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1. WO2009013443 - INACTIVATED STAPHYLOCOCCAL WHOLE-CELL VACCINE

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Claims
1. A vaccine composition comprising an inactivated staphylococcal cell wherein said composition is prepared using a staphylococcal cell characterised in that said cell:
i) is a gram positive cocci;
ii) expresses at least the enzyme catalase;
iii) induces an immune response that produces antibodies that bind at least staphylococcal collagen-binding protein; and
iv) is resistant to the antibiotic penicillin.

2. The vaccine composition according to claim 1 wherein said staphylococcal cell also expresses the enzymes coagulase and/or Dnase.

3. The vaccine composition according to claim 1 or 2 wherein said staphylococcal cell induces an immune response that produces antibodies that bind collagen binding protein

4. The vaccine composition according to any of claims 1-3 wherein said inactivated staphylococcal cell induces an immune response that produces antibodies that cross react with methicillin resistant, vancomycin resistant and vancomycin intermediate resistant staphylococcal species.

5. The vaccine composition according to any of claims 1-4 wherein said staphylococcal cell is sensitive to the antibiotics cloxacillin, erythromycin, tetracycline or gentamicin

6. The vaccine according to any of claims 1-5 wherein said staphylococcal cell is selected from the group consisting of: S.epidermidis, S.aureus, S.hominis,

S.haemolyticus, S.warneή, S.capitis, S.saccharolyticus, S.auήcularis, S.simulans, S.saprophyticus, S.cohnii, S.xylosus, S.cohnii, S.warneri, S.hyicus, S.caprae, S.gallinarum, S.intermedius, S.hominis.

7. The vaccine composition according to claim 6 wherein said staphylococcal cell is S. aureus or S. epidermidis.

8. The vaccine composition according to claim 6 or 7 wherein said S. aureus or S. epidermidis is antibiotic resistant.

9. The vaccine composition according to claim 8 wherein said antibiotic resistance is a methicillin resistant staphylococcal cell (MRSA).

10. The vaccine composition according to claim 8 wherein said antibiotic resistance staphylococcal species is a vancomycin resistant staphylococcal cell (VRSA).

11. The vaccine composition according to any of claims 1-7 wherein said staphylococcal cell is Staphylococcus aureus (accession number 13408).

12. The vaccine composition according to any of claims 1-11 wherein said staphylococcal cell is provided at a protein concentration of not more than about 1.Omg or 0.45mg bacterial protein/ml.

13. The vaccine composition according to any of claims 1-11 wherein said staphylococcal cell is provided at a protein concentration of at least 0.0001 mg or 0.1 mg bacterial protein/ml

14. The vaccine composition according to any of claims 1-11 wherein said staphylococcal cell is provided at a protein concentration of between 0.0001 -1mg bacterial protein/ml.

15. The vaccine composition according to any of claims 1-11 wherein said staphylococcal cell is provided at a protein concentration of between 0.1-0.45mg bacterial protein/ml.

16. The vaccine composition according to any of claims 1-11 wherein said staphylococcal cell is provided at between 0.25-0.36mg bacterial protein/ml.

17. The vaccine composition according to any of claims 1-11 wherein said staphylococcal cell is provided at about 0.35mg bacterial protein/ml.

18. The vaccine composition according to any of claims 1-17 wherein said vaccine comprises an adjuvant and/or excipient.

19. The vaccine composition according to any of claims 1-18 wherein said composition includes at least one additional anti-bacterial agent to provide a combination therapy.

20. The vaccine composition according to claim 19 wherein said agent is a second different vaccine and/or immunogenic agent.

21. The vaccine composition according to any of claims 1-20 wherein said vaccine composition is adapted for administration as a nasal spray.

22. The vaccine composition according to claim 21 wherein said composition is provided in an inhaler and delivered as an aerosol.

23. An inhaler comprising a vaccine composition according to any of claims 1-22.

24. A staphylococcal cell wherein said cell comprises the following characterising features:
i) is a gram positive cocci;
ii) expresses at least the enzyme catalase;
iii) induces an immune response that produces antibodies that bind at least staphylococcal collagen-binding protein; and
iv) is resistant to the antibiotic penicillin,
for use in the preparation of a vaccine.

25. A staphylococcal cell wherein said cell comprises the following characterising features:
i) is a gram positive cocci;
ii) expresses at least the enzyme catalase;
iii) induces an immune response that produces antibodies that bind at least staphylococcal collagen-binding protein;
iv) is resistant to the antibiotic penicillin;

for use in the manufacture of a vaccine composition for the vaccination of an animal subject with respect to a bacterial infection wherein said infection is not caused by a staphylococcal bacterial species.

