Alphavirus and compositions, methods, and kits related thereto
Inventors
Kehn-Hall, Kylene Wesley • Carey, Brian D. • Akhrymuk, Ivan V. • Lehman, Caitlin W.
Assignees
Publication Number
US-11406699-B2
Publication Date
2022-08-09
Expiration Date
2040-03-16
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Abstract
The present invention provides modified alphaviruses and compositions, methods, and kits for preparing and using them to elicit an immune response to an alphavirus in a subject.
Core Innovation
The invention provides modified alphaviruses, particularly Venezuelan equine encephalitis virus (VEEV) and related alphaviruses, having a capsid protein that contains specific modifications to decrease phosphorylation compared to a nonmodified capsid. The modification comprises substitutions at one or more amino acid residues—specifically T93, T108, S124, and/or T127, or their equivalent positions in analogous alphaviruses—to prevent phosphorylation by a serine/threonine kinase such as PKCδ.
This invention addresses the problem that members of the alphavirus genus, such as VEEV, pose a significant health threat due to the lack of FDA-approved therapeutics or vaccines for treatment or prevention in humans. By decreasing phosphorylation of the capsid protein, the modified alphaviruses can be used to elicit an immune response in a subject, providing a path toward new attenuated vaccine candidates.
The patent further provides compositions (including vaccines), methods, and kits utilizing these modified viruses or components thereof for administration to subjects in order to elicit a prophylactic or therapeutic immune response against alphavirus infection. The invention also includes polynucleotides encoding these modified capsid proteins, methods for preparing the modified viruses, and host cells or kits comprising the modified virus.
Claims Coverage
There are multiple independent inventive features covered, focusing on genetically modified alphavirus capsid proteins, compositions, methods of use, and methods of preparation.
A live, attenuated VEEV alphavirus with decreased capsid phosphorylation
An alphavirus having a capsid protein with one or more substitutions at amino acid residues T93, T108, S124, and/or T127 (or equivalent positions), the substitutions preventing phosphorylation by a serine/threonine kinase, thereby decreasing phosphorylation of the capsid protein compared to a nonmodified capsid.
Composition containing the modified alphavirus and a pharmaceutically acceptable carrier
A composition comprising the genetically modified alphavirus with decreased capsid phosphorylation and a pharmaceutically acceptable carrier.
Isolated host cell comprising the modified alphavirus
A host cell, isolated and containing the genetically modified alphavirus with a capsid protein modified to decrease phosphorylation at designated residues compared to a nonmodified capsid.
Kit comprising the modified alphavirus
A kit containing the genetically modified alphavirus with the specified capsid modification.
Method for eliciting an immune response against VEEV in a subject
A method comprising administering to a subject a prