Pneumococcal conjugate vaccine formulations

Abstract

The present invention provides pneumococcal conjugate vaccine formulations comprising surfactant systems incorporating polysorbate 20 or a combination of a poloxamer and a polyol.

1 . A formulation comprising (i) one or more polysaccharide-protein conjugates; (ii) a pH buffered saline solution having a pH in the range from 5.0 to 7.5; (ii) an aluminum salt; and (iv) a surfactant system selected from a) polysorbate 20 and (b) a poloxamer having a molecular weight in the range from 1100 Da to 17,400 Da and a polyol selected from propylene glycol and polyethylene glycol 400. 
     
     
         2 . The formulation of  claim 1 , wherein one or more of the polysaccharide-protein conjugates are made in an aprotic solvent. 
     
     
         3 . The formulation of  claim 1 , wherein 10 to 100% of the polysaccharide-protein conjugates by weight protein are made in an aprotic solvent. 
     
     
         4 . The formulation of  claim 2  or  3 , wherein the aprotic solvent is DMSO. 
     
     
         5 . The formulation of  claim 1 , wherein the surfactant system comprises a poloxamer which has a molecular weight in the range from 1100 Da to 17,400 Da. 
     
     
         6 . The formulation of  claim 5 , wherein the poloxamer has a molecular weight in the range from 7,500 Da to 15,000 Da. 
     
     
         7 . The formulation of  claim 5 , wherein the poloxamer has a molecular weight in the range from 7,500 Da to 10,000 Da. 
     
     
         8 . The formulation of  claim 1 , wherein the poloxamer is poloxamer 188 or poloxamer 407. 
     
     
         9 . The formulation of  claim 1 , wherein the final concentration of the poloxamer is from 0.001% to 5% weight/volume. 
     
     
         10 . The formulation of  claim 9 , wherein the final concentration of the poloxamer is from 0.025% to 1% weight/volume. 
     
     
         11 . The formulation of  claim 1 , wherein the polyol is propylene glycol and is at final concentration from 1% to 20% weight/volume. 
     
     
         12 . The formulation of  claim 1 , wherein the polyol is polyethylene glycol 400 and is at final concentration from 1% to 20% weight/volume. 
     
     
         13 . The formulation of  claim 1 , wherein the surfactant system comprises polysorbate 20. 
     
     
         14 . The formulation of  claim 13 , wherein the final concentration of the polysorbate 20 is in the range from 0.001% to 10% weight/volume. 
     
     
         15 . The formulation of  claim 13 , wherein the final concentration of the polysorbate 20 is in the range from 0.025% to 2.5% weight/volume. 
     
     
         16 . The formulation of  claim 13 , wherein the final concentration of the polysorbate 20 is in the range from 0.025% to 0.1% weight/volume. 
     
     
         17 . The formulation of  claim 13 , further comprising a polyol selected from propylene glycol and polyethylene glycol. 
     
     
         18 . The formulation of  claim 17 , wherein the polyethylene glycol or propylene glycol is at a final concentration of 6% to 20% weight/volume. 
     
     
         19 . The formulation of  claim 18 , wherein the polyethylene glycol is polyethylene glycol 400. 
     
     
         20 . The formulation of  claim 1 , wherein the pH buffered saline solution has a pH in the range from 5.0 to 7.0. 
     
     
         21 . The formulation of  claim 20 , wherein the buffer selected from the group consisting of phosphate, succinate, L-histidine, MES, MOPS, HEPES, acetate and citrate. 
     
     
         22 . The formulation of  claim 21 , wherein the buffer is L-histidine at a final concentration of 5 mM to 50 mM, or succinate at a final concentration of 1 mM to 10 mM. 
     
     
         23 . The formulation of  claim 22 , wherein the L-histidine is at a final concentration of 20 mM±2 mM. 
     
     
         24 . The formulation of  claim 1 , wherein the salt in the pH buffered saline solution is magnesium chloride, potassium chloride, sodium chloride or a combination thereof. 
     
     
         25 . The formulation of  claim 24 , wherein the salt in the pH buffered saline solution is sodium chloride. 
     
     
         26 . The formulation of  claim 1 , wherein the saline is present at a concentration from 20 mM to 170 mM. 
     
     
         27 . The formulation of  claim 1 , wherein the polysaccharide-protein conjugates comprise one or more pneumococcal polysaccharides conjugated to a carrier protein. 
     
     
         28 . The formulation of  claim 27 , wherein the carrier protein is selected from CRM 197 , diphtheria toxin fragment B (DTFB), DTFB C8, Diphtheria toxoid (DT), tetanus toxoid (TT), fragment C of TT, pertussis toxoid, cholera toxoid,  E. coli  LT,  E. coli  ST, exotoxin A from  Pseudomonas aeruginosa , and combinations thereof. 
     
     
         29 . The formulation of  claim 28 , wherein one or more of the polysaccharide-protein conjugates are conjugated to CRM 197 . 
     
     
         30 . The formulation of  claim 29 , wherein the polysaccharide-protein conjugate formulation is a 15-valent pneumococcal conjugate (15vPnC) formulation consisting essentially of  S. pneumoniae  polysaccharide from serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23 F and 33F conjugated to CRM 197 . 
     
     
         31 . The formulation of  claim 30 , wherein one or more of the polysaccharide protein conjugates are prepared using reductive amination under DMSO conditions. 
     
     
         32 . The formulation of  claim 31 , wherein polysaccharide protein conjugates from serotypes 6A, 6B, 7F, 18C, 19A, 19F, and 23F are prepared under DMSO conditions and polysaccharide protein conjugates from serotypes 1, 3, 4, 5, 9V, 14, 22F, and 33F are prepared using aqueous conditions. 
     
     
         33 . The formulation of  claim 32 , wherein each dose is formulated to contain: 4 μg/mL or 8 μg/mL of each saccharide, except for 6B at 8 μg/mL or 16 μg/mL; and about 64 μg/mL or 128 μg/mL CRM 197  carrier protein. 
     
     
         34 . The formulation of  claim 33 , further comprising 20 mM L-histidine, pH 5.8, 150 mM sodium chloride, 0.25 mg/mL of Aluminum Phosphate Adjuvant (APA) and 0.2% w/v PS-20. 
     
     
         35 . A formulation comprising a 15-valent pneumococcal conjugate composition consisting essentially of  S. pneumoniae  polysaccharide from serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23 F and 33F conjugated to CRM 197 ; 20 mM Histidine pH 5.8; 150 mM NaCl; 250 μg/mL APA; and 0.2% w/v PS-20; formulated as a dosage form containing 4 μg/mL of each saccharide, except for 6B at 8 μg/mL; and about 64 μg/mL CRM 197  carrier protein; wherein polysaccharide protein conjugates from serotypes 6A, 6B, 7F, 18C, 19A, 19F, and 23F prepared under DMSO conditions and polysaccharide protein conjugates from serotypes 1, 3, 4, 5, 9V, 14, 22F, and 33F prepared using aqueous conditions.