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.
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0. 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.
0. 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.
0. 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.
0. 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.
0. 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.
0. 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.
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.
0. 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.
3. The composition of
4. The composition of
5. The composition 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
7. The composition of
0. 8. The composition of
0. 9. The composition of
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
12. The composition of
0. 13. The composition of
0. 14. The composition of
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
19. The composition of
23. The composition of
24. The composition of
25. A method for raising an immune response in a mammal comprising the step of administering an effective amount of the composition of
26. The method of
27. The method of
28. The method of
29. The method of
30. The method of
31. The method of
32. A process for producing the antigenic composition of
0. 33. The process of
34. The process of
35. The process of
36. The process of
37. The process of
38. The process of
39. The process of
40. A vaccine comprising the composition of
0. 42. The vaccine of
0. 43. The vaccine of
46. The method of
47. The method of
48. The method of
49. The method of
50. The method of
51. The method of
52. The method of
53. The method of
0. 57. The composition of any one of claims 54-56, wherein the histidine has a concentration from about 1 mm to about 100 mm.
0. 58. The composition of claim 57, wherein the histidine has a concentration from about 1 mm to about 10 mm.
0. 59. The composition of claim 58, wherein the histidine has a concentration from about 5 mm to about 10 mm.
0. 60. The composition of any one of claims 1, 54, and 56, wherein the one or more antigens are protein antigens from n. meningitidis.
0. 61. The composition of any one of claims 1, 54, and 55, wherein the aluminium salt is an aluminum phosphate salt.
0. 62. The composition of any one of claims 1, 55, and 56, further comprising a sodium salt.
0. 65. The composition of any one of claims 54-56, wherein the histidine has a concentration from about 1 mm to about 100 mm.
0. 67. The composition of claim 66 comprising from about 2.5 to about 5 mm of free phosphate.
0. 68. The composition of claim 66, wherein one of the one or more protein antigens is ΔG287 from n. meningitidis serogroup b.
0. 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.
0. 70. The composition of claim 66, wherein the aluminium salt is selected from the group consisting of aluminium oxyhydroxide, aluminium hydroxyphosphate, and mixtures thereof.
0. 71. The composition of claim 66, wherein aluminium salt is aluminium hydroxyphosphate and the antigen is an acidic antigen.
0. 72. The composition of claim 66, wherein the histidine has a concentration from about 1 mm to about 10 mm.
0. 73. The composition of claim 72, wherein the histidine has a concentration from about 5 mm to about 10 mm.
0. 74. The composition of claim 66, further comprising a sodium salt.
0. 75. The composition of claim 66, wherein the composition has a ph between 6 and 7.
0. 76. The composition of claim 66, further comprising a pharmaceutically acceptable carrier.
0. 77. The composition of claim 66, comprising two protein antigens from n. meningitidis.
0. 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.
0. 79. The method of claim 78, wherein the mammal is a human.
0. 80. The method of claim 78, wherein the composition comprises from about 2.5 mm to about 5 mm of free phosphate.
0. 81. The method of claim 78, wherein the composition comprises histidine in a concentration from about 1 mm to about 10 mm.
0. 82. The method of claim 81, wherein the composition comprises histidine in a concentration from about 5 mm to about 10 mm.
0. 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.
0. 84. The process of claim 83, further comprising combining the antigenic composition with another antigenic composition.
0. 85. The process of claim 83, wherein the antigenic composition comprises from about 2.5 mm to about 5 mm of free phosphate.
0. 86. The process of claim 83, wherein the antigenic composition comprises from about 1 mm to about 10 mm of histidine.
0. 87. The process of claim 86, wherein the antigenic composition comprises from about 5 mm to about 10 mm of histidine.
0. 88. A vaccine comprising the composition of claim 66 and a pharmaceutically acceptable carrier or excipient.
0. 89. The vaccine of claim 88, comprising from about 2.5 mm to about 5 mm of free phosphate.
0. 90. The vaccine of claim 88, comprising from about 1 mm to about 10 mm of histidine.