26. A vaccine composition according to claim 25 wherein said bacterial infection is caused by at least one bacterial species selected from the group consisting of: Enterococcus faecalis; Mycobacterium tuberculsis; Streptococcus group B; Streptoccocus pneumoniae; Helicobacter pylori; Neisseria gonorrhoea; Streptococcus group A; Borrelia burgdorferi; Coccidiodes immitis; Histoplasma sapsulatum; Klebsiella edwardii; Neisseria meningitidis type B; Proteus mirabilis; Shigella flexneri; Escherichia coli; Haemophilus influenzae, Chalmydia trachomatis, Chlamydia pneumoniae, Chlamydia psittaci, Francisella tularensis, Pseudomonas aeruginos, Bacillus anthracis, Clostridium botulinum, Yersinia pestis, Burkholderia mallei or B pseudomallei.

27. A vaccine composition according to claim 25 or 26 wherein said animal subject is human.

28. A method to vaccinate an animal against a bacterial infection comprising administering an effective amount of the vaccine composition according to any of claims 1-22.

29. A method according to claim 28 wherein said animal is a human.

30. A method according to claim 28 or 29 wherein said bacterial infection is caused by a bacterial pathogen selected from the group consisting of: Staphylococcus aureus or Staphylococcus epidermidis; Enterococcus faecalis; Mycobacterium tuberculsis; Streptococcus group B; Streptoccocus pneumoniae; Helicobacter pylori; Neisseria gonorrhoea; Streptococcus group A; Borrelia burgdorferi; Coccidiodes immitis; Histoplasma sapsulatum; Klebsiella edwardii; Neisseria meningitidis type B; Shigella flexneri; Escherichia coli; Haemophilus influenzae, Chalmydia trachomatis, Chlamydia pneumoniae, Chlamydia psittaci, Francisella tularensis, Pseudomonas aeruginos, Bacillus anthracis, Clostridium botulinum, Yersinia pestis, Burkholderia mallei or B pseudomallei.

31. A method according to claim 28 wherein said bacterial pathogen is selected from the group consisting of: S.epidermidis, S.aureus, S.hominis, S.haemolyticus, S.warneri, S.capitis, S.saccharolyticus, S.auricularis, S.simulans, S.saprophyticus, S.cohnii, S.xylosus, S.cohnii, S.warneri, S.hyicus, S.caprae, S.gallinarum, S.intermedius, S.hominis.

32. A method according to claim 31 wherein said bacterial species is Staphylococcus aureus or Staphylococcus epidermidis.

33. A method according to any of claims 28-32 wherein said bacterial infection is caused by an antibiotic resistant bacterial species.

34. A method according to claim 33 wherein said antibiotic resistance bacterial species is a staphylococcal bacterial species.

35. A method according to claim 33 wherein said antibiotic resistance staphylococcal species is a methicillin resistant staphylococcal species (MRSA).

36. A method according to claim 33 wherein said antibiotic resistance staphylococcal species is a vancomycin resistant staphylococcal species (VRSA).

37. A method according to any of claims 28-36 wherein said bacterial infection results in a disease associated with a staphylococcal infection.

38. A method according to claim 37 wherein said staphylococcal associated disease is selected from the group consisting of: tuberculosis; bacteria-associated food poisoning; blood infections; peritonitis; endocarditis; osteomyelitis; sepsis; skin disorders, meningitis; pneumonia; stomach ulcers; gonorrhoea; strep throat; streptococcal-associated toxic shock; necrotizing fasciitis; impetigo; histoplasmosis; Lyme disease; gastro-enteritis; dysentery; shigellosis; and arthritis.

39. A method according to claim 38 wherein said animal is a live stock animal.

40. A method according to claim 39 wherein said live stock animal is vaccinated against bacterial mastitis.

41. A method according to claim 40 wherein said live stock animal is vaccinated against bacterial mastitis caused by gram positive cocci.

42. A method according to claim 41 wherein said gram positive cocci are staphylococcal and/or streptococci bacteria.

43. A method according to claim 42 wherein said bacteria are Staphylococcus aureus and/or Streptococcus agalactiae.

44. A method according to any of claims 35-43 said life stock animal is a caprine or bovine animal.

45. The use of a composition according to any of claims 1-20 in the manufacture of a vaccine for the prevention and/or treatment of bacterial mastitis.

46. Use according to claim 45 wherein bacterial mastitis is caused by gram positive cocci.

47. Use according to claim 46 wherein said gram positive cocci are staphylococcal and/or streptococci bacteria.

48. Use according to claim 47 wherein said bacteria are Staphylococcus aureus and/or Streptococcus agalactiae.

49. A method for preparing a hybridoma cell-line producing monoclonal antibodies that bind staphylococcal bacterial polypeptides comprising the steps of:
i) vaccinating an immunocompetent mammal with a vaccine composition according to any of claims 1-20;
ii) fusing lymphocytes of the vaccinated immunocompetent mammal with myeloma cells to form hybridoma cells;
iii) screening monoclonal antibodies produced by the hybridoma cells of step (ii) for binding activity with respect to staphylococcal bacterial polypeptides;
v) cloning the hybridoma cells and culturing the cells to proliferate and to secrete said monoclonal antibody; and
vi) recovering the monoclonal antibody from the culture supernatant.

