Methods of using a vaccine composition containing synthetic adjuvant

Abstract

Compositions and methods, including vaccines and pharmaceutical compositions for inducing or enhancing an immune response are disclosed based on the discovery of useful immunological adjuvant properties in a synthetic, glycopyranosyl lipid adjuvant (GLA) that is provided in substantially homogeneous form. Chemically defined, synthetic GLA offers a consistent vaccine component from lot to lot without the fluctuations in contaminants or activity that compromise natural-product adjuvants. Also provided are vaccines and pharmaceutical compositions that include GLA and one or more of an antigen, a Toll-like receptor (TLR) agonist, a co-adjuvant and a carrier such as a pharmaceutical carrier.

1 .- 9 . (canceled) 
     
     
         10 . A method of eliciting or enhancing a desired antigen-specific
 immune response in a subject, the method comprising administering to the subject a composition that comprises (a) an antigen; and (b) a glucopyranosyl lipid adjuvant (GLA), wherein the antigen is derived from, or is immunologically cross-reactive with, (i) at least one infectious pathogen that is associated with an infectious disease, (ii) at least one epitope, biomolecule, cell or tissue that is associated with a cancer, or (iii) at least one epitope, biomolecule, cell or tissue that is associated with an autoimmune disease, and thereby eliciting or enhancing a desired antigen-specific immune response.   
     
     
         11 . The method of  claim 10 , wherein the composition further comprises at least one additional component selected from the group consisting of:
 (a) a toll-like receptor (TLR) agonist;   (b) a saponin or saponin mimetic;   (c) a carrier that comprises at least one of an oil and ISCOMATRIX™;   (d) an imidazoquinoline immune response modifier;   (e) a double stem loop immune modifier (dSLIM);   (f) a co-adjuvant; and   (g) a pharmaceutically acceptable carrier.   
     
     
         12 . The method of  claim 11  wherein:
 (i) the co-adjuvant, when present, is selected from the group consisting of alum, a plant alkaloid and a detergent, wherein the plant alkaloid is selected from tomatine and the detergent is selected from saponin, Polysorbate 80, Span 85 and Stearyl tyrosine, 
 (ii) the TLR agonist, when present, is selected from the group consisting of lipopolysaccharide, peptidoglycan, polyl:C, CpG, 3M003, flagellin,  Leishmania  homolog of eukaryotic ribosomal elongation and initiation factor 4a (LeIF) and at least one hepatitis C antigen, and 
 (iii) the imidazoquinoline immune response modifier, when present, is selected from the group consisting of resiquimod (R848), imiquimod and gardiquimod; 
 (iv) the co-adjuvant, when present, is selected from the group consisting of a cytokine, a detergent, and a block copolymer or biodegradable polymer, and 
 (v) the pharmaceutically acceptable carrier, when present, comprises a carrier that is selected from the group consisting of calcium phosphate, an oil-in-water emulsion, a water-in-oil emulsion, a liposome, and a microparticle. 
 
     
     
         13 . The method of  claim 10  wherein the GLA is not 3′-de-O-acylated. 
     
     
         14 . The method of  claim 10  wherein the GLA is a derivative of 3-acylated monophosphorylated lipid A, wherein the 2 amine position comprises a single acyl chain. 
     
     
         15 . The method of  claim 10  wherein the GLA comprises:
 (i) a diglucosamine backbone having a reducing terminus glucosamine linked to a non-reducing terminus glucosamine through an ether linkage between hexosamine position 1 of the non-reducing terminus glucosamine and hexosamine position 6 of the reducing terminus glucosamine; 
 (ii) an O-phosphoryl group attached to hexosamine position 4 of the non-reducing terminus glucosamine; and 
 (iii) up to six fatty acyl chains; 
 wherein one of the fatty acyl chains is attached to 3-hydroxy of the reducing terminus glucosamine through an ester linkage, 
 wherein one of the fatty acyl chains is attached to a 2-amino of the non-reducing terminus glucosamine through an amide linkage and comprises a tetradecanoyl chain linked to an alkanoyl chain of greater than 12 carbon atoms through an ester linkage, 
 and wherein one of the fatty acyl chains is attached to 3-hydroxy of the non-reducing terminus glucosamine through an ester linkage and comprises a tetradecanoyl chain linked to an alkanoyl chain of greater than 12 carbon atoms through an ester linkage. 
 
     
     
         16 . The method of  claim 10  wherein the GLA has the formula: 
       
         
           
           
               
               
           
         
         where: 
         R 1 , R 3 , R 5  and R 6  are C 11 -C 20  alkyl; and R 2  and R 4  are C 12 -C 20  alkyl. 
       
     
     
         17 . The method of  claim 10  wherein the antigen comprises at least one polypeptide antigen or at least one recombinant expression construct which comprises a promoter operably linked to a nucleic acid sequence encoding a polypeptide antigen. 
     
     
         18 . The method of  claim 10  wherein the antigen is derived from, or is immunologically cross-reactive with, (i) at least one infectious pathogen that is associated with an infectious disease, (ii) at least one epitope, biomolecule, cell or tissue that is associated with the cancer or (iii) at least one epitope, biomolecule, cell or tissue that is associated with an autoimmune disease. 
     
     
         19 .- 25 . (canceled)