Non-toxic adjuvant formulation comprising a monophosphoryl lipid A (MPLA)-containing liposome composition and a saponin
Provided herein is an adjuvant formulation comprising a monophosphoryl lipid A (MPLA)-containing liposome composition to saponin (e.g., QS-21), wherein the liposome composition comprises i) a lipid bilayer comprising phospholipids in which the hydrocarbon chains have a melting temperature in water of ≥23° C. and ii) cholesterol at a mole percent concentration of greater than about 50% (mol/mol), preferably about 55% to about 71% (mol/mol), or more preferably about 55% (mol/mol). The adjuvant formulation displays minimal toxicity of either lipid A or saponin.
1. An adjuvant formulation comprising unilamellar liposomes having a liposome bilayer that consists of:
(a) at least one phosphatidylcholine (PC) and/or phosphatidylglycerol (PG), as phospholipids, selected from the group consisting of: dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), distearyl phosphatidylcholine (DSPC), dimyristoyl phosphatidylglycerol (DMPG), dipalmitoyl phosphatidylglycerol (DPPG), and distearyl phosphatidylglycerol (DSPG);
(b) cholesterol;
(c) monophosphoryl lipid A (MPLA); and
(d) a saponin; and
wherein the mole ratio of the cholesterol (b) to the phospholipids (a) is greater than about 50:50; and
wherein the unilamellar liposomes have a median diameter size in micrometer range as detected by light scattering analysis.
2. The adjuvant formulation of claim 1 , wherein the saponin is QS-7, QS-18, QS-21, or a mixture thereof.
3. The adjuvant formulation of claim 1 , wherein the saponin is QS-21.
4. The adjuvant formulation of claim 1 , wherein the mole ratio of the cholesterol (b) to the phospholipids (a) is about 55:45 to about 71:29.
5. The adjuvant formulation of claim 1 , wherein the mole ratio of the cholesterol (b) to the phospholipids (a) is about 55:45.
6. The adjuvant formulation of claim 1 , wherein dimyristoyl phosphatidylcholine (DMPC) is selected as a phospholipid.
7. The adjuvant formulation of claim 6 , wherein additionally dimyristoyl phosphatidylglycerol (DMPG) is selected as a phospholipid.
8. The adjuvant formulation of claim 1 , wherein both a PC and a PG are selected as phospholipids, and wherein the ratio of the PC to the PG (mol/mol) is about 0.5:1, about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 11:1, about 12:1, about 13:1, about 14:1, or about 15:1.
9. A liposome suspension comprising the adjuvant formulation of claim 1 and phosphate-buffered saline (PBS), pH 7.4, wherein the liposome suspension comprises (i) 1.272 mM to 50 mM of the phospholipids (a), and (ii) about 5 mg/ml or less of the MPLA (c).
10. The adjuvant formulation of claim 1 , wherein the mole ratio of the MPLA (c) to the phospholipids (a) is about 1:5.6 to about 1:880.
11. A liposome suspension comprising the adjuvant formulation of claim 1 and phosphate-buffered saline (PBS), pH 7.4, wherein the liposome suspension comprises (i) 1.272 mM to 50 mM of the phospholipids (a), and (ii) about 1 mg/ml or less of the saponin (d).
12. An immunogenic composition comprising an immunogen and the adjuvant formulation of claim 1 .
13. The immunogenic composition of claim 12 , further comprising a physiologically acceptable vehicle.
14. The immunogenic composition of claim 12 , wherein the immunogen is selected from the group consisting of a naturally-occurring or artificially-created protein, a recombinant protein, a glycoprotein, a peptide, a carbohydrate, a hapten, a whole virus, a bacterium, a protozoan, and a virus-like particle.
15. The immunogenic composition of claim 14 , wherein the immunogen is an HIV-1 envelope protein.
16. The adjuvant formulation of claim 10 , wherein the mole ratio of the MPLA (c) to the phospholipids (a) is about 1:88 to about 1:220.