Adjuvant compositions

Abstract

Adjuvant compositions comprising type 1 interferon inducers, such as double-stranded RNA, in combination with antigen delivery systems and/or immunostimulatory molecules, such as immunostimulatory nucleic acid sequences, for enhancing the immune response of a coadministered antigen, are described.

1 . A composition comprising: (1) a type 1 interferon inducer; and (2) an antigen delivery system and/or an immunostimulatory molecule,
 wherein the composition is capable of increasing the immune response to a coadministered antigen as compared to delivery of the antigen and type 1 interferon inducer alone without the antigen delivery system and/or the immunostimulatory molecule.   
     
     
         2 . The composition of  claim 1 , wherein the composition comprises a type 1 interferon inducer, an antigen delivery system and an immunostimulatory molecule. 
     
     
         3 . The composition of  claim 1 , wherein the composition comprises a type 1 interferon inducer and an antigen delivery system. 
     
     
         4 . The composition of  claim 1 , wherein the coadministered antigen is present in the composition. 
     
     
         5 . The composition of  claim 1 , wherein the type 1 interferon inducer is dsRNA. 
     
     
         6 . The composition of  claim 1 , wherein the antigen delivery system comprises a submicron oil-in-water emulsion and/or a microparticle. 
     
     
         7 . The composition of  claim 1 , wherein the immunostimulatory molecule is an immunostimulatory nucleic acid sequence (ISS). 
     
     
         8 . The composition of  claim 7 , wherein the ISS is a CpG oligonucleotide. 
     
     
         9 . A composition comprising a dsRNA, a submicron oil-in-water emulsion and a selected antigen, wherein the composition is capable of increasing the immune response to the antigen as compared to delivery of the antigen and dsRNA alone without the submicron oil-in-water emulsion. 
     
     
         10 . The composition of  claim 9 , wherein the antigen is an HCV antigen, an HIV antigen or a meningococcal protein. 
     
     
         11 . The composition of  claim 10 , wherein the antigen is an HCV antigen and the HCV antigen is an E1E2 polypeptide. 
     
     
         12 . The composition of  claim 10 , wherein the antigen is an HIV antigen and the HV antigen is gp120 or p55gag. 
     
     
         13 . The composition of  claim 10 , wherein the antigen is a meningococcal antigen and the meningococcal antigen is a MenB protein from ORFs 287 and/or 961. 
     
     
         14 . The composition of  claim 9 , wherein the antigen is associated with a microparticle. 
     
     
         15 . The composition of  claim 14 , wherein the antigen is adsorbed to a microparticle comprising poly(D,L-lactide-co-glycolide) (PLG). 
     
     
         16 . The composition of  claim 9 , wherein the dsRNA is associated with a microparticle. 
     
     
         17 . The composition of  claim 16 , wherein the dsRNA is adsorbed to a microparticle comprising poly(D,L-lactide-co-glycolide) (PLG). 
     
     
         18 . The composition of  claim 9 , wherein the dsRNA is viral dsRNA or synthetic dsRNA. 
     
     
         19 . The composition of  claim 18 , wherein the dsRNA is polyriboinosinic-polyribocytidylic acid (poly[rI-rC]), polyriboguanylic-polyribocytidylic acid (poly[rG-rC]) or polyriboadenylic-polyribouridylic acid (poly[rA-rU]). 
     
     
         20 . The composition of  claim 9 , wherein the submicron oil-in-water emulsion comprises:
 (1) a metabolizable oil, wherein the oil is present in an amount of 0.5% to 20% of the total volume and   (2) an emulsifying agent, wherein the emulsifying agent is 0.01% to 2.5% by weight (w/v), and wherein the oil and the emulsifying agent are present in the form of an oil-in-water emulsion having oil droplets substantially all of which are about 100 nm to less than 1 micron in diameter.   
     
     
         21 . The composition of  claim 20 , wherein the emulsifying agent comprises a polyoxyethylene sorbitan mono-, di-, or triester and/or a sorbitan mono-, di-, or triester. 
     
