P
USRE45587EExpiredUtilityPatentIndex 49

Vaccines comprising aluminum adjuvants and histidine

Assignee: CONTORNI MARIOPriority: Jul 26, 2001Filed: Feb 2, 2012Granted: Jun 30, 2015
Est. expiryJul 26, 2021(expired)· nominal 20-yr term from priority
Inventors:CONTORNI MARIOMAFFEI MASSIMO
A61P 31/00A61P 31/04A61P 31/20A61P 37/00A61P 31/16A61K 39/39A61K 38/00A61K 2039/55505A61K 39/095Y02A50/30
49
PatentIndex Score
0
Cited by
307
References
107
Claims

Abstract

To improve the stability of vaccines comprising aluminum salt(s), the invention uses the amino acid histidine. This can improve pH stability and adjuvant adsorption and can reduce antigen hydrolysis. Histidine is preferably present during adsorption to the aluminum salt(s). The antigen in the vaccine may be a protein or a saccharide and is preferably from N. meningitidis.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
       1. A composition comprising an antigen a mixture comprising one or more antigens selected from the group consisting of an outer-membrane vesicle (OMV) preparation from N. meningitidis and a saccharide antigen from N. meningitidis, an aluminium salt, and histidine, said composition further comprising at least about 2.5 mM of free phosphate wherein the one or more antigens are adsorbed to the aluminium salt, wherein the composition does not comprise an antigen from B. pertussis, and wherein the histidine has a concentration from about 1 mM to about 100 mM. 
     
     
       2. The composition of  claim 1  comprising from about 2.5 to about 5 mM of free phosphate. 
     
     
       3. The composition of  claim 1 , wherein one of the antigen one or more antigens is a protein antigen or a saccharide antigen. 
     
     
       4. The composition of  claim 3 , wherein the saccharide antigen is a conjugated oligosaccharide antigen. 
     
     
       5. The composition of  claim 1 , wherein the antigen is a bacterial antigen selected from the group consisting of:
 a protein antigen from N. meningitidis; 
 an outer-membrane vesicle (OMV) preparation from N. meningitidis; 
 a saccharide antigen from N. meningitidis; 
 a saccharide antigen from Streptococcus pnemnoniae; 
 an antigen from Bordetella pertussis; 
 a diphtheria antigen; 
 a tetanus antigen; 
 a protein antigen from Helicobacter pylori; 
 a saccharide antigen from Haemophilus influenzae; 
 an antigen from N. gonorrhoeae; 
 an antigen from Chlamydia pneumoniae; 
 an antigen from Chlamydia trachomatis; 
 an antigen from Porphyromonas gingivalis; 
 an antigen from Moraxella catarrhalis; 
 an antigen from Streptococcus agalactiae; 
 an antigen from Streptococcus pyogenes; and 
 an antigen from Staphylococcus aureus. 
 
     
     
       6. The composition of  claim 5 , wherein one of the antigen one or more antigens is a protein antigen from N. meningitides serogroup B or a saccharide antigen from N. meningitides serogroup C. 
     
     
       7. The composition of  claim 1 , wherein one of the antigen one or more antigens is selected from the group consisting of a protein antigen from N. meningitidis serogroup B; a saccharide antigen from N. meningitidis serogroup A, C, W135 or Y; a diphtheria antigen; a tetanus antigen; and an antigen from hepatitis B virus. 
     
     
       8. The composition of  claim 7 , wherein the antigen is the protein antigen ΔG287 from N. meningitidis serogroup B or the diphtheria toxoid antigen CRM 197  mutant. 
     
     
       9. The composition of  claim 1 , wherein the antigen is adsorbed onto the aluminum salt. 
     
     
       10. The composition of claim  9  1, wherein the aluminium salt is selected from the group consisting of an aluminum hydroxide salt, an aluminum phosphate salt, and mixtures thereof. 
     
     
       11. The composition of  claim 10 , wherein the aluminium salt is selected from the group consisting of aluminum oxyhydroxide, aluminum hydroxyphosphate, and mixtures thereof. 
     
     
       12. The composition of  claim 11 , wherein aluminium salt is aluminium hydroxyphosphate and the antigen is an acidic antigen. 
     
