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Formulations of dengue virus vaccine compositions

Inactive Publication Date: 2020-12-17
MERCK SHARP & DOHME LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention provides stable live attenuated dengue vaccine formulations that can be dried or microwaved for use. The formulations include a live attenuated dengue virus or chimeric flavivirus, a buffer, a sugar, a glycol or sugar alcohol, and a cellulose derivative. The addition of a cellulose derivative and a glycol or glycerol improved stability and yield after drying or microwaving. The formulations also include a live attenuated dengue vaccine with improved stability and yield after drying or microwaving. The live attenuated dengue vaccine has been found to be effective in inducing immunity against dengue virus in humans.

Problems solved by technology

Without diagnosis and prompt medical intervention, the sudden onset and rapid progression of DHF / DSS can be fatal if untreated.
With the global increase in population, urbanization of the population especially throughout the tropics, and the lack of sustained mosquito control measures, the mosquito vectors of dengue have expanded their distribution throughout the tropics, subtropics, and some temperate areas, bringing the risk of dengue infection to over half the world's population.
Despite the successes of the YF, JE, and TBE vaccines highlighted above, the use of live-attenuated virus and inactivated virus methods to develop vaccines for dengue virus has been met with significant challenges.
Vaccine products containing whole viruses are challenging to stabilize as these are sensitive to heat, freeze / thaw and other processing stresses leading to significant potency losses.
Frozen products are not easy to store and distribute as they need a stringent cold-chain requirement to prevent potency loss.
Drying of whole viruses, especially enveloped viruses, often leads to significant loss of potency due to the freezing and drying stresses encountered during the drying process.

Method used

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  • Formulations of dengue virus vaccine compositions
  • Formulations of dengue virus vaccine compositions
  • Formulations of dengue virus vaccine compositions

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0160]Effect of CMC, PG, and Amino Acids (Compared with Dengvaxia® Formulation) on DENV4

[0161]Three separate studies were performed to investigate the effects of various excipients on the lyophilization yield and stability of DENV4. The formulations are listed in Table 5.

TABLE 5Formulation CompositionsFormulationNumberComposition111 mM potassium phosphate, 90 mg / mL sucrose, 30 mM sodium chloride pH 7.5211 mM potassium phosphate, 90 mg / mL sucrose pH 7.5311 mM potassium phosphate, 90 mg / mL sucrose, 75 mM sodium chloride pH 7.5411 mM potassium phosphate, 90 mg / mL sucrose, 75 mM sodium chloride,5 mg / mL sodium carboxymethylcellulose pH 7.5511 mM potassium phosphate, 90 mg / mL sucrose, 75 mM sodium chloride,5 mg / mL sodium carboxymethylcellulose, 5 mg / mL propylene glycol pH 7.51311 mM potassium phosphate, 90 mg / mL sucrose, 25 mg / mL sorbitol, 75 mMsodium chloride, 5 mg / mL sodium carboxymethylcellulose pH 7.51811 mM potassium phosphate, 90 mg / mL sucrose, 50 mM sodium chloride,5 mg / mL sodium c...

example 2

Effect of Sugar Alcohol on DENV4:

[0169]DENV4 was formulated in a base formulation of 11 mM potassium phosphate, 90 mg / mL sucrose, 75 mM NaCl, and 5 mg / mL sodium CMC pH 7.5 with 5 mg / mL propylene glycol (formulation 5), 5 mg / mL glycerol (formulation 22), or 25 mg / mL sorbitol (formulation 13) as sugar alcohols.

[0170]Samples were frozen and a portion were stored at −70° C. as frozen liquid controls and a portion were lyophilized. After lyophilization, some samples were stored at −70° C. and the remainder were placed at 25° C. for 1 week. After incubation, the 25° C. samples were frozen and tested with a dengue relative infectivity assay along with the frozen liquid controls and frozen lyophilized controls. Two individual vials of each sample were tested.

[0171]Lyophilization yields were calculated by dividing the lyophilized infectivity result by the frozen liquid control infectivity result. To calculate log loss after storage at 25° C. for one week, infectivity values were converted in...

example 3

Effect of pH on DENV4:

[0173]DENV4 was formulated in formulation 22 (11 mM potassium phosphate, 90 mg / mL sucrose, 75 mM NaCl, 5 mg / mL sodium CMC, 5 mg / mL glycerol at pH 7.0, 7.5 or 8.0).

[0174]Samples were frozen and a portion were stored at −70° C. as frozen liquid controls and a portion were lyophilized. After lyophilization, some samples were stored at −70° C. and the remainder were placed at 25° C. for 1 week. After incubation, the 25° C. samples were frozen and tested with a dengue relative infectivity assay along with the frozen liquid controls and frozen lyophilized controls. Two individual vials of each sample were tested.

[0175]Lyophilization yields were calculated by dividing the lyophilized infectivity result by the frozen liquid control infectivity result. To calculate log loss after storage at 25° C. for one week, infectivity values were converted into log scale and the 1 week 25° C. log result was subtracted from the −70° C. lyophilized control result for each formulation...

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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.

Description

FIELD OF THE INVENTION[0001]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 and a sugar alcohol or glycol, and optionally an amino acid and an alkali or alkaline salt; 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, or, alkali or alkaline salt and an amino acid.BACKGROUND OF THE INVENTION[0002]The family Flaviviridae includes the prototype yellow fever virus (YF), the four serotypes of dengue virus (DENV-1, DENV-2, DENV-3, and DENV-4), Japanese encephalitis virus (JE), tick-borne encephalitis virus (TBE), West Nile virus (WN), Saint Louis encephalitis virus (SLE), and about 70 other disease causing viruses. Flaviviruses are small, enveloped viruse...

Claims

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Application Information

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IPC IPC(8): A61K39/12A61K47/26A61K47/36A61K47/32A61K47/10A61K47/42A61K39/39A61K9/19
CPCA61K39/39A61K47/26A61K39/12A61K47/32A61K9/19A61K47/36A61K2039/5254A61K47/42A61K2039/70A61K47/10A61K2039/55505Y02A50/30C12N2770/24134A61K9/0019A61K9/146A61K47/38A61K47/183A61K47/22A61K9/08A61P31/14
Inventor RYAN, MICHAEL S.MARTIN, SHERRIE-ANN P.JONES, MORRISASTANBRO, JUSTINBHAMBHANI, AKHILESHBLUE, JEFFREY THOMASPIXLEY, HEIDI JOANNEGREEN-TREXLER, ERIN J.ISOPI, LYNNE ANN
Owner MERCK SHARP & DOHME LLC
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