Novel parenteral vaccine formulations and uses thereof

Abstract

Parenteral vaccine formulations and adjuvant compositions comprising certain salts as adjuvants are disclosed. Such parenteral vaccine formulations are used for generating an immune response in a subject following administration of the vaccine formulation or the adjuvant composition. Also disclosed is the use of these salts as adjuvants in parenteral vaccine formulations and adjuvant compositions, and to vaccine adjuvants comprising such salts.

1 . A parenteral vaccine formulation comprising at least one immunogenic substance, and as an adjuvant one or more salts selected from salts formed with a Group 2 element of the Periodic Table selected from Mg, Ca, Sr, Ba and Ra, or a Group 4 element of the Periodic Table selected from Ti, Zr, Hf, and Rf, 
 and hydrates thereof,    with the proviso that the salt is not calcium phosphate, is not magnesium hydroxide in combination with aluminium hydroxide or aluminium oxide and is not calcium hydroxide in gel combination with zinc hydroxide, lecithin and polyalphaolefine.    
     
     
         2 . A parenteral vaccine formulation according to  claim 1 , wherein the adjuvant is selected from inorganic salts.  
     
     
         3 . A parenteral vaccine formulation according to  claim 1 , wherein the adjuvant is selected from organic salts.  
     
     
         4 . A parenteral vaccine formulation according to claims  1 - 2 , wherein the adjuvant is selected from salts formed with oxides, peroxides, hydroxides, carbonates, phosphates, pyrophosphates, hydrogenphosphates, dihydrogenphosphates, sulphates, and/or silicates, 
 and hydrates thereof.    
     
     
         5 . A parenteral vaccine formulation according to claims  1 - 2 , and  4 , wherein the adjuvant is selected from salts formed between Mg, Ca, Ba, Ti, or Zr, and oxide, peroxide, hydroxide, and/or carbonate, 
 and hydrates thereof.    
     
     
         6 . A parenteral vaccine formulation according to claims  1 - 2 , and  4 - 5 , wherein the adjuvant is selected from salts formed between 
 magnesium and oxide, peroxide, hydroxide, and/or carbonate,    calcium and oxide, peroxide, hydroxide, and/or carbonate, barium and oxide, peroxide, hydroxide, and/or carbonate, titanium and oxide, peroxide, hydroxide, and/or carbonate, and    zirconium and oxide, peroxide, hydroxide, and/or carbonate,    and hydrates thereof.    
     
     
         7 . A parenteral vaccine formulation according to claims  1 - 2 , and  4 - 6 , wherein the adjuvant is selected from magnesium hydroxide, magnesium carbonate hydroxide pentahydrate, titanium dioxide, calcium carbonate, barium hydroxide, barium peroxide, barium carbonate, barium sulphate, beryllium oxide, calcium sulphate, calcium silicate, dicalcium silicate, tricalcium silicate, calcium pyrophosphate, calcium peroxide, calcium hydroxide, tricalcium phosphate, calcium hydrogen- phosphate, calcium dihydrogenphosphate, calcium sulphate dihydrate, magnesium carbonate, magnesium oxide, magnesium dioxide, magnesium sulphate, trimagnesium phosphate, magnesium silicate, dimagnesium trisilicate, magnesium trisilicate, titantium disulphate, zirconium dioxide, zirconium hydroxide, zirconium sulphate, strontium peroxide, and strontium carbonate.  
     
     
         8 . A parenteral vaccine formulation according to claims  1 - 2 , and  4 - 7 , wherein the adjuvant is selected from magnesium hydroxide, magnesium carbonate hydroxide pentahydrate, and titanium dioxide.  
     
     
         9 . A parenteral vaccine formulation according to claims  1 - 8  further comprising an additional adjuvant.  
     
     
         10 . A parenteral vaccine formulation according to  claim 9 , wherein the additional adjuvant is selected from saponins such as Quil A and Qs-21, MF59, MPL, PLG, PLGA, calcium phosphate, and aluminium salts.  
     
     
         11 . A parenteral vaccine formulation according to claims  1 - 10  further comprising pharmaceutically acceptable excipients and/or carriers.  
     
     
         12 . A parenteral vaccine formulation according to claims  1 - 11  further comprising diluents, buffers, suspending agents, solubilising agents, pH-adjusting agents, dispersing agents, and/or colorants.  
     
     
         13 . A parenteral vaccine formulation according to claims  1 - 12  for intravenous, intramuscular, intraarticular, subcutaneous, intradermal, epicutantous, and intraperitoneal administration.  
     
     
         14 . A parenteral vaccine formulation according to claims  1 - 13 , wherein the cation of the adjuvant is present in an amount of from about 0.0004 to about 120 M, such as from about 0.004 to about 12 M.  
     