     
       13. The composition of  claim 1 , wherein the histidine has a concentration from about 1 mM to about 250 mM. 
     
     
       14. The composition of  claim 13 , wherein the histidine has a concentration from about 1 mM to about 100 mM. 
     
     
       15. The composition of claim  14  1, wherein the histidine has a concentration from about 1 mM to about 10 mM. 
     
     
       16. The composition of  claim 15 , wherein the histidine has a concentration from about 5 mM to about 10 mM. 
     
     
       17. The composition of  claim 1 , further comprising a sodium salt. 
     
     
       18. The composition of  claim 17 , wherein the sodium salt is sodium phosphate. 
     
     
       19. The composition of  claim 17 , wherein the sodium salt has a concentration from about 2.5 mM to about 5 mM. 
     
     
       20. The composition of  claim 1 , wherein the composition has a pH between 6 and 7. 
     
     
       21. The composition of  claim 1 , further comprising a pharmaceutically acceptable carrier. 
     
     
       22. The composition of  claim 1 , comprising more than one antigen. 
     
     
       23. The composition of  claim 22 , wherein more than one of the antigens is adsorbed onto an the aluminum salt. 
     
     
       24. The composition of  claim 23 , comprising 2, 3, 4, 5, 6, 7 or 8 antigens selected from the following antigens: a protein antigen from N. meningitidis serogroup B; an antigen from Bordetella pertussis; a diphtheria antigen; a tetanus antigen; an antigen from hepatitis B virus; a saccharide antigen from Haemophilus influenzae; inactivated polio virus; and a saccharide antigen from N. meningitidis serogroup C. 
     
     
       25. A method for raising an immune response in a mammal comprising the step of administering an effective amount of the composition of  claim 1 . 
     
     
       26. The method of  claim 25 , wherein the mammal is a human. 
     
     
       27. The method of  claim 25 , wherein the composition comprises from about 2.5 mM to about 5 mM of free phosphate. 
     
     
       28. The method of  claim 25 , wherein the composition comprises histidine in a concentration from about 1 mM to about 250 mM. 
     
     
       29. The method of  claim 28 , wherein the composition comprises histidine in a concentration from about 1 mM to about 100 mM. 
     
     
       30. The method of  claim 29 , wherein the composition comprises histidine in a concentration from about 1 mM to about 10 mM. 
     
     
       31. The method of  claim 30 , wherein the composition comprises histidine in a concentration from about 5 mM to about 10 mM. 
     
     
       32. A process for producing the antigenic composition of  claim 1 , the process comprising admixing the antigen, the aluminium salt, and histidine, wherein histidine is present during adsorption of the antigen to the aluminum salt , a first step of admixing (i) the aluminium salt and (ii) histidine, to give a histidine/aluminium salt admixture; and a second step of admixing (i) said histidine/aluminium salt admixture and (ii) the antigen, wherein the antigen is adsorbed to the aluminium salt. 
     
     
       33. The process of  claim 32 , wherein the admixing comprises: a first step of admixing (i) the aluminium salt and (ii) histidine, to give a histidine/aluminium salt admixture; and a second step of admixing (i) said histidine/aluminium salt admixture and (ii) one or more antigens. 
     
     
       34. The process of  claim 32 , further comprising combining the antigenic composition with another antigenic composition. 
     
     
       35. The process of  claim 32 , wherein the antigenic composition comprises from about 2.5 mM to about 5 mM of free phosphate. 
     
     
       36. The process of  claim 32 , wherein the antigenic composition comprises from about 1 mM to about 250 mM of histidine. 
     
     
       37. The process of  claim 36 , wherein the antigenic composition comprises from about 1 mM to about 100 mM of histidine. 
     
     
       38. The process of  claim 37 , wherein the antigenic composition comprises from about 1 mM to about 10 mM of histidine. 
     
     
       39. The process of  claim 38 , wherein the antigenic composition comprises from about 5 mM to about 10 mM of histidine. 
     
     
       40. A vaccine comprising the composition of  claim 1  and a pharmaceutically acceptable carrier or excipient. 
     
     
       41. The vaccine of  claim 40 , comprising from about 2.5 mM to about 5 mM of free phosphate. 
     
     
       42. The vaccine of  claim 40 , comprising from about 1 mM to about 250 mM of histidine. 
     
     
       43. The vaccine of  claim 42 , comprising from about 1 mM to about 100 mM of histidine. 
     
     
       44. The vaccine of claim  43  40, comprising from about 1 mM to about 10 mM of histidine. 
     
     
       45. The vaccine of  claim 44 , comprising from about 5 mM to about 10 mM of histidine. 
     
     
       46. The method of  claim 25 , wherein the composition comprises a mixture of antigens, essentially a single aluminium salt, histidine, and at least about 2.5 mM of free phosphate, wherein said single aluminum salt is present in a ratio of at least 100:1 relative to any other aluminum salt in the composition. 
     
     
       47. The method of  claim 46 , wherein the composition comprises from about 2.5 mM to about 5 mM of free phosphate. 
     
     
       48. The method of  claim 46 , wherein the composition comprises histidine in a concentration from about 1 mM to about 250 mM. 
     
