Formulations of dengue virus vaccine compositions

Abstract

The present invention relates to formulations of dengue virus vaccine comprising at least one live attenuated dengue virus or live attenuated chimeric flavivirus, a buffer, a sugar, a cellulose derivative, a glycol or sugar alcohol, optionally an alkali or alkaline salt and an amino acid; and formulations of dengue virus vaccine comprising at least one live attenuated dengue virus or live attenuated chimeric flavivirus, a buffer, a sugar of at least 150 mg/ml, a carrier, and optionally an alkali or alkaline salt and an amino acid.

1 . A formulation comprising a live attenuated dengue vaccine comprising at least one live attenuated dengue virus (LAV) or at least one live attenuated chimeric flavivirus (LACV), a buffer at pH about 6.5 to 8.5, a sugar, a glycol or sugar alcohol, and a cellulose derivative selected from the group consisting of carboxymethyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), 2-hydroxyethyl cellulose (2-HEC), crosscarmellose, and methyl cellulose, or a pharmaceutically acceptable salt thereof, and optionally an alkali or alkaline salt and/or an amino acid selected from the group consisting of Ala, Asp, His, Leu, Lys, Gln, Pro, Glu, and a combination thereof. 
     
     
         2 . The formulation of  claim 1 , wherein the buffer is selected from the group consisting of succinate, histidine, phosphate, TRIS, Bis-Tris, MES, MOPS, HEPES, acetate, citrate, and a combination thereof. 
     
     
         3 . The formulation of  claim 1 , wherein the alkali or alkaline salt is magnesium chloride, calcium chloride, potassium chloride, sodium chloride or a combination thereof. 
     
     
         4 . The formulation of  claim 1 , wherein the sugar is trehalose or sucrose. 
     
     
         5 . The formulation of  claim 1 , wherein the cellulose derivative is a pharmaceutically acceptable salt of carboxymethyl cellulose. 
     
     
         6 . The formulation of  claim 1 , wherein the glycol is selected from the group consisting of propylene glycol, polypropylene glycol, ethylene glycol, polyethylene glycol, and polyethylene glycol monomethyl ethers. 
     
     
         7 . The formulation of  claim 1 , wherein the glycol or sugar alcohol is propylene glycol or glycerol. 
     
     
         8 . The formulation of  claim 1  that comprises a live attenuated dengue vaccine comprising at least one live attenuated dengue virus (LAV) or at least one live attenuated chimeric flavivirus at about 100-10,000,000 pfu/ml, a buffer at pH about 6.5 to 8.5, about 50-300 mg/ml sugar, about 2.5-10.0 mg/ml propylene glycol (PG) or glycerol, and about 0.3-10 mg/ml sodium carboxymethylcellulose (sodium CMC), and optionally about 10-150 mM NaCl and/or about 10-100 mM amino acid selected from the group consisting of Ala, Asp, His, Leu, Lys, Gln, Pro, Glu and a combination thereof. 
     
     
         9 . The formulation of  claim 1  that comprises the live attenuated dengue vaccine at about 100-100,000 pfu/ml, about 5-300 mM histidine, TRIS, Bis-Tris or phosphate buffer, or a combination thereof at pH about 7.0 to 8.0, about 50-300 mg/ml sugar, about 3-10 mg/ml propylene glycol or glycerol, and about 3-10 mg/ml sodium carboxymethylcellulose, and optionally about 15-75 mM NaCl and/or about 10-75 mM amino acid selected from the group consisting of Ala, Asp, His, Leu, Lys, Gln, Pro, Glu and a combination thereof. 
     
     
         10 . The formulation of  claim 1  that comprises the live attenuated dengue vaccine at about 600-20,000 pfu/ml, about 5-300 mM potassium phosphate buffer at pH about 7.0-8.0, about 60-120 mg/ml sucrose or trehalose or a combination thereof, about 3-7 mg/ml propylene glycol or glycerol, and about 3-7 mg/ml sodium carboxymethylcellulose with average molecular weight of about 90,000, and about 30-90 mM NaCl, and optionally about 10-75 mM amino acid Leu, Lys or Glu, or a combination thereof. 
     
