Adjuvant compositions
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.