Stable vaccine compositions comprising inter alia live attenuated recombinant flavivirus and process for preparation thereof
Inventors
DHERE, Rajeev Mhalasakant • YEOLEKAR, LEENA RAVINDRA • Kumar, Vinit • SONAR, ROHIT BAPURAV • BARASKAR, SANDEEP DINKAR • MEHLA, RAJEEV • GHODEKAR, SHASHIKANT JANARDAN • Poonawalla, Cyrus Soli • Poonawalla, Adar Cyrus
Assignees
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Publication Number
US-11660333-B2
Publication Date
2023-05-30
Expiration Date
Abstract
Stable lyophilized immunogenic compositions include inter alia live attenuated recombinant flaviviruses, more preferably live attenuated recombinant dengue viruses, at least one carbohydrate, at least one amino acid and is particularly amenable to rapid freeze-drying treatments wherein, the composition preserves desired characteristics of a virus, including virus viability, immunogenicity and stability. The immunogenic composition is devoid of preservatives, polymers and surfactants. The methods for manufacturing the stable lyophilized immunogenic compositions are also provided.
Core Innovation
The invention relates to a stable lyophilized immunogenic composition comprising one or more live attenuated dengue (DEN) viruses. The composition includes sucrose at about 3 to 6% (w/v) and glycine at about 3 to 6% (w/v), and is freeze dried. After reconstitution, the composition preserves desired characteristics of the virus, including virus viability, immunogenicity and stability.
The composition is characterized by the absence of preservatives, polymers and surfactants. It is also characterized by the absence of an excipient or stabilizer of animal origin, or an excipient or stabilizer which contains an animal component. In the described formulations, sucrose and glycine are the stabilizing components, and other classes of stabilizers are excluded.
The disclosed approach is supported by live attenuated recombinant/chimeric flaviviruses, including dengue, with defined 3′ untranslated region deletions and additional gene mutations, as well as specified phenotypic constraints. Manufacturing is described as multiple harvesting from a single MEM batch and subsequent filtration and concentration steps, followed by stabilization with sucrose and glycine, optionally sterilization and freeze drying.
Claims Coverage
The document contains three independent claims: an immunogenic composition, a manufacturing method, and a kit. The inventive features center on a freeze-dried dengue composition using sucrose and glycine while excluding preservatives, polymers, surfactants, and animal-origin components; a manufacturing process with multiple harvesting, filtration/concentration, benzonase testing, stabilization, and optional freeze-drying; and a kit with the lyophilized composition plus a reconstitution solution.
Freeze-dried live attenuated dengue immunogenic composition with sucrose and glycine
An immunogenic composition comprising one or more live attenuated dengue (DEN) viruses, sucrose in an amount of about 3 to 6% (w/v), and glycine in an amount of about 3 to 6% (w/v), wherein the composition is freeze dried and the reconstituted composition preserves the desired characteristics of a virus, including virus viability, immunogenicity and stability.
Devoid of preservatives, polymers and surfactants; devoid of animal-origin excipients or stabilizers
The immunogenic composition is devoid of preservatives, polymers and surfactants, and is devoid of an excipient or stabilizer of animal origin or an excipient or stabilizer which contains an animal component.
Multiple harvesting and filtration/concentration with benzonase, TFF and sucrose/glycine stabilization
A method of manufacturing an immunogenic composition comprising multiple harvesting from a single batch, filtering the viral harvest by direct flow filtration through at least one clarification filter, testing with benzonase, concentrating by tangential flow filtration, stabilizing with sucrose and glycine, sterilizing by direct flow filtration, and optionally freeze drying.
Two-container kit with lyophilized immunogenic composition and aqueous reconstitution solution
A kit comprising a first container containing a lyophilized immunogenic composition comprising one or more live attenuated dengue virus, sucrose 3 to 6% (w/v), and glycine 3 to 6% (w/v), and a second container containing an aqueous solution selected from saline or WFI for reconstitution.
Overall, the claims focus on a freeze-dried live attenuated dengue immunogenic composition formulated with sucrose and glycine at 3 to 6% (w/v), while excluding preservatives, polymers, surfactants, and animal-origin excipients or stabilizers. The manufacturing claim links this formulation to a filtration and concentration process with benzonase testing and optional freeze-drying, and the kit claim packages the lyophilized composition with saline or WFI for reconstitution.
Stated Advantages
Preserves desired characteristics of the virus, including virus viability, immunogenicity and stability, after reconstitution.
Improved thermostability across 2–8°C, 25°C, 37°C, 42°C, and 55°C.
Improved stability of sucrose and glycine lyophilized formulations versus liquid formulations and versus gelatin/sorbitol-containing stabilizers.
Manufacturing yield improvements with multiple harvests from a single MEM batch.
Overall recovery of purified viruses is at least 50%.
Documented Applications
Vaccine immunogenic compositions comprising live attenuated dengue viruses.
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