     
         22 . A composition comprising:
 (1) a dsRNA, wherein the dsRNA is polyriboinosinic-polyribocytidylic acid (poly[rI-rC]), polyriboguanylic-polyribocytidylic acid (poly[rG-rC]) or polyriboadenylic-polyribouridylic acid (poly[rA-rU]);   (2) a submicron oil-in-water emulsion, wherein the submicron oil-in-water emulsion comprises (a) a metabolizable oil, wherein the oil is present in an amount of 0.5% to 20% of the total volume and (b) an emulsifying agent, wherein the emulsifying agent is 0.01% to 2.5% by weight (w/v), and wherein the oil and the emulsifying agent are present in the form of an oil-in-water emulsion having oil droplets substantially all of which are about 100 nm to less than 1 micron in diameter; and   (3) a selected antigen, wherein the selected antigen is an HCV, HIV or a meningococcal antigen,   and wherein the composition is capable of increasing the immune response to the antigen as compared to delivery of the antigen alone, without the dsRNA and/or the submicron oil-in-water emulsion.   
     
     
         23 . The composition of  claim 22 , wherein the antigen is adsorbed to a microparticle comprising poly(D,L-lactide-co-glycolide) (PLG). 
     
     
         24 . The composition of  claim 22 , wherein the dsRNA is adsorbed to a microparticle comprising poly(D,L-lactide-co-glycolide) (PLG). 
     
     
         25 . The composition of  claim 23 , wherein the dsRNA is adsorbed is a microparticle comprising poly(D,L-lactide-co-glycolide) (PLG). 
     
     
         26 . The composition of  claim 22 , wherein the oil is present in an amount of 1% to 12% of the total volume and the emulsifying agent is present in an amount of 0.01% to 1% by weight (w/v). 
     
     
         27 . The composition of  claim 22 , wherein the emulsifying agent comprises a polyoxyethylene sorbitan mono-, di-, or triester and/or a sorbitan mono-, di-, or triester. 
     
     
         28 . The composition of  claim 26 , wherein the submicron oil-in-water emulsion comprises 4-5% w/v squalene, 0.25-1.0% w/v polyoxyelthylenesorbitan monooleate, and/or 0.25-1.0% sorbitan trioleate. 
     
     
         29 . The composition of  claim 22 , wherein the submicron oil-in-water emulsion consists essentially of 5% by volume of squalene; and one or more emulsifying agents selected from the group consisting of polyoxyeithylenesorbitan monooleate and sorbitan trioleate, wherein the total amount of emulsifying agent(s) present is 1% by weight (w/v). 
     
     
         30 . The composition of  claim 29 , wherein the one or more emulsifying agents are polyoxyelthylenesorbitan monooleate and sorbitan trioleate and the total amount of polyoxyelthylenesorbitan monooleate and sorbitan trioleate present is 1% by weight (w/v). 
     
     
         31 . The composition of  claim 22 , further comprising an immunostimulatory molecule. 
     
     
         32 . The composition of  claim 31 , wherein the immunostimulatory molecule is an immunostimulatory nucleic acid sequence (ISS). 
     
     
         33 . The composition of  claim 32 , wherein the ISS is a CpG oligonucleotide. 
     
     
         34 . The composition of  claim 33 , wherein the CpG oligonucleotide comprises the sequence 5′-X 1 X 2 CGX 3 X 4 , where X 1  and X 2  are a sequence selected from the group consisting of GpT, GpG, GpA, ApA, ApT, ApG, CpT, CpA, CpG, TpA, TpT and TpG; and X 3  and X 4  are selected from the group consisting of TpT, CpT, ApT, ApG, CpG, TpC, ApC, CpC, TpA, ApA, GpT, CpA, and TpG, wherein p signifies a phosphate bond. 
     
     
         35 . The composition of  claim 33 , wherein the CpG oligonucleotide comprises the sequence GACGTT, GACGTC, GTCGTT or GTCGCT. 
     
     
         36 . The composition of  claim 35 , wherein the CpG motif is 5′-TCCATGACGTTCCTGACGTT-3′ (SEQ ID NO:3). 
     
     
         37 . The composition of  claim 22 , wherein the antigen is an HCV antigen and the HCV antigen is an E1E2 polypeptide. 
     
