Vaccines comprising aluminum adjuvants and histidine
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.
1. A composition comprising an antigen, an aluminium salt and histidine, said composition further comprising at least about 2.5 mM of free phosphate.
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 the antigen 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 the antigen 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 the antigen 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 , 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 , 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 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.
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 , 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.