Compositions for use as a prophylactic agent to those at risk of infection of tuberculosis, or as secondary agents for treating infected tuberculosis patients
Inventors
MARTÍN MONTAÑES, Carlos • AGUILÓ ANENTO, Juan Ignacio • GONZALO ASENSIO, Jesús Ángel • MARINOVA, DESSISLAVA VANEVA • UGANDA MAÍZ, Santiago • RODRÍGUEZ SÁNCHEZ, Esteban • PUENTES COLORADO, Eugenia • FERNÁNDEZ ÁLVAREZ-SANTULLANO, Concepción
Assignees
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Publication Number
US-11826411-B2
Publication Date
2023-11-28
Expiration Date
Abstract
The present invention refers to a freeze-dried composition consisting of an isolated microorganism belonging to the Mycobacterium tuberculosis complex, preferably a M. tuberculosis clinical isolate, more preferably M. tuberculosis clinical isolate, characterized in that it comprises a PhoP− phenotype by the inactivation by a genetic deletion of the Rv0757 gene and the deletion of a second gene, Rv2930 (fadD26), that prevents PDIM production (PDIM− phenotype) (the MTBVAC strain), and sucrose and sodium glutamate as stabilizers or excipients. The present invention further refers to the reconstituted composition obtained by adding water, preferably sterilized water for injection, to the freeze-dried composition as well as uses thereof, in particular for use as a prophylactic agent to those at risk of infection with M. tuberculosis or those at risk of developing tuberculosis disease, or as secondary agents for treating infected tuberculosis patients.
Core Innovation
The invention describes a freeze-dried and reconstituted live-attenuated M. tuberculosis complex vaccine based on an MTBVAC strain with unmarked deletions of Rv0757 (PhoP− phenotype) and Rv2930/fadD26 (PDIM− phenotype). The double-deletion non-reverting concept is described as a genetic construction strategy without antibiotic markers.
The problem being solved is to obtain a live-attenuated M. tuberculosis complex vaccine composition with the specified PhoP− and PDIM− phenotypes, and to enable production and formulation as a freeze-dried vaccine that maintains stability and viability after lyophilization and reconstitution. The document frames the intended use as prophylactic vaccination, including in neonates at risk, with described booster vaccination use cases and secondary treatment/booster uses.
The documented formulation and production concept includes defined animal-origin–free culture media for seed, SD, and SDG, and lyophilization stabilizer screening. GSA (sodium glutamate plus sucrose) is identified as best for stabilizing the vaccine during lyophilization, and the document reports viability-loss and stability results, including batch and industrial-scale lyophilized product specifications such as residual moisture, viable counts, and lyophilization loss.
Claims Coverage
The partial content identifies one independent claim and describes a process for producing a live-attenuated M. tuberculosis MTBVAC-based vaccine composition with two specific genetic phenotypes. The coverage is expressed through three inventive features.
PhoP− and PDIM− MTBVAC double-deletion bacterium
An isolated bacterium belonging to an MTBVAC strain having a PhoP− phenotype by inactivation through a genetic deletion of the Rv0757 gene and a deletion of Rv2930/fadD26 that prevents PDIM production.
Seed-to-mass culture aerobic production in defined seed, SD and SDG media
A process comprising starting a culture of the MTBVAC strain in a seed medium, expanding or amplifying the bacterium in an SD medium, and growing the bacterium for mass culture in an SDG medium, conducted under aerobic conditions.
Specified seed, SD, and SDG medium component ranges
Using defined component ranges for L-asparagine, monopotassium phosphate, magnesium sulfate, ammonium ferric citrate, dextrose monohydrate, glycerol, citric acid, polysorbate 80, and purified water across the seed medium, SD medium, and SDG medium tables.
Across the independent claim, the inventive concept centers on producing an MTBVAC-based live-attenuated vaccine bacterium with PhoP− and PDIM− phenotypes, and culturing it under aerobic conditions through seed, SD, and SDG media defined by specific component ranges to generate biomass for the vaccine composition.
Stated Advantages
The document states that the freeze-dried vaccine maintains stability and viability after lyophilization and reconstitution.
GSA is identified as best for stabilizing the vaccine during lyophilization.
Storage stability is reported for 2–8°C and −15 to −30°C.
Early preclinical/clinical trial outcomes support dose-immunogenicity/protection concepts, including newborn mouse immunogenicity/protection independence of dose, neonatal Th1 responses, and safety/reactogenicity and QFT conversion trends after intradermal administration.
Documented Applications
Prophylactic vaccination, including in neonates at risk.
Booster vaccination.
Secondary treatment/booster uses.
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