Compositions of vaccines and adjuvants and methods for the treatment of urinary tract infections
Inventors
Eldridge, Gary • Martin, Steven M
Assignees
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Publication Number
US-11110169-B2
Publication Date
2021-09-07
Expiration Date
Abstract
This invention describes novel adjuvant compositions and formulations with excellent stability at refrigerated and room temperatures and up to and about 37° C. that can be produced at remarkably low costs. This invention describes novel vaccine compositions and formulations to treat and prevent urinary tract infections caused by gram-negative bacteria including Escherichia coli and multi-drug resistant E. coli. This invention also describes methods of administration of said novel vaccine compositions and formulations and methods of treatment to prevent and treat urinary tract infections caused by gram-negative bacteria including E. coli and multi-drug resistant E. coli.
Core Innovation
The disclosure describes a vaccine composition for urinary tract infections caused by gram-negative bacteria, including uropathogenic and multi-drug resistant Escherichia coli, using antigen components of FimCH or truncated FimH. The vaccine antigen complex comprises non-covalent FimC/FimH expressed in transgenic E. coli, including FimH and FimC, and also includes truncated FimH.
The vaccine/adjuvant system uses synthetically produced Toll-like receptor 4 agonists based on phosphorylated hexaacyl disaccharide (PHAD) and/or 3-deacyl-phosphorylated hexaacyl disaccharide, and includes phosphatidylcholine, including DPPC, in aqueous buffered suspensions. The buffers include citrate, succinate, and phosphate, and the disclosure further provides analytical characterization and release testing for DPPC, including purity by HPLC, exact mass by NMR/MS, Karl Fischer water content, residual solvents, and heavy metals.
The formulations are described as stable at room temperature, with extended stability up to about 37°C, and maintain PHAD particle size below about 150 nm over projected shelf life. The disclosure also describes in vitro potency and specificity of a FimCH/anti-FimH assay using HRP binding and a mannose-binding-deficient mutant, together with immunogenicity and tolerability evaluations, while forced-degradation and mass spectrometry studies show degradation pathways involving acyl-group loss for PHAD/3-deacyl-PHAD and MLA (PtHA).
Claims Coverage
The independent claim covers a vaccine composition with three required components: an antigen of FimCH or truncated FimH, phosphatidylcholine, and an adjuvant formulation containing one or more specified compounds or pharmaceutically acceptable salts. Dependent claims further refine the formulation with an aqueous buffered suspension, pH and particle size limits, low NaCl content, and a phosphatidylcholine-to-adjuvant molar ratio range.
Vaccine composition with FimCH or truncated FimH antigen, phosphatidylcholine, and specified adjuvant compounds
A vaccine composition comprising an effective amount of an antigen of FimCH or truncated FimH, phosphatidylcholine, and an adjuvant formulation containing one or more specified compounds or mixtures thereof, or pharmaceutically acceptable salts.
Aqueous buffered suspension with pH and mean particle size limits
The vaccine composition is an aqueous buffered suspension with a pH of about 4.5 to about 6.5 and has a mean particle size of 150 nanometers or less.
Low NaCl content threshold
The vaccine composition contains less than 30 mM NaCl.
Phosphatidylcholine-to-adjuvant molar ratio range
Phosphatidylcholine is present at a molar ratio with a compound of claim 1 of about 1:1 to about 20:1.
FimCH selection tied to phosphatidylcholine-to-adjuvant molar ratio range
The vaccine composition comprises FimCH, and the phosphatidylcholine is at a molar ratio with a compound of claim 1 at about 1:1 to about 20:1.
Overall claim coverage centers on a vaccine composition combining FimCH or truncated FimH antigen with phosphatidylcholine and a specified adjuvant formulation, and then narrows the formulation toward an aqueous buffered suspension with controlled pH and mean particle size, reduced NaCl, and a defined phosphatidylcholine-to-adjuvant molar ratio range.
Stated Advantages
Improved stability of the described formulations at room temperature, including extended stability up to about 37°C.
Maintenance of PHAD particle size below about 150 nm over projected shelf life.
Prevention or significant reduction of acyl losses as shown by forced-degradation and mass spectrometry studies.
Comparative immunogenicity and tolerability results versus comparator adjuvant formulations are described.
Lower cost.
Reduced injection-site reactions.
Reduced systemic reactions.
Documented Applications
Vaccine composition for inducing or evaluating anti-FimH responses in urinary tract infections caused by gram-negative bacteria, including uropathogenic and multi-drug resistant Escherichia coli.
Use in preliminary human cGMP study tolerability and measurement of injection-site and systemic reactions versus comparator adjuvant formulations.
Stability assessment and forced-degradation study context for PHAD/3-deacyl-PHAD and MLA (PtHA) degradation pathways involving acyl-group loss.
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