0. 91. The vaccine of claim 90, comprising from about 5 mm to about 10 mm of histidine.
0. 92. The composition of any one of claims 54-56 and 66, wherein the Al+++ has a concentration of at least 10 μg/mL.
0. 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.
0. 94. The composition of any one of claims 54-56 and 66, wherein the composition comprises no viral antigens.
0. 95. The composition of any one of claims 54-56 and 66, wherein the composition comprises a sodium chloride salt.
0. 96. The composition of any one of claims 54-56 and 66, wherein the composition does not comprise a preservative.
0. 97. The composition of any one of claims 54-56 and 66, wherein the composition does not comprise an H. influenzae saccharide antigen.
0. 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.
0. 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.
0. 100. The process of claim 99, further comprising combining the antigenic composition with another antigenic composition.
0. 101. The process of claim 99, wherein the antigenic composition comprises from about 5 mm to about 10 mm of histidine.
0. 102. A vaccine comprising the composition of claim 55 and a pharmaceutically acceptable carrier or excipient.
0. 103. The vaccine of claim 102, comprising from about 5 mm to about 10 mm of histidine.
0. 104. The composition of claim 55, wherein the aluminium phosphate salt is the only aluminium salt in the composition.
0. 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.
0. 106. The composition of claim 64, wherein the composition does not comprise not comprise an antigen from b. pertussis.
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Tween 80TWEEN ™ 80
Reference 94 discloses CRM197 conjugates of capsular oligosaccharides from meningococcus serogroups C, W135 and Y. A trivalent mixture of the three conjugates either adsorbed onto an aluminium oxyhydroxide adjuvant (2 mg/ml) or an aluminium hydroxyphosphate adjuvant (0.6 mg/ml Al3+) was prepared. The compositions of the two trivalent mixtures were as follows:
Component
Concentration
Concentration
Aluminium
0.68 mg Al3+/ml
—
oxyhydroxide
Aluminium
—
0.6 mg Al3+/ml
hydroxyphosphate*
CRM-MenC
20 μg saccharide/ml
20 μg saccharide/ml
CRM-MenY
20 μg saccharide/ml
20 μg saccharide/ml
CRM-MenW135
20 μg saccharide/ml
20 μg saccharide/ml
Sodium phosphate
—
10 mM
buffer
Histidine buffer
10 mM
—
Sodium chloride
9 mg/ml
9 mg/ml
Tween 80
0.005%
0.005%
TWEEN ™ 80
(sorbitan monooleate)
*amorphous hydroxyphosphate, PO4/Al molar ratio between 0.84 and 0.92
For the oxyhydroxide/histidine formulation, stability of the saccharide components either in the bulk mixture or after packaging into vials was as follows:
Stored at 2-8° C.
Stored at 36-38° C.
Free
Free
Free
Free
Time
saccharide
saccharide
saccharide
saccharide
(days)
(μg/ml)
%
(μg/ml)
%
MenC bulk
0
<1.2
<6
<1.2
<6
15
<1.2
<6
<1.2
<6
30
<1.2
<6
<1.2
<6
MenC vials
0
<1.2
<6
<1.2
<6
15
<1.2
<6
<1.2
<6
30
<1.2
<6
1.3
6.6
MenW135 bulk
0
2.5
12.5
2.5
12.5
15
2.3
11.4
3.4
16.8
30
2.3
11.5
3.5
17.3
MenW135 vials
0
2.1
10.6
2.1
10.6
15
2.3
11.7
2.7
13.3
30
20.
10.2
3.3
16.3
MenY bulk
0
1.7
8.3
1.7
8.3
15
<1.3
<6.3
2.0
10.2
30
1.3
6.3
2.4
12.2
MenY Vials
0
1.4
7.1
1.4
7.1
15
1.5
7.6
2.1
10.7
30
1.3
6.3
2.9
14.3
Free saccharide levels are thus stable for at least 1 month at 2-8° C., before and after packaging.