50. A method according to claim 49 wherein said immunocompetent mammal is a mouse.

51. A method according to claim 49 wherein said immunocompetent mammal is a rat.

52. A hybridoma cell line formed by the method according to any of claims 49-50.

53. A monoclonal antibody produced by the hybridoma cell-line according to claim 52.

54. A monoclonal antibody according to claim 53 wherein said monoclonal antibody is an opsonic antibody.

55. A monoclonal antibody according to claim 53 or 54 wherein said monoclonal antibody is a chimeric or humanized antibody.

56. An active binding fragment of the monoclonal antibody according to claim 53 or 54.

57. Serum obtained by vaccination of a human subject with a vaccine composition according to any of claims 1-20.

59. A human antibody obtained by vaccination of a human subject with a vaccine composition according to any of claims 1-20.

60. The human antibody according to claim 59 wherein said antibody is an isotype selected from the group consisting of: IgA, IgM, IgD, IgE and IgG.

61. The use of human sera obtained by the vaccination of a human subject with a vaccine composition according to any of claims 1-20 in the manufacture of a medicament for the treatment of a bacterial infection.

62. Use according to claim 61 wherein said bacterial infection is a staphylococcal infection.

63. The use of a human antibody obtained by the vaccination of a human subject with a vaccine composition according to any of claims 1-20 in the manufacture of a medicament for the treatment of a bacterial infection.

64. Use according to claim 63 wherein said bacterial infection is a staphylococcal infection.

65. A method to prepare a vaccine to a bacterial pathogen comprising the steps of: i) forming a cell culture preparation comprising at least one bacterial pathogen and nutrient broth comprising plant derived products;
ii) culturing said cell culture preparation; and
iii) contacting said cell culture preparation with an agent that inactivates said bacterial pathogen.

66. A method according to claim 65 wherein said bacterial pathogen is selected from the group consisting of: Enterococcus faecalis; Mycobacterium tuberculsis; Streptococcus group B; Streptoccocus pneumoniae; Helicobacter pylori; Neisseria gonorrhoea; Streptococcus group A; Borrelia burgdorferi; Coccidiodes immitis; Histoplasma sapsulatum; Klebsiella edwardii; Neisseria meningitidis type B; Proteus mirabilis; Shigella flexneri; Escherichia coli; Haemophilus influenzae, Chalmydia trachomatis, Chlamydia pneumoniae, Chlamydia psittaci, Francisella tularensis, Pseudomonas aeruginos, Bacillus anthracis, Clostridium botulinum, Yersinia pestis, Burkholderia mallei or B pseudomallei.

67. A method according to claim 65 wherein said bacterial pathogen is selected from the group consisting of: S.epidermidis, S.aureus, S.hominis, S.haemolyticus, S.warneri, S.capitis, S.saccharolyticus, S.auricularis, S.simulans, S.saprophyticus, S.cohnii, S.xylosus, S.cohnii, S.warneri, S.hyicus, S.caprae, S.gallinarum, S. intermedins, S.hominis.

68. A method according to claim 67 wherein said bacterial pathogen is Staphylococcus aureus or Staphylococcus epidermidis.

69. A method according to claim 65 wherein said bacterial pathogen is selected from the group consisting of: Streptococcus pneumoniae, Pseudomonas aeruginosa or Eschericia coli.

70. A method according to any of claims 65-69 wherein said plant derived product is vegetable peptone.

71. A method according to claim 70 wherein said vegetable peptone includes pea flour and/or tryptone soya.

72. A method according to any of claims 65-71 wherein said bacterial pathogen is inactivated with chloroform.

73. A method according to any of claims 65-72 wherein said bacterial pathogen is isolated from said cell culture preparation and freeze dried.

74. A process for the production of a vaccine comprising the steps of:
i) forming a preparation comprising a staphylococcal bacterial cells;
ii) contacting the preparation with an agent that inactivates the staphylococcal bacterial cells;
iii) isolating the inactivated staphylococcal bacterial cells;
iv) shearing said preparation to disaggregate the inactivated bacteria; and optionally
v) freeze drying said inactivated staphylococcal bacterial cells

75. A process according to claim 74 wherein said staphylococcal cell is selected from the group consisting of: S.epidermidis, S.aureus, S.hominis, S.haemolyticus, S.warneri, S. capitis, S.saccharolyticus, S.auricularis, S.simulans, S.saprophyticus, S.cohnii, S.xylosus, S.cohnii, S.warneri, S.hyicus, S.caprae, S.gallinarum, S.intermedius, S.hominis.

76. A process according to claim 75 wherein said staphylococcal bacterial cells are Staphylococcus aureus or Staphylococcus epidermidis.

77. A process according to any of claims 74 to 76 wherein said agent is chloroform.

78. A process according to any of claims 74-77 wherein shear force is provided by a dounce homogenizer.

79. A Staphylococcus aureus cell as deposited under accession 13408.

80. A bacterial cell culture comprising a Staphylococcus aureus cell as deposited under accession number 13408.