Adjuvant formulations comprising tlr4 agonists and methods of using the same

Abstract

Formulations and methods, including vaccines and pharmaceutical compositions for inducing or enhancing an immune response are disclosed. The formulations generally comprise a TLR4 agonist and a metabolizable oil at a concentration of about 0.01%-1% v/v, wherein the hydrophobic:lipophilic balance (HLB) of the emusion is greater than about 9.

1 . An oil-in-water emulsion comprising a TLR4 agonist, a surfactant, and a metabolizable oil, wherein the TLR4 agonist comprises synthetic GLA, wherein the metabolizable oil is present in the oil-in-water emulsion at a concentration of 0.01%-1% v/v, and wherein the hydrophobic:lipophilic balance (HLB) of the oil-in-water emulsion is greater than about 9. 
     
     
         2 . The oil-in-water emulsion of  claim 1 , wherein the metabolizable oil is present in the oil-in-water emulsion at a concentration of 0.01%-0.5% v/v. 
     
     
         3 . The oil-in-water emulsion of  claim 1 , wherein the emulsion further comprises 1,2-dimyristoyl-sn-glycero-3-phosphocholine(DMPC). 
     
     
         4 . The oil-in-water emulsion of  claim 3 , wherein the emulsion does not comprise an antioxidant. 
     
     
         5 . The oil-in-water emulsion of  claim 1 , wherein the HLB of the emulsion is greater than about 10. 
     
     
         6 . The oil-in-water emulsion of  claim 1 , wherein the HLB of the emulsion is between about 9-12. 
     
     
         7 . (canceled) 
     
     
         8 . The oil-in-water emulsion of  claim 1 , wherein the synthetic GLA has the following structure: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, where: R 1 , R 3 , R 5 , and R 6  are C11-C 20  alkyl; and R 2  and R 4  are C 12 -C 20  alkyl. 
     
     
         9 . The oil-in-water emulsion of  claim 8 , wherein R 1 , R 3 , R 5 , and R 6  are C 11  alkyl; and R 2  and R 4  are C 13  alkyl. 
     
     
         10 . The oil-in-water emulsion of  claim 8 , wherein R 1 , R 3 , R 5 , and R 6  are C 10  alkyl; and R 2  and R 4  are C 8  alkyl. 
     
     
         11 . (canceled) 
     
     
         12 . The oil-in-water emulsion of  claim 1 , wherein the surfactant is pluronic F68. 
     
     
         13 . The oil-in-water emulsion of  claim 1 , wherein the metabolizable oil is squalene. 
     
     
         14 . The oil-in-water emulsion of  claim 1 , wherein the emulsion further comprises an antioxidant. 
     
     
         15 . The oil-in-water emulsion of  claim 14 , wherein the antioxidant is vitamin E. 
     
     
         16 . The oil-in-water emulsion of  claim 1 , wherein the emulsion further comprises at least one antigen. 
     
     
         17 - 21 . (canceled) 
     
     
         22 . A method of stimulating an immune response in a subject comprising administering an oil-in-water emulsion of  claim 1  to the subject and thereby stimulating an immune response in the subject. 
     
     
         23 . The method of  claim 22 , wherein the immune response is a non-specific immune response. 
     
     
         24 . The method of  claim 22 , wherein the immune response is an antigen-specific immune response. 
     
     
         25 . The method of  claim 22 , wherein the oil-in-water emulsion is administered intradermally. 
     
     
         26 . The oil-in-water emulsion of  claim 1 , wherein the emulsion does not comprise egg phosphatidyl choline (PC). 
     
     
         27 . The oil-in-water emulsion of  claim 1 , wherein the surfactant is present in the oil-and-water emulsion at a concentration of 0.002% to 2% w/v.