     
         15 . A parenteral vaccine formulation according to  claim 14 , wherein the cation of the adjuvant is present in an amount of from about 0.008 to about 6 M.  
     
     
         16 . A parenteral vaccine formulation according to claims  1 - 15 , wherein the adjuvant is magnesium hydroxide.  
     
     
         17 . A parenteral vaccine formulation according to claims  1 - 15 , wherein the adjuvant is magnesium carbonate hydroxide pentahydrate.  
     
     
         18 . A parenteral vaccine formulation according to claims  1 - 15 , wherein the adjuvant is titanium dioxide.  
     
     
         19 . A parenteral vaccine formulation according to claims  1 - 15 , wherein the adjuvant is a combination of magnesium hydroxide and magnesium carbonate hydroxide pentahydrate, magnesium hydroxide and titanium dioxide, magnesium carbonate hydroxide pentahydrate and titanium dioxide, or magnesium hydroxide, magnesium carbonate hydroxide pentahydrate, and titanium dioxide.  
     
     
         20 . A parenteral vaccine formulation according to claims  16 - 19  further comprising an additional adjuvant selected from saponins such as Quil A and Qs-21, MF59, MPL, PLG, PLGA, calcium phosphate, and aluminium salts.  
     
     
         21 . An adjuvant composition for parenteral use comprising one or more salts selected from salts formed with a Group 2 element of the Periodic Table selected from Mg, Ca, Sr, Ba and Ra, or a Group 4 element of the Periodic Table selected from Ti, Zr, Hf, and Rf, 
 and hydrates thereof,    with the proviso that the salt is not calcium phosphate, is not magnesium hydroxide in combination with aluminium hydroxide or aluminium oxide and is not calcium hydroxide in gel combination with zinc hydroxide, lecithin and polyalphaolefine.    
     
     
         22 . An adjuvant composition according to  claim 21 , wherein the salt is selected from inorganic salts.  
     
     
         23 . An adjuvant composition according to  claim 21 , wherein the salt is selected from organic salts.  
     
     
         24 . An adjuvant composition according to claims  21 - 22 , wherein the salt is selected from salts formed with oxides, peroxides, hydroxides, carbonates, phosphates, pyrophosphates, hydrogenphosphates, dihydrogenphosphates, sulphates, and/or silicates, 
 and hydrates thereof.    
     
     
         25 . An adjuvant composition according to claims  21 - 22 , and  24 , wherein the salt is selected from salts formed between Mg, Ca, Ba, Ti or Zr, and oxide, peroxide, hydroxide, and/or carbonate, 
 and hydrates thereof.    
     
     
         26 . An adjuvant composition according to claims  21 - 22 , and  24 - 25 , wherein the salt is selected from salts formed between 
 magnesium and oxide, peroxide, hydroxide, and/or carbonate,    calcium and oxide, peroxide, hydroxide, and/or carbonate, barium and oxide, peroxide, hydroxide, and/or carbonate, titanium and oxide, peroxide, hydroxide, and/or carbonate, and    zirconium and oxide, peroxide, hydroxide, and/or carbonate,    and hydrates thereof.    
     
     
         27 . An adjuvant composition according to claims  21 - 22 , and  24 - 26 , wherein the salt is selected from magnesium hydroxide, magnesium carbonate hydroxide pentahydrate, titanium dioxide, calcium carbonate, barium hydroxide, barium peroxide, barium carbonate, barium sulphate, beryllium oxide, calcium sulphate, calcium silicate, dicalcium silicate, tricalcium silicate, calcium pyrophosphate, calcium peroxide, calcium hydroxide, tricalcium phosphate, calcium hydrogenphosphate, calcium dihydrogenphosphate, calcium sulphate dihydrate, magnesium carbonate, magnesium oxide, magnesium dioxide, magnesium sulphate, trimagnesium phosphate, magnesium silicate, dimagnesium trisilicate, magnesium trisilicate, titantium disulphate, zirconium dioxide, zirconium hydroxide, zirconium sulphate, strontium peroxide, and strontium carbonate.  
     
     
         28 . An adjuvant composition according to claims  21 - 22 , and  24 - 27 , wherein the salt is selected from magnesium hydroxide, magnesium carbonate hydroxide pentahydrate, and titanium dioxide.  
     
     
         29 . An adjuvant composition according to claims  21 - 28  further comprising an additional adjuvant.  
     
     
         30 . An adjuvant composition according to  claim 29 , wherein the additional adjuvant is selected from saponins such as Quil A and Qs-21, MF59, MPL, PLG, PLGA, calcium phosphate, and aluminium salts.  
     
     
         31 . An adjuvant composition according to claims  21 - 30  further comprising pharmaceutically acceptable excipients and/or carriers.  
     
     
         32 . An adjuvant composition according to claims  21 - 31  further comprising diluents, buffers, suspending agents, solubilising agents, pH-adjusting agents, dispersing agents, and/or colorants.  
     
