating vaccine efficacy evaluation and diagnostics.
Documented Applications
Vaccination of bovine animals, especially calves 28 days or older, against Mannheimia haemolytica serotypes A1 and A6 to prevent or treat infections causing shipping fever and bovine respiratory disease complex.
Use of multi-valent vaccines combining attenuated M. haemolytica with other bovine respiratory pathogens such as Pasteurella multocida and Histophilus somni for broader respiratory disease protection.
Intranasal vaccination protocols to induce mucosal immunity and reduce bacterial colonization in the upper respiratory tract of cattle.
Diagnostic application of PCR-based methods to distinguish and monitor M. haemolytica serotypes A1 and A6 in vaccinated or field animal populations.
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