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Publication Number
US-10517943-B2
Publication Date
2019-12-31
Expiration Date
Abstract
The present invention relates to liquid formulations of poxvirus, in particular vaccinia virus, stable during storage. Such stable liquid formulations comprise a) a poxvirus, preferably a vaccinia virus, b) a pharmaceutically acceptable buffer, c) a monovalent salt, d) a pharmaceutically acceptable disaccharide or sugar alcohol, and e) a pharmaceutically acceptable chelating agent, wherein the pH of the formulation is comprised between 6.5 and 8.5.
Core Innovation
The invention relates to stable aqueous liquid formulations for vaccinia and other poxviruses for storage. The formulation comprises a poxvirus, a pharmaceutically acceptable buffer, a monovalent salt, a pharmaceutically acceptable disaccharide or sugar alcohol, and a pharmaceutically acceptable chelating agent, with a pH between 6.5 and 8.5.
A key feature is the use of the chelating agent together with a C2–C3 alcohol in a concentration of 0.05 to 5% (v/v) and/or sodium glutamate in a concentration lower than 10 mM. Buffered sucrose plus a monovalent salt plus EDTA, optionally with ethanol, is described as providing particularly good stability.
The document describes liquid stability relative to freeze-drying, including maintaining infectious titer during long storage without reconstitution and reducing aggregation. It also describes protection against UV and ICH-light damage with EDTA, and stability across vaccinia/MVA formulations, associated vectors, and parapoxvirus (pseudocowpox).
Claims Coverage
The claim coverage centers on one independent liquid poxvirus formulation claim with two main inventive features, supported by dependent claim refinements for storage performance and recombinant vaccinia constructs.
Liquid pH-controlled poxvirus formulation with buffer, monovalent salt, disaccharide or sugar alcohol, and chelating agent
A liquid formulation comprising a poxvirus, a pharmaceutically acceptable buffer, a monovalent salt, a pharmaceutically acceptable disaccharide or sugar alcohol, and a pharmaceutically acceptable chelating agent, wherein the pH of the formulation is between 6.5 and 8.5.
C2–C3 alcohol and/or low-mM sodium glutamate in the poxvirus formulation
The liquid formulation further comprises a C2–C3 alcohol in a concentration of 0.05 to 5% (v/v) and/or sodium glutamate in a concentration lower than 10 mM.
Defined storage titer loss constraint
The liquid formulation has less than 0.3 log10 loss of infectious poxvirus titer during storage for at least 12 months at +5°C.
Recombinant vaccinia with specified exogenous sequence
The vaccinia virus is a recombinant vaccinia virus that includes at least one exogenous sequence encoding one or more listed antigens or therapeutic genes.
The claims are directed to a pH 6.5–8.5 liquid poxvirus formulation combining a buffer, monovalent salt, disaccharide or sugar alcohol, and a chelating agent, together with a C2–C3 alcohol and/or sodium glutamate. Additional claim coverage specifies long-term infectious titer retention and, for vaccinia, recombinant constructs including defined exogenous sequences.
Stated Advantages
Improved stability of infectious poxvirus in liquid form during long storage compared with freeze-drying approaches, including enhanced infectious titer retention over extended periods.
Liquid storage avoids reconstitution associated with freeze-drying and reduces aggregation.
Synergistic enhancement of liquid stability from the combination of chelating agent with low concentrations of C2–C3 alcohol.
Protection against UV/ICH-light damage with EDTA.
Not significantly reduced immunogenicity after 12–24 months storage at +5°C to +3°C.
Robust stability of infectious poxvirus titer with less than 0.3 log10 loss during at least 12 months storage at +5°C.
Stabilization of a parapoxvirus (pseudocowpox) with the claimed formulation.
Documented Applications
Storage use of poxvirus, including vaccinia, in stable aqueous liquid formulations.
Vaccinia UV protection using formulation chelating agent.
Liquid vaccinia/MVA formulations, including multiple vaccinia/MVA vectors (MVA-HCV, MVA-MUC1, and MVA-HPV) and recombinant MVA.
Stabilization of a parapoxvirus, pseudocowpox.
Use of recombinant vaccinia in liquid formulation for therapeutic or antigen encoding constructs.
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