     
         33 . An adjuvant composition according to claims  21 - 32 , wherein the cation of the salt is present in an amount of from about 0.0004 to about 120 M, such as from about 0.004 to about 12 M.  
     
     
         34 . An adjuvant composition according to  claim 33 , wherein the cation of the salt is present in an amount of from about 0.008 to about 6 M.  
     
     
         35 . An adjuvant composition according to claims  21 - 34 , wherein the salt is magnesium hydroxide.  
     
     
         36 . An adjuvant composition according to claims  21 - 34 , wherein the salt is magnesium carbonate hydroxide pentahydrate.  
     
     
         37 . An adjuvant composition according to claims  21 - 34 , wherein the salt is titanium dioxide.  
     
     
         38 . An adjuvant composition according to claims  21 - 34 , wherein the salt is a combination of magnesium hydroxide and magnesium carbonate hydroxide pentahydrate, magnesium hydroxide and titanium dioxide, magnesium carbonate hydroxide pentahydrate and titanium dioxide, or magnesium hydroxide, magnesium carbonate hydroxide pentahydrate, and titanium dioxide.  
     
     
         39 . An adjuvant composition according to claims  35 - 38  further comprising an additional adjuvant selected from saponins such as Quil A and Qs-21, MF59, MPL, PLG, PLGA, calcium phosphate, and aluminium salts.  
     
     
         40 . An adjuvant comprising one or more salts selected from salts formed with a Group 2 element of the Periodic Table selected from Mg, Ca, Sr, Ba and Ra, or a Group 4 element of the Periodic Table selected from Ti, Zr, Hf, and Rf, 
 and hydrates thereof,    with the proviso that the salt is not calcium phosphate, is not magnesium hydroxide in combination with aluminium hydroxide or aluminium oxide and is not calcium hydroxide in gel combination with zinc hydroxide, lecithin and polyalphaolefine.    
     
     
         41 . An adjuvant according to  claim 40 , wherein the salt is selected from inorganic salts.  
     
     
         42 . An adjuvant according to claims  40 , wherein the salt is selected from organic salts.  
     
     
         43 . An adjuvant according to claims  40 - 41 , wherein the salt is selected from salts formed with oxides, peroxides, hydroxides, carbonates, phosphates, pyrophosphates, hydrogenphosphates, dihydrogenphosphates, sulphates, and/or silicates, and hydrates thereof.  
     
     
         44 . An adjuvant according to claims  40 - 41 , and  43 , wherein the salt is selected from salts formed between Mg, Ca, Ba, Ti or Zr, and oxide, peroxide, hydroxide, and/or carbonate, and hydrates thereof.  
     
     
         45 . An adjuvant according to claims  40 - 41 , and  43 - 44  wherein the salt is selected from salts formed between 
 magnesium and oxide, peroxide, hydroxide, and/or carbonate,  
 calcium and oxide, peroxide, hydroxide, and/or carbonate, barium and oxide, peroxide, hydroxide, and/or carbonate, titanium and oxide, peroxide, hydroxide, and/or carbonate, and  
 zirconium and oxide, peroxide, hydroxide, and/or carbonate,  
 and hydrates thereof.  
 
     
     
         46 . An adjuvant according to claims  40 - 41 , and  43 - 45  wherein the salt is selected from magnesium hydroxide, magnesium carbonate hydroxide pentahydrate, titanium dioxide, calcium carbonate, barium hydroxide, barium peroxide, barium carbonate, barium sulphate, calcium sulphate, tricalcium silicate, calcium pyrophosphate, calcium peroxide, calcium hydroxide, tricalcium phosphate, calcium hydrogenphosphate, calcium dihydrogenphosphate, calcium sulphate dihydrate, magnesium carbonate, magnesium sulphate, trimagnesium phosphate, magnesium silicate, magnesium trisilicate, titantium disulphate, zirconium sulphate, strontium peroxide, and strontium carbonate.  
     
     
         47 . An adjuvant according to claims  40 - 41 , and  43 - 46 , wherein the salt is selected from magnesium hydroxide, magnesium carbonate hydroxide pentahydrate, and titanium dioxide, or the salt is selected from a combination of magnesium hydroxide and magnesium carbonate hydroxide pentahydrate, magnesium hydroxide and titanium dioxide, magnesium carbonate hydroxide pentahydrate and titanium dioxide, or magnesium hydroxide, magnesium carbonate hydroxide pentahydrate, and titanium dioxide.  
     
     
         48 . Use of an adjuvant according to claims  40 - 47  or an adjuvant composition according to claims  21 - 39  as a component of a parenteral vaccine formulation.  
     
