Compositions and methods for enhancing immune responses to vaccines

Abstract

The disclosure provides adjuvants, immunogenic compositions, and methods useful for vaccination and immune response. In particular, the disclosure provides a class of adjuvants comprising cationic lipid:co-lipid mixtures and methods for delivering formulated compositions.

1 . A compound having formula I: 
       
         
           
           
               
               
           
         
         or an enantiomer, diastereomer, or a pharmaceutically acceptable salt or solvate thereof, wherein: 
         R 1  and R 2  are each independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted carboxyalkyl, wherein R 1  and R 2  are each optionally independently substituted with 1 to 5 R 16  groups; 
         L 1  and L 2  are each independently a direct bond, O, NH, N(C 1 -C 6  alkyl), or S(O) m , wherein m is an integer from 0 to 2; 
         n is an integer from 0 to 6; 
         Q is independently —Z 1 N + Z 2 — or —Z 1 P + Z 2 —; 
         Z 1  and Z 2  are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted carboxyalkyl, or substituted or unsubstituted —(CH 2 ) m —R 3  wherein m is an integer from 1 to 6, and wherein Z 1  and Z 2  are each optionally independently substituted with 1 to 5 R 16  groups; 
         T is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted carboxyalkyl; wherein T is optionally independently substituted with 1 to 5 R 16  groups; and 
         R 3  is —NR 6 R 7 ; 
         R 6  and R 7  are each independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted carboxyalkyl, or R 6  and R 7 , together with the N atom to which they are attached, form substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycloalkyl, wherein R 6  and R 7  are each optionally independently substituted with 1 to 5 R 16  groups; 
         R 16  is hydrogen, halogen, nitro, cyano, hydroxyl, alkyl, cycloalkyl, perfluoroalkyl, heteroalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —(CH 2 ) j CN, —(CH 2 ) j OR 17 , —(CH 2 ) j C(O)R 17 , —(CH 2 ) j C(O)OR 17 , —(CH 2 ) j NR 18 R 19 , —(CH 2 ) j C(O)NR 18 R 19 , —(CH 2 ) j OC(O)NR 18 R 19 , —(CH 2 ) j NR 20 C(O)R 17 , —(CH 2 ) j NR 20 C(O)OR 17 , —(CH 2 ) j N 20 C(O)NR 18 R 19 , —(CH 2 ) j S(O) m R 21 , —(CH 2 ) j S(O) 2 NR 18 R 19 , or —(CH 2 ) j NR 20 S(O) 2 R 21 , wherein each j is independently an integer from 0 to 6, and each m is independently an integer from 0 to 2; 
         R 17 , R 18 , R 19 , R 20  and R 21  are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, perfluoroalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted —O-aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted —O-heteroaryl, or substituted or unsubstituted heteroarylalkyl, or 
         R 17 , R 20  and R 21  are as described above, and R 18  and R 19 , together with the N atom to which they are attached, form substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl; and 
         one or more counter ions. 
       
     
     
         2 . The compound of  claim 1 , wherein:
 R 1  and R 2  are each independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;   L 1  and L 2  are each independently O or NH;   n is 1; and   Q is independently —Z 1 N + Z 2 —.   
     
     
         3 . The compound of  claim 1 , wherein R 1  and R 2  are each independently substituted or unsubstituted (C 1 -C 20 )alkyl, substituted or unsubstituted (C 2 -C 20 )alkenyl, or substituted or unsubstituted (C 2 -C 20 )alkynyl. 
     
     
         4 . The compound of  claim 1 , wherein:
 Z 1  and Z 2  are each independently substituted or unsubstituted —(CH 2 ) m —R 3 ;   T is substituted or unsubstituted alkyl.   
     
     
         5 . The compound of  claim 4 , wherein:
 T is independently (C 1 -C 6 )alkyl; and   R 6  and R 7  are each independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or R 6  and R 7 , together with the N atom to which they are attached, form substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycloalkyl.   
     
     
         6 . The compound of  claim 5 , wherein R 6  and R 7  are each independently substituted or unsubstituted (C 1 -C 6 )alkyl. 
     
     
         7 . The compound of  claim 5 , wherein R 6  and R 7 , together with the N atom to which they are attached, form substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted pyrazolinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted thiomorpholinyl. 
     
     
         8 . The compound of  claim 1 , wherein the compound of formula I has formulae: 
       
         
           
           
               
               
           
         
       
     
     
         9 . An adjuvant composition comprising a mixture of one or more compounds of formula I according to  claim 1 ,
 one or more counter ions, and   one or more co-lipids.   
     
     
         10 . The adjuvant composition of  claim 9 , wherein the co-lipid is a neutral lipid. 
     
     
         11 . The adjuvant composition of  claim 10 , wherein the neutral lipid is a phosphatidylethanolamine, and/or a phosphatidylcholine, and/or a mono-, di-, or trialkylglycerol, and/or a mono-, di-, or triacylglycerol. 
     
     
         12 . The adjuvant composition of  claim 11 , wherein the phosphatidylethanolamine is 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) and/or 1,2-diphytanoyl-sn-glycero-3-phosphoethanolamine (DPyPE), and/or 1,2-dimyristoyl-glycero-3-phosphoethanolamine (DMPE). 
     
     
         13 . The adjuvant composition of  claim 12 , wherein the phosphatidylethanolamine is 1,2-diphytanoyl-sn-glycero-3-phosphoethanolamine (DPyPE). 
     
     
         14 . The adjuvant composition of  claim 9 , wherein the compound of formula I and the co-lipid ratio is from about 9:1 to about 1:9. 
     
     
         15 . The adjuvant composition of  claim 2 , wherein the compound of formula I and the co-lipid are in molar ratio of from about 2:1 to about 1:2. 
     
     
         16 . The adjuvant composition of  claim 2 , wherein the compound of formula I and DPyPE are in molar ratio of about 1:1. 
     
     
         17 . The adjuvant composition of  claim 2 , wherein the compound of formula I has formulae: 
       
         
           
           
               
               
           
         
       
     
     
         18 . An immunogenic composition comprising one or more immunogens and the adjuvant composition of  claim 8 . 
     
     
         19 . The immunogenic composition of  claim 18 , wherein the immunogen is one or more immunogen-encoding polynucleotides, peptides or polypeptides, or polysaccharides. 
     
     
         20 . A method for immunizing a vertebrate comprising administering into a tissue or cavity of the vertebrate an immunogenic composition comprising (a) one or more immunogen-encoding polynucleotide, peptides or polypeptides, or polysaccharides in an amount sufficient to generate an immune response to the one or more peptides or polypeptides, or polysaccharides, and (b) the adjuvant composition of  claim 9 .