     
         38 . The composition of  claim 22 , wherein the antigen is an HIV antigen and the HIV antigen is gp120 or p55gag. 
     
     
         39 . The composition of  claim 22 , wherein the antigen is a meningococcal antigen and the meningococcal antigen is a MenB protein from ORFs 287 and/or 961. 
     
     
         40 . A composition comprising:
 (1) polyriboinosinic-polyribocytidylic acid (poly[rI-rC]);   (2) a submicron oil-in-water emulsion, wherein the submicron oil-in-water emulsion comprises (a) a metabolizable oil, wherein the oil is present in an amount of 0.5% to 20% of the total volume and (b) an emulsifying agent, wherein the emulsifying agent is 0.01% to 2.5% by weight (w/v), and wherein the oil and the emulsifying agent are present in the form of an oil-in-water emulsion having oil droplets substantially all of which are about 100 nm to less than 1 micron in diameter;   (3) a CpG oligonucleotide; and   (4) an HCV antigen, an HIV antigen or a meningococcal protein,   and wherein the composition is capable of increasing the immune response to the antigen as compared to delivery of the antigen alone, without the dsRNA, the submicron oil-in-water emulsion and/or the CpG oligonucleotide.   
     
     
         41 . The composition of  claim 40 , wherein the antigen is an HCV antigen and the HCV antigen is an E1E2 polypeptide. 
     
     
         42 . The composition of  claim 41 , wherein the HCV E1E2 polypeptide comprises a sequence of amino acids with at least 80% sequence identity to the contiguous sequence of amino acids depicted at positions 192-809 of  FIGS. 1A-1C . 
     
     
         43 . The composition of  claim 42 , wherein the HCV E1E2 polypeptide comprises the sequence of amino acids depicted at positions 192-809 of  FIGS. 1A-1C . 
     
     
         44 . The composition of  claim 40 , wherein the antigen is an HIV antigen and the HIV antigen is gp120 or p55gag. 
     
     
         45 . The composition of  claim 40 , wherein the antigen is a meningococcal antigen and the meningococcal antigen is a MenB protein from ORFs 287 and/or 961. 
     
     
         46 . The composition of  claim 40 , wherein the CpG oligonucleotide comprises the sequence 5′-X 1 X 2 CGX 3 X 4 , where X 1  and X 2  are a sequence selected from the group consisting of GpT, GpG, GpA, ApA, ApT, ApG, CpT, CpA, CpG, TpA, TpT and TpG; and X 3  and X 4  are selected from the group consisting of TpT, CpT, ApT, ApG, CpG, TpC, ApC, CpC, TpA, ApA, GpT, CpA, and TpG, wherein p signifies a phosphate bond. 
     
     
         47 . The composition of  claim 40 , wherein the CpG oligonucleotide comprises the sequence GACGTT, GACGTC, GTCGTT or GTCGCT. 
     
     
         48 . The composition of  claim 47 , wherein the CpG motif is 5′-TCCATGACGTTCCTGACGTT-3′ (SEQ ID NO:3). 
     
     
         49 . The composition of  claim 40 , wherein the oil is present in an amount of 1% to 12% of the total volume and the emulsifying agent is present in an amount of 0.01% to 1% by weight (w/v). 
     
     
         50 . The composition of  claim 40 , wherein the emulsifying agent comprises a polyoxyethylene sorbitan mono-, di-, or triester and/or a sorbitan mono-, di-, or triester. 
     
     
         51 . The composition of  claim 40 , wherein the submicron oil-in-water emulsion comprises 4-5% w/v squalene, 0.25-1.0% w/v polyoxyelthylenesorbitan monooleate, and/or 0.25-1.0% sorbitan trioleate. 
     
     
         52 . The composition of  claim 40 , wherein the submicron oil-in-water emulsion consists essentially of 5% by volume of squalene; and one or more emulsifying agents selected from the group consisting of polyoxyelthylenesorbitan monooleate and sorbitan trioleate, wherein the total amount of emulsifying agent(s) present is 1% by weight (w/v). 
     
