ADJUVANTING MENINGOCOCCAL FACTOR H BINDING PROTEIN

• US 20120148619A1
• Filed: 02/23/2012
• Published: 06/14/2012
• Est. Priority Date: 03/24/2009
• Status: Active Grant

• Current Assignee: Glaxosmithkline Biologicals SA (GlaxoSmithKline PLC)
• Original Assignee: Novartis Ag
• Inventors: CONTORNI, Mario, Tarli, Lorenzo
• Granted Patent: US 8,398,988 B2
• Time in Patent Office: Days
• US Class Current: 424/190.1
• CPC Class Codes: A61K 2039/55505 Inorganic adjuvants
• CPC Class Codes: A61K 2039/55583 Polysaccharides
• CPC Class Codes: A61K 2039/6018 Lipids, e.g. in lipopeptides
• CPC Class Codes: A61K 2039/70 Multivalent vaccine
• CPC Class Codes: A61K 39/095 Neisseria
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 37/04 Immunostimulants

Abstract

Factor H binding protein (fHBP) has been proposed for use in immunising against serogroup B meningococcus (‘MenB’). This antigen can be efficiently adsorbed to an aluminium hydroxyphosphate adjuvant by (i) ensuring that adsorption takes place at a pH which is equal to or below the adjuvant'"'"'s point of zero charge (PZC), and/or (ii) selecting a fHBP and adjuvant with an isoelectric point/PZC within the range of 5.0 to 7, and/or (iii) selecting a fHBP with an isoelectric point above the adjuvant'"'"'s PZC and using a buffer to bring the pH to within 1.2 pH units of the PZC. The adsorption is particularly useful for compositions which include multiple fHBP variants, and also in situations where an aluminium hydroxide adjuvant should be avoided. Buffered pharmaceutical compositions can include at least two different meningococcal fHBP antigens, both of which are at least 85% adsorbed to aluminium hydroxyphosphate adjuvant.

Claims

1. An immunogenic composition comprising two different meningococcal fHBP antigens, both of which are adsorbed to aluminium hydroxyphosphate adjuvant, wherein (i) both of the meningococcal fHBP antigens have an isoelectric point between 5.0 and 7.0, and (ii) the aluminium hydroxyphosphate adjuvant has a point of zero charge between 5.0 and 7.0.

2. The composition of claim 1, wherein (i) both of the meningococcal fHBP antigens have an isoelectric point which is greater than the adjuvant'"'"'s point of zero charge and (ii) the composition has a pH which is within 1.2 pH units of the adjuvant'"'"'s point of zero charge.

3. The composition of claim 1, including a buffer to maintain pH in the range of 5.0 to 7.0.

4. The composition of claim 3, including a histidine buffer.

5. The composition of claim 1, wherein the immunogenic composition includes a buffer to maintain pH in the range of 5.0 to 6.0.

6. The composition of claim 1, including a buffer which maintains the pH within 1.2 pH units of the adjuvant'"'"'s point of zero charge.

7. The composition of claim 1, including a buffer which maintains the pH within 0.5 pH unit of the adjuvant'"'"'s point of zero charge.

8. The composition of claim 1, wherein both of the meningococcal fHBP antigens have an isoelectric point between 5.0 and 6.0.

9. The composition of claim 1, wherein both of the meningococcal fHBP antigens have an isoelectric point between 5.2 and 6.2.

10. The composition of claim 1, wherein the aluminium hydroxyphosphate has a point of zero charge between 5.4 and 6.2.

11. The composition of claim 1, wherein (i) both of the meningococcal fHBP antigens have an isoelectric point between 5.2 and 6.2 and (ii) the aluminium hydroxyphosphate has a point of zero charge between 5.0 and 6.0.

12. The composition of claim 1, wherein the composition does not include an aluminium hydroxide adjuvant.

13. The composition of claim 1, including a conjugated bacterial capsular saccharide.

14. The composition of claim 13, including a pneumococcal capsular saccharide conjugated to a carrier protein.

15. The composition of claim 14, including capsular saccharide from each of pneumococcal serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F.

16. The composition of claim 15, including capsular saccharide from:

(a) each of pneumococcal serotypes 1, 4, 5, 6B, 9V, 14, 18C, 19F and 23F;

(b) each of pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F;

(c) each of pneumococcal serotypes 1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F;

or (d) each of pneumococcal serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19, 19F and 23F.

17. The composition of claim 1, wherein the aluminium hydroxyphosphate has a P/A1 molar ratio between 0.85 and 1.0.

18. The composition of claim 1, wherein the aluminium hydroxyphosphate is amorphous and particulate comprising plates with diameters 10-100 nm.

19. The composition of claim 1, wherein the Al⁺⁺⁺ concentration is <

2 mg/ml.

20. The composition of claim 19, wherein the Al⁺⁺⁺ concentration is between 0.2 and 1 mg/ml.

21. The composition of claim 1, wherein the composition includes NaCl.

22. The composition of claim 21, wherein the concentration of NaCl is 10±

2 mg/ml.

23. The composition of claim 21, comprising polysorbate 80.

24. The composition of claim 1, including between 1 and 500 μ

g/dose of each fHbp polypeptide.

25. The composition of claim 24, having 20, 40, 50, 60, 80, 100 or 200 μ

g of each fHBP polypeptide.

26. The composition of claim 1, wherein the fHBP polypeptides are lipidated at a N-terminus cysteine.

27. The composition of claim 1, wherein the two different fHBP antigens are:

(i) a first polypeptide comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO;

4; and

(ii) a second polypeptide comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO;

6.

28. The composition of claim 26, wherein the two different fHBP antigens are:

(a) a first polypeptide comprising an amino acid sequence having at least 98% sequence identity to SEQ ID NO;

4; and

(b) a second polypeptide comprising an amino acid sequence having at least 98% sequence identity to SEQ ID NO;

6.

29. The composition of claim 27, wherein the first polypeptide is a lipoprotein having amino acid sequence SEQ ID NO:

23 and the second polypeptide is a lipoprotein having amino acid sequence SEQ ID NO;

25.

30. The composition of claim 1, wherein the two different fHBP antigens are:

(a) a first polypeptide comprising an amino acid sequence having at least 98% sequence identity to SEQ ID NO;

4 and being lipidated at a N-terminus cysteine; and

(b) a second polypeptide comprising an amino acid sequence having at least 98% sequence identity to SEQ ID NO;

6 and being lipidated at a N-terminus cysteine, and wherein the composition;

(i) includes a histidine buffer to maintain a pH in the range of 5.0 to 7.0;

(ii) has an Al⁺⁺⁺ concentration between 0.2 and 1 mg/ml;

(iii) includes NaCl;

(iv) includes polysorbate 80; and

(v) includes between 1 and 500 μ

g/dose of each fHbp polypeptide.