     
         49 . Use of a salt formed with a Group 2 element of the Periodic Table selected from Mg, Ca, Sr, Ba and Ra, or a Group 4 element of the Periodic Table selected from Ti, Zr, Hf, and Rf, 
 and hydrates thereof,    as an adjuvant in a vaccine formulation for parenteral administration,    with the proviso that the salt is not calcium phosphate, is not magnesium hydroxide in combination with aluminium hydroxide or aluminium oxide and is not calcium hydroxide in gel combination with zinc hydroxide, lecithin and polyalphaolefine.    
     
     
         50 . Use of a salt formed with a Group 2 element of the Periodic Table selected from Mg, Ca, Sr, Ba and Ra, or a Group 4 element of the Periodic Table selected from Ti, Zr, Hf, and Rf, 
 and hydrates thereof,    as a component of an adjuvant composition,    with the proviso that the salt is not calcium phosphate, is not magnesium hydroxide in combination with aluminium hydroxide or aluminium oxide and is not calcium hydroxide in gel combination with zinc hydroxide, lecithin and polyalphaolefine.    
     
     
         51 . Use according to claims  49 - 50 , wherein the salt is selected from inorganic salts.  
     
     
         52 . Use according to claims  49 - 50 , wherein the salt is selected from organic salts.  
     
     
         53 . Use according to claims  49 - 51 , wherein the salt is selected from salts formed with oxides, peroxides, hydroxides, carbonates, phosphates, pyrophosphates, hydrogenphosphates, dihydrogenphosphates, sulphates, and/or silicates, 
 and hydrates thereof.    
     
     
         54 . Use according to claims  49 - 51 , and  53  wherein the salt is selected from salts formed between Mg, Ca, Ba, Ti, or Zr, and oxide, peroxide, hydroxide, and/or carbonate, 
 and hydrates thereof.  
 
     
     
         55 . Use according to claims  49 - 51 , and  53 - 54 , wherein the salt is selected from salts formed between 
 magnesium and oxide, peroxide, hydroxide, and/or carbonate,    calcium and oxide, peroxide, hydroxide, and/or carbonate, barium and oxide, peroxide, hydroxide, and/or carbonate, titanium and oxide, peroxide, hydroxide, and/or carbonate, and    zirconium and oxide, peroxide, hydroxide, and/or carbonate,    and hydrates thereof.    
     
     
         56 . Use according to claims  49 - 51 , and  53 - 55 , wherein the salt is selected from magnesium hydroxide, magnesium carbonate hydroxide pentahydrate, titanium dioxide, calcium carbonate, barium hydroxide, barium peroxide, barium carbonate, barium sulphate, beryllium oxide, calcium sulphate, calcium silicate, dicalcium silicate, tricalcium silicate, calcium pyrophosphate, calcium peroxide, calcium hydroxide, tricalcium phosphate, calcium hydrogenphosphate, calcium dihydrogenphosphate, calcium sulphate dihydrate, magnesium carbonate, magnesium oxide, magnesium dioxide, magnesium sulphate, trimagnesium phosphate, magnesium silicate, dimagnesium trisilicate, magnesium trisilicate, titantium disulphate, zirconium dioxide, zirconium hydroxide, zirconium sulphate, strontium peroxide, and strontium carbonate.  
     
     
         57 . Use according to claims  49 - 51 , and  53 - 56  wherein the salt is selected from magnesium hydroxide, magnesium carbonate hydroxide pentahydrate, and titanium dioxide, or wherein the salt is selected from a combination of magnesium hydroxide and magnesium carbonate hydroxide pentahydrate, magnesium hydroxide and titanium dioxide, magnesium carbonate hydroxide pentahydrate and titanium dioxide, or magnesium hydroxide, magnesium carbonate hydroxide pentahydrate, and titanium dioxide.  
     
     
         58 . A method of generating an immune response in a subject comprising administering to the subject a parenteral vaccine formulation according to claims  1 - 20 .  
     
     
         59 . Vaccination or treatment of a vertebrate including a human being comprising administering a vaccine formulation according to claims  1 - 20 .  
     
     
         60 . A process for preparing a parenteral vaccine formulation according to claims  1 - 20  comprising adding liquid to a dry form of or a pre-formed gel of the salt formed with a Group 2 element of the Periodic Table selected from Mg, Ca, Sr, Ba and Ra, or a Group 4 element of the Periodic Table selected from Ti, Zr, Hf, and Rf, the salt not being calcium phosphate, not being magnesium hydroxide in combination with aluminium hydroxide or aluminium oxide and not being calcium hydroxide in gel combination with zinc hydroxide, lecithin and polyalphaolefine, thereby obtaining an adjuvant composition, and mixing said adjuvant composition with one or more immunogenic substances and optionally pharmaceutically acceptable carriers and/or excipients, thereby obtaining the parenteral vaccine formulation.  
     
     
         61 . Parenteral vaccine formulation obtainable by the process according to claim  60 .