Attenuated Mannheimia haemolytica strains
Inventors
Briggs, Robert E. • Tatum, Fred M.
Assignees
Biotechnology Research and Development Corp • US Department of Agriculture USDA
Publication Number
US-10039819-B2
Publication Date
2018-08-07
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 strains, particularly serotypes A1 and A6, which elicit an immune response in animals against M. haemolytica. These attenuated strains have genomic modifications, including deletions such as a partial gene deletion in the leukotoxin CA (lktCA) locus, resulting in secretion of a truncated, noncytotoxic form of leukotoxin A (LktA). The invention also includes compositions and methods of vaccination using these strains, as well as multi-valent vaccines combining attenuated M. haemolytica with other bacteria like Pasteurella multocida and Histophilus somni to provide protective immunity against bovine respiratory diseases such as shipping fever.
M. haemolytica is a gram-negative bacterium commonly found in the respiratory tract of cattle, causing severe fibrinous and necrotizing bronchopneumonia (bovine respiratory disease complex, BRDC) when animals are stressed. The problem addressed is that current vaccines are only moderately protective against shipping fever caused mainly by serotypes A1 and A6 and generally ineffective against neonatal dairy calf pneumonia. Achieving cross-protection among serotypes and inducing broad, effective immunity have been challenging due to complex virulence factors and limited cross-protection by existing vaccines.
The innovation includes genetically engineered M. haemolytica strains with deletions in virulence genes, particularly in the lktCA locus, reducing virulence while maintaining immunogenicity. These attenuated strains secrete truncated leukotoxin incapable of cytolytic activity but stimulating protective immunity. The invention further provides compositions comprising these strains formulated with pharmaceutically or veterinarily acceptable carriers and optionally mucosal adjuvants such as chitosan derivatives. Intranasal administration methods are emphasized for eliciting protective immune responses in bovine.
Claims Coverage
The patent discloses several inventive features primarily relating to kits containing attenuated M. haemolytica strains and related components. The independent claims define key inventive aspects encompassing attenuated bacteria with specific mutations and related kit compositions.
Kit comprising attenuated M. haemolytica with lktCA gene deletion
A kit containing a first container with an attenuated M. haemolytica bacterium having a deletion within the LktCA gene locus encoding acylase (LktC) and leukotoxin A (LktA), which secretes a truncated LktCA protein with an amino acid sequence set forth in SEQ ID NO: 18, along with instructions for administration to an animal.
Kit comprising attenuated M. haemolytica serotypes A1 and A6
A kit comprising a first container with attenuated M. haemolytica serotype A1 D153 and a second container with attenuated M. haemolytica serotype A6 D174, each having mutated LktCA gene loci encoding the truncated LktCA protein (SEQ ID NO: 18), and instructions for administration to an animal.
The independent claims focus on kits comprising attenuated M. haemolytica strains with specific deletions in the LktCA locus resulting in secretion of a truncated leukotoxin, specifically including serotypes A1 and A6, with instructions and optionally carriers or excipients for vaccination use.
Stated Advantages
The vaccine provides broad, safe, and effective protection against infections caused by M. haemolytica, particularly serotypes A1 and A6.
The attenuated strains elicit neutralizing antibodies against leukotoxin and surface antigens, thereby providing protective immunity.
The attenuated bacteria have reduced virulence and do not cause cytolysis but still stimulate a strong immune response.
Intranasal administration of the vaccine enables mucosal immunity and reduces nasopharyngeal colonization with wild-type M. haemolytica.
Multi-valent vaccines combining attenuated M. haemolytica with other bacteria offer comprehensive protection against bovine respiratory disease.
Documented Applications
Vaccination of bovine animals, particularly cattle, against M. haemolytica infections to prevent or treat bovine respiratory disease complex, including shipping fever.
Use of multi-valent vaccines comprising attenuated M. haemolytica strains in combination with other bacterial pathogens for broader respiratory disease protection in production animals.
Intranasal administration methods for delivering the attenuated M. haemolytica vaccines to stimulate mucosal and systemic immunity.
Diagnostic application of PCR methods to distinguish and monitor M. haemolytica serotypes A1 and A6 in vaccinated and field animals.
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