     
         11 . The formulation of  claim 1  that comprises the live attenuated dengue vaccine at about 600-20,000 pfu/ml, about 11 mM potassium phosphate buffer at pH about 7.0-8.0, about 90 mg/ml sucrose, about 5 mg/ml propylene glycol or glycerol, about 5 mg/ml sodium carboxymethylcellulose with average molecular weight of about 90,000, and about 75 mM NaCl. 
     
     
         12 . The formulation of  claim 1  that comprises the live attenuated dengue vaccine at about 600-20,000 pfu/ml, about 11 mM potassium phosphate buffer at pH about 7.0-8.0, about 90 mg/ml sucrose, about 5 mg/ml propylene glycol, about 5 mg/ml sodium carboxymethylcellulose with average molecular weight of about 90,000, about 50 mM NaCl, and about 25 mM Leu. 
     
     
         13 . The formulation of  claim 1  that comprises the live attenuated dengue vaccine at about 600-20,000 pfu/ml, about 11 mM potassium phosphate buffer at pH about 7.5, about 90 mg/ml sucrose, about 5 mg/ml propylene glycol, about 5 mg/ml sodium carboxymethylcellulose with average molecular weight of about 90,000, and about 30 mM NaCl. 
     
     
         14 . The formulation of  claim 9 , further comprising about 90-200 mg/ml trehalose. 
     
     
         15 . The formulation of  claim 1  that comprises the live attenuated dengue vaccine at about 600-20,000 pfu/ml, about 11 mM potassium phosphate buffer at pH about 7.5-8, about 90 mg/ml sucrose, about 110 mg/ml trehalose, about 5 mg/ml propylene glycol, about 5 mg/ml sodium carboxymethylcellulose with average molecular weight of about 90,000, about 50 mM NaCl, and about 25 mM Leu. 
     
     
         16 . The formulation of  claim 1 , wherein the formulation further comprises a surfactant selected from poloxamer 188 and poloxamer 407 at about 0.0001 to 5% w/v. 
     
     
         17 . A formulation that comprises a live attenuated dengue vaccine comprising at least one live attenuated dengue virus (LAV) or at least one live attenuated chimeric flavivirus at about 20-200,000,00 pfu/ml, a buffer at pH about 6.5 to 8.5, a sugar at about 150-300 mg/ml, a carrier selected from the group consisting of polyvinylpyrrolidone (PVP), carboxymethyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), 2-hydroxyethyl cellulose (2-HEC), crosscarmellose, and methyl cellulose or a pharmaceutically acceptable salt thereof, Human Serum Albumin (HSA) and gelatin; and optionally an alkali salt or alkaline salt at about 5-100 mM and/or an amino acid Gln, Pro or Glu, or a combination thereof. 
     
     
         18 . The formulation of  claim 17 , wherein the buffer is selected from the group consisting of succinate, histidine, phosphate, TRIS, Bis-Tris, MES, MOPS, HEPES, acetate, citrate, and a combination thereof. 
     
     
         19 . The formulation of  claim 17 , wherein the alkali or alkaline salt is magnesium chloride, calcium chloride, potassium chloride, sodium chloride or a combination thereof. 
     
     
         20 . The formulation of  claim 17 , wherein the sugar is trehalose or sucrose, or a combination thereof. 
     
     
         21 . The formulation of  claim 20 , wherein the sucrose to trehalose ratio is between 1:1 to 1:4. 
     
     
         22 . The formulation of  claim 17 , wherein the carrier is a sodium carboxymethyl cellulose, HPMC, HSA or gelatin. 
     