     
       49. The method of  claim 48 , wherein the composition comprises histidine in a concentration from about 1 mM to about 100 mM. 
     
     
       50. The method of  claim 49 , wherein the composition comprises histidine in a concentration from about 1 mM to about 10 mM. 
     
     
       51. The method of  claim 50 , wherein the composition comprises histidine in a concentration from about 5 mM to about 10 mM. 
     
     
       52. The method of  claim 46 , wherein the single aluminum salt is an aluminum hydroxide or an aluminum phosphate. 
     
     
       53. The method of  claim 52 , wherein the single aluminum salt is aluminum oxyhydroxide or aluminum hydroxyphosphate. 
     
     
       54. A composition comprising a mixture comprising one or more antigens selected from the group consisting of an outer-membrane vesicle (OMV) preparation from N. meningitidis and a saccharide antigen from N. meningitidis, an aluminium salt, a sodium salt, and histidine, wherein the one or more antigens are adsorbed to the aluminium salt, and wherein the composition does not comprise an antigen from B. pertussis. 
     
     
       55. A composition comprising a mixture comprising one or more protein antigens from N. meningitidis, an aluminium salt, and histidine, wherein the one or more antigens are adsorbed to the aluminium salt, and wherein the composition does not comprise an antigen from B. pertussis. 
     
     
       56. A composition comprising a mixture comprising one or more antigens selected from the group consisting of a protein antigen from N. meningitidis; an outer-membrane vesicle (OMV) preparation from N. meningitidis and a saccharide antigen from N. meningitidis, an aluminium phosphate salt, and histidine, wherein the one or more antigens are adsorbed to the aluminium phosphate salt, and wherein the composition does not comprise an antigen from B. pertussis. 
     
     
       57. The composition of any one of claims 54-56, wherein the histidine has a concentration from about 1 mM to about 100 mM. 
     
     
       58. The composition of claim 57, wherein the histidine has a concentration from about 1 mM to about 10 mM. 
     
     
       59. The composition of claim 58, wherein the histidine has a concentration from about 5 mM to about 10 mM. 
     
     
       60. The composition of any one of claims 1, 54, and 56, wherein the one or more antigens are protein antigens from N. meningitidis. 
     
     
       61. The composition of any one of claims 1, 54, and 55, wherein the aluminium salt is an aluminum phosphate salt. 
     
     
       62. The composition of any one of claims 1, 55, and 56, further comprising a sodium salt. 
     
     
       63. A formulation which stabilizes a N. meningitidis 741 protein composition, the formulation comprising (i) a pH buffered solution comprising histidine (ii) a detergent, and (iii) a N. meningitidis 741 protein. 
     
     
       64. A composition comprising a mixture comprising one or more protein antigens from N. meningitidis, an aluminium salt, and histidine, wherein the composition does not comprise an H. influenzae saccharide antigen. 
     
     
       65. The composition of any one of claims 54-56, wherein the histidine has a concentration from about 1 mM to about 100 mM. 
     
     
       66. A composition comprising a mixture comprising one or more protein antigens from N. menigitidis, an aluminium salt, and histidine, wherein the one or more protein antigens are adsorbed to the aluminium salt and wherein the histidine has a concentration from about 1 mM to about 100 mM. 
     
     
       67. The composition of claim 66 comprising from about 2.5 to about 5 mM of free phosphate. 
     
     
       68. The composition of claim 66, wherein one of the one or more protein antigens is ΔG287 from N. meningitidis serogroup B. 
     
     
       69. The composition of claim 66, wherein the aluminium salt is selected from the group consisting of an aluminium hydroxide salt, an aluminium phosphate salt, and mixtures thereof. 
     
     
       70. The composition of claim 66, wherein the aluminium salt is selected from the group consisting of aluminium oxyhydroxide, aluminium hydroxyphosphate, and mixtures thereof. 
     
     
       71. The composition of claim 66, wherein aluminium salt is aluminium hydroxyphosphate and the antigen is an acidic antigen. 
     
     
       72. The composition of claim 66, wherein the histidine has a concentration from about 1 mM to about 10 mM. 
     
     
       73. The composition of claim 72, wherein the histidine has a concentration from about 5 mM to about 10 mM. 
     
     
       74. The composition of claim 66, further comprising a sodium salt. 
     
     
       75. The composition of claim 66, wherein the composition has a pH between 6 and 7. 
     
     
       76. The composition of claim 66, further comprising a pharmaceutically acceptable carrier. 
     
     
       77. The composition of claim 66, comprising two protein antigens from N. meningitidis. 
     
     
       78. A method for raising an immune response in a mammal comprising the step of administering an effective amount of the composition of claim 66. 
     