     
         53 . The composition of  claim 52 , wherein the one or more emulsifying agents are polyoxyelthylenesorbitan monooleate and sorbitan trioleate and the total amount of polyoxyelthylenesorbitan monooleate and sorbitan trioleate present is 1% by weight (w/v). 
     
     
         54 . A composition comprising: (1) dsRNA, wherein the dsRNA is polyriboinosinic-polyribocytidylic acid (poly[rI-rC]), polyriboguanylic-polyribocytidylic acid (poly[rG-rC]) or polyriboadenylic-polyribouridylic acid (poly[rA-rU]); and (2) a selected antigen, wherein said selected antigen is an HCV antigen, an HIV antigen or a meningococcal protein,
 wherein said dsRNA and/or said selected antigen are adsorbed to a microparticle, and further wherein the composition is capable of increasing the immune response to the selected antigen as compared to delivery of the antigen alone without the dsRNA and/or the microparticle.   
     
     
         55 . The composition of  claim 54 , wherein the dsRNA is poly[rI-rC]. 
     
     
         56 . The composition of  claim 55 , wherein the microparticle comprises a polymer selected from the group consisting of a poly(α-hydroxy acid), a polyhydroxy butyric acid, a polycaprolactone, a polyorthoester, and a polyanhydride. 
     
     
         57 . The composition of  claim 56 , wherein the microparticle comprises poly(D,L-lactide-co-glycolide) (PLG). 
     
     
         58 . The composition of  claim 57 , wherein the antigen is adsorbed to the microparticle. 
     
     
         59 . The composition of  claim 57 , wherein the dsRNA is adsorbed to the microparticle. 
     
     
         60 . The composition of  claim 58 , wherein the dsRNA is adsorbed to the microparticle. 
     
     
         61 . The composition of  claim 57 , wherein the antigen is an HCV antigen and the HCV antigen is an E1E2 polypeptide. 
     
     
         62 . The composition of  claim 61 , wherein the HCV E1E2 polypeptide comprises a sequence of amino acids with at least 80% sequence identity to the contiguous sequence of amino acids depicted at positions 192-809 of  FIGS. 1A-1C . 
     
     
         63 . The composition of  claim 62 , wherein the HCV E1E2 polypeptide comprises the sequence of amino acids depicted at positions 192-809 of  FIGS. 1A-1C . 
     
     
         64 . The composition of  claim 58 , wherein the antigen is an HIV antigen and the HIV antigen is gp120 or ps5gag. 
     
     
         65 . The composition of  claim 58 , wherein the antigen is a meningococcal antigen and the meningococcal antigen is a MenB protein from ORFs 287 and/or 961. 
     
     
         66 . A method of stimulating an immune response in a vertebrate subject, said method comprising administering to the subject a therapeutically effective amount of a selected antigen and a composition according to  claim 1 . 
     
     
         67 . The method of  claim 66 , wherein the antigen is administered prior to administering the composition. 
     
     
         68 . The method of  claim 66 , wherein the antigen is administered subsequent to administering the composition. 
     
     
         69 . A method of stimulating an immune response in a vertebrate subject, said method comprising administering to the subject a therapeutically effective amount of a composition according to  claim 4 . 
     
     
         70 . A method of stimulating an immune response in a vertebrate subject, said method comprising administering to the subject a therapeutically effective amount of a composition according to  claim 9 . 
     
     
         71 . A method of stimulating an immune response in a vertebrate subject, said method comprising administering to the subject a therapeutically effective amount of a composition according to  claim 22 . 
     
     
         72 . A method of stimulating an immune response in a vertebrate subject, said method comprising administering to the subject a therapeutically effective amount of a composition according to  claim 40 . 
     
     
         73 . A method of stimulating an immune response in a vertebrate subject, said method comprising administering to the subject a therapeutically effective amount of a composition according to  claim 54 . 
     
     
         74 . A method of making a composition comprising combining a type 1 interferon inducer with an antigen delivery system and/or an immunostimulatory molecule. 
     
     
         75 . The method of  claim 74 , wherein the method further comprises combining an antigen with said type 1 interferon inducer, and said antigen delivery system and/or said immunostimulatory molecule.