Under thermal stress conditions, small increases in free saccharide are seen over time for MenW135 and MenY, but MenC remains stable.
Over the 30 days, pH in vials and bulk was stable at 7.15±0.05 at both storage temperatures.
The two trivalent liquid compositions of example 8 were diluted and 0.5 ml used to reconstitute the lyophilised MenA conjugate of example 7. The resulting tetravalent mixture was administered to ten Balb/c mice (female 68 weeks old) per group by subcutaneous injection at day 0 and 28. The mixture contained 2 μg of each saccharide conjugate per dose, which represents ⅕ of the single human dose (SHD). Controls were saline or unconjugated homologous polysaccharides. Bleedings were performed before immunization and then at day 42, with sera stored at −70° C.
All the conjugates used were safe and immunogenic in the animals. GMT post-II ELISA titres (with 95% confidence intervals) were as follows:
Vaccine
Adjuvant
A
Y
W135
C
MenA (lyophilised
Hydroxyphosphate
172
—
—
—
and resuspended)
(69-439)
Oxyhydroxide
619
—
—
—
(419-906)
MenY
Hydroxyphosphate
—
328
(147-731)
Oxyhydroxide
—
452
—
—
(344-593)
MenW
Hydroxyphosphate
—
—
80
—
(28-225)
Oxyhydroxide
—
—
277
—
(185-411)
MenC
Hydroxyphosphate
—
—
—
317
(152-659)
Oxyhydroxide
—
—
—
723
(615-851)
MenA (lyophilized) +
Hydroxyphosphate
32
397
99
114
MenC, W135, Y
(15-68)
(252-627)
(35-288)
(53-246)
Oxyhydroxide
206
141
139
163
(112-372)
(97-205)
(76-251)
(122-218)
Typically, therefore, titres are higher in the aluminium oxyhydroxide+histidine groups. Serum bactericidal titres were also generally better in the aluminium oxyhydroxide+histidine groups.
In parallel experiments, mice were immunised as described above but the vaccine compositions contained different ratios of the various oligosaccharide conjugates. Lyophilised MenA oligo-conjugate was used in all experiments. ELISA titres were as follows:
Antigen quantity
GMT ELISA
(ug/dose)
Aluminium
(95% confidence interval)
A
C
W135
Y
adjuvant
A
C
W135
Y
4
2
2
2
Hydroxyphosphate
177
367
239
239
(107-291)
(263-510)
(135-424)
(184-311)
4
2
2
2
Oxyhydroxide
390
494
338
158
(313-486)
(345-706)
(266-430)
(96-260)
2
2
2
2
Hydroxyphosphate
132
582
143
247
(59-296)
(268-1155)
(75-272)
(152-400)
2
2
2
2
Oxyhydroxide
337
569
171
100
(239-476)
(462-679)
(117-251)
(59-169)
A second set of experiments was performed using a dosage of 2 μg/ml saccharide for MenA and MenC, half that dosage for MenY, and a quarter dosage for MenW135. ELISA titres were as follows:
Antigen quantity
GMT ELISA
(ug/dose)
Aluminium
(95% confidence interval)
A
C
W135
Y
adjuvant
A
C
W135
Y
2
2
2
2
Hydroxyphosphate
32
114
99
397
(15-68)
(53-246)
(35-288)
(252-627)
Oxyhydroxide
206
163
139
141
(112-372)
(122-218)
(76-251)
(97-205)
2
2
1
0.5
Hydroxyphosphate
96
238
42
315
(49-187)
(101-561)
(20-89)
(114-867)
Oxyhydroxide
293
267
83
244
(144-597)
(158-451)
(43-163)
(152-392)
At least for serogroups A, C and W135, therefore, the oxyhydroxide+histidine formulation generally gives better titres than hydroxyphosphate at these different antigen ratios.
It will be understood that the invention has been described by way of example only and modifications may be made whilst remaining within the scope and spirit of the invention.
Contorni, Mario, Maffei, Massimo
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