     
         23 . The formulation of  claim 17  that comprises the live attenuated dengue vaccine at about 100-10,000,000 pfu/ml, a buffer at pH about 6.5-8.0, about 150-300 mg/ml sugar as a combination of sucrose and trehalose, about 0.3 to 40 mg/ml sodium CMC, HSA, HPMC or gelatin, and optionally about 10-100 mM alkali or alkaline salt and/or about 5-25 mM glutamic acid. 
     
     
         24 . The formulation of  claim 17  that comprises the live attenuated dengue vaccine at about 100-100,000 pfu/ml, about 5-300 mM histidine, TRIS or phosphate buffer, or a combination thereof at pH about 7.0 to 8.0, about 50-100 mg/ml sucrose, about 90-200 mg/ml trehalose, about 0.3-10 mg/ml sodium CMC or about 10-40 mg/ml gelatin, and about 30-90 mM alkali or alkaline salt. 
     
     
         25 . The formulation of  claim 17  that comprises the live attenuated dengue vaccine at about 600-20,000 pfu/ml, about 5-20 mM potassium phosphate at pH about 7.0-8.0, about 75 mg/ml sucrose, about 175 mg/ml trehalose, about 5 mg/ml sodium CMC with average molecular weight of about 90,000, and about 30 mM NaCl. 
     
     
         26 . The formulation of  claim 17  that comprises the live attenuated dengue vaccine at about 600-20,000 pfu/ml, about 5-20 mM potassium phosphate at pH about 7.0-8.0, about 75 mg/ml sucrose, about 175 mg/ml trehalose, about 25 mg/ml gelatin, and about 30 mM NaCl. 
     
     
         27 . The formulation of  claim 17  that comprises the live attenuated dengue vaccine at about 600-20,000 pfu/ml, about 5-20 mM potassium phosphate at pH about 7-8, about 250 mg/ml sucrose, and about 50 mg/ml PVP K12. 
     
     
         28 . The formulation of  claim 17 , further comprising a surfactant selected from poloxamer 188 and poloxamer 407 at about 0.0001 to 5% w/v. 
     
     
         29 . The formulation of  claim 1  that further comprises an aluminum adjuvant. 
     
     
         30 . The formulation of  claim 1  that is frozen or lyophilized. 
     
     
         31 . The formulation of  claim 8  that is reconstituted in solution. 
     
     
         32 . The formulation of  claim 8  that is an aqueous solution prior to lyophilization or microwave vacuum drying. 
     
     
         33 . The formulation of  claim 31 , wherein the reconstitution is performed with solution is about 0.5-1.0 ml saline solution, water or Bacteriostatic Water for Injection (BWFI) and optionally comprises a diluent comprising an aluminum adjuvant. 
     
     
         34 . The formulation of  claim 1 , wherein the live attenuated dengue vaccine is tetravalent. 
     
     
         35 . The formulation of  claim 1 , wherein the LAV or the LACV comprise a viral genome that contains a deletion of about 30 nucleotides corresponding to the TL-2 stem-loop structure of the 3′ untranslated (UTR) region (UTR). 
     
     
         36 . The formulation of  claim 1 , wherein the live attenuated dengue virus (LAV) comprises a viral genome that contains a deletion of about 30 nucleotides corresponding to the TL-2 stem-loop structure of the 3′ untranslated (UTR) region (UTR), and is immunogenic against dengue serotype 3, wherein the viral genome of the LAV further contains a deletion of nucleotides upstream from the Δ30 deletion corresponding to the TL-3 structure of the 3′UTR. 
     
     
         37 . The formulation of  claim 1 , wherein the live attenuated dengue virus (LAV) comprises rDEN1Δ30, rDEN2/4Δ30, rDEN3Δ30/31, and rDEN4Δ30. 
     
     
         38 . The formulation of  claim 1 , wherein the live attenuated dengue virus (LAV) comprises rDEN1Δ30-1545, rDEN2/4Δ30 (ME)-1495,7163, rDEN3Δ30/31-7164, and rDEN4Δ30-7132,7163,8308.