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-10137192-B2
Publication Date
2018-11-27
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 patent discloses a vaccine composition for urinary tract infection that combines FimCH or truncated FimH with an effective amount of phosphorylated hexaacyl disaccharide or pharmaceutically acceptable salts thereof. Phosphorylated hexaacyl disaccharide is described as a TLR4 agonist, and the disclosure includes phosphorylated hexaacyl disaccharide and 3-deacyl-phosphorylated hexaacyl disaccharide as vaccine adjuvant components together with the FimCH/FimH antigen elements.
The disclosure further describes aqueous buffered suspensions that avoid lyophilization and are stable at refrigerated and room temperatures and up to about 37°C for extended periods. The formulation includes citrate buffer, succinate buffer, and/or phosphate buffer, and supports inclusion of phosphatidylcholine such as DPPC at defined PC:PHAD molar ratios.
The disclosure states that the buffered adjuvant formulations and vaccine combinations are designed to reduce severe injection-site and systemic reactions versus prior adjuvants such as alum/MF59/MPL, while supporting PtHA diglucosamine analogue adjuvants with chemical formulas and R1 chain-length constraints. It also describes vaccine compositions combining FimCH or truncated FimH with the PHAD/PtHA adjuvant and provides supporting rationale for improved hydrolysis reduction and stability.
Claims Coverage
The document includes two independent claims. The independent claim set covers a vaccine composition with an antigen component selected from FimCH or truncated FimH together with an effective amount of phosphorylated hexaacyl disaccharide or pharmaceutically acceptable salts thereof, and a method for preparing a vaccine by providing the phosphorylated hexaacyl disaccharide adjuvant formulation and combining it with an effective amount of an antigen of FimCH or truncated FimH. Across the dependent claims, additional inventive features refine the composition by adding phosphatidylcholine, constraining the phosphorylated hexaacyl disaccharide amount to microgram ranges, and limiting NaCl concentration to less than 30 mM.
FimCH or truncated FimH with phosphorylated hexaacyl disaccharide
A vaccine composition comprising an effective amount of FimCH or truncated FimH and an effective amount of phosphorylated hexaacyl disaccharide or pharmaceutically acceptable salts thereof.
Lower NaCl concentration in the vaccine
The vaccine composition contains less than 30 mM of NaCl.
Phosphatidylcholine-containing formulation
The vaccine composition includes phosphatidylcholine.
Phosphorylated hexaacyl disaccharide microgram range
The vaccine composition includes phosphorylated hexaacyl disaccharide in an amount of about 20 micrograms to about 50 micrograms.
Method combining phosphorylated hexaacyl disaccharide adjuvant with FimCH or truncated FimH antigen
A method for preparing a vaccine comprising providing an adjuvant formulation comprising phosphorylated hexaacyl disaccharide or pharmaceutically acceptable salts thereof and combining the adjuvant formulation with an effective amount of an antigen of FimCH or truncated FimH.
NaCl limitation in the method-prepared vaccine
The vaccine contains less than 30 mM of NaCl.
Phosphatidylcholine in the method-prepared vaccine
The method includes a vaccine comprising phosphatidylcholine.
Narrow phosphorylated hexaacyl disaccharide microgram range within the vaccine
The vaccine contains approximately 20 to 50 micrograms of phosphorylated hexaacyl disaccharide.
Further narrowed phosphorylated hexaacyl disaccharide range
The method includes a vaccine that contains about 40 micrograms to about 50 micrograms of phosphorylated hexaacyl disaccharide.
Overall, the claim coverage centers on pairing FimCH or truncated FimH with an effective amount of phosphorylated hexaacyl disaccharide or salts, with dependent refinements focused on reducing ionic strength via NaCl less than 30 mM, optionally including phosphatidylcholine, and constraining the phosphorylated hexaacyl disaccharide dose to defined microgram ranges. The method claim corresponds to preparing the vaccine by providing the phosphorylated hexaacyl disaccharide adjuvant formulation and combining it with an effective amount of the FimCH or truncated FimH antigen, with parallel dependent constraints.
Stated Advantages
Improved immunogenic response versus a formulation ratio comparison described in the document.
Reduced E. coli bladder CFU in a mouse UTI efficacy model when formulated with the stated phosphorylated hexaacyl disaccharide-adjuvanted FimCH.
Improved PHAD stability, including prevention or reduction of acyl loss during forced degradation, supported by stability readouts.
Early human clinical interim safety observations show no severe injection-site or systemic reactions in early female cohorts.
Stated to reduce severe injection-site and systemic reactions versus prior adjuvants such as alum/MF59/MPL.
Described as remarkably stable at refrigerated and room temperatures and up to about 37°C for extended periods.
Documented Applications
Vaccination against E. coli-associated urinary tract infection, including mouse efficacy evaluation using reduced E. coli bladder CFU and related rabbit immunogenicity and efficacy context.
In vitro potency assessment of FimH binding dependency, including a HRP binding assay showing dose-dependent HRP binding to FimH and dependence on mannose-binding.
Rabbit intramuscular toxicity and immunogenicity evaluation of PHAD formulations with tolerability and anti-FimH IgG titers.
Human clinical interim safety and immune response monitoring for FimCH with PHAD formulation, including observations of injection-site and systemic reactions.
Stability characterization and forced degradation analysis of phosphorylated hexaacyl disaccharide-containing formulations, including MS/TOF-MS ratio-based stability readouts.
Vaccine/adjuvant technology for urinary tract infection, including multi-drug resistant E. coli.
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