     
       79. The method of claim 78, wherein the mammal is a human. 
     
     
       80. The method of claim 78, wherein the composition comprises from about 2.5 mM to about 5 mM of free phosphate. 
     
     
       81. The method of claim 78, wherein the composition comprises histidine in a concentration from about 1 mM to about 10 mM. 
     
     
       82. The method of claim 81, wherein the composition comprises histidine in a concentration from about 5 mM to about 10 mM. 
     
     
       83. A process for producing the antigenic composition of claim 66, the process comprising, a first step of admixing (i) the aluminium salt and (ii) histidine, to give a histidine/aluminium salt admixture; and a second step of admixing (i) said histidine/aluminium salt admixture and (ii) the antigen, wherein the antigen is adsorbed to the aluminium salt. 
     
     
       84. The process of claim 83, further comprising combining the antigenic composition with another antigenic composition. 
     
     
       85. The process of claim 83, wherein the antigenic composition comprises from about 2.5 mM to about 5 mM of free phosphate. 
     
     
       86. The process of claim 83, wherein the antigenic composition comprises from about 1 mM to about 10 mM of histidine. 
     
     
       87. The process of claim 86, wherein the antigenic composition comprises from about 5 mM to about 10 mM of histidine. 
     
     
       88. A vaccine comprising the composition of claim 66 and a pharmaceutically acceptable carrier or excipient. 
     
     
       89. The vaccine of claim 88, comprising from about 2.5 mM to about 5 mM of free phosphate. 
     
     
       90. The vaccine of claim 88, comprising from about 1 mM to about 10 mM of histidine. 
     
     
       91. The vaccine of claim 90, comprising from about 5 mM to about 10 mM of histidine. 
     
     
       92. The composition of any one of claims 54-56 and 66, wherein the Al +++  has a concentration of at least 10 μg/mL. 
     
     
       93. The composition of any one of claims 54-56 and 66, wherein the one or more antigens are present at a concentration of at least 1 μg/mL. 
     
     
       94. The composition of any one of claims 54-56 and 66, wherein the composition comprises no viral antigens. 
     
     
       95. The composition of any one of claims 54-56 and 66, wherein the composition comprises a sodium chloride salt. 
     
     
       96. The composition of any one of claims 54-56 and 66, wherein the composition does not comprise a preservative. 
     
     
       97. The composition of any one of claims 54-56 and 66, wherein the composition does not comprise an H. influenzae saccharide antigen. 
     
     
       98. The composition of any one of claims 54-56 and 66, wherein one of the one or more antigens is the protein antigen 741 from N. meningitidis serogroup B. 
     
     
       99. A process for producing the antigenic composition of claim 55, the process comprising, a first step of admixing (i) the aluminium salt and (ii) histidine, to give a histidine/aluminium salt admixture; and a second step of admixing (i) said histidine/aluminium salt admixture and (ii) the protein antigen from N. meningitidis serogroup B, wherein the protein antigen from N. meningitidis serogroup B is adsorbed to the aluminium salt. 
     
     
       100. The process of claim 99, further comprising combining the antigenic composition with another antigenic composition. 
     
     
       101. The process of claim 99, wherein the antigenic composition comprises from about 5 mM to about 10 mM of histidine. 
     
     
       102. A vaccine comprising the composition of claim 55 and a pharmaceutically acceptable carrier or excipient. 
     
     
       103. The vaccine of claim 102, comprising from about 5 mM to about 10 mM of histidine. 
     
     
       104. The composition of claim 55, wherein the aluminium phosphate salt is the only aluminium salt in the composition. 
     
     
       105. The composition of claim 64, wherein the aluminium salt is an aluminium phosphate salt, and the aluminium phosphate salt is the only aluminium salt in the composition. 
     
     
       106. The composition of claim 64, wherein the composition does not comprise not comprise an antigen from B. pertussis. 
     
     
       107. A composition comprising a mixture comprising two protein antigens from N. meningitidis, an aluminium hydroxyphosphate salt, histidine, and a sodium chloride salt, wherein the two protein antigens are adsorbed to the aluminium hydroxyphosphate salt, wherein the histidine has a concentration from about 5 mM to about 10 mM L-histidine, wherein the composition has a pH between 6 and 7, wherein the Al +++  of the alumninium hydroxyphosphate has a concentration of at least 10 μg/mL, wherein the two protein antigens are each present at a concentration of at least 1 μg/mL, wherein the composition comprises no viral antigens, wherein the composition does not comprise a preservative, and wherein the composition does not comprise an H. influenzae saccharide antigen or an antigen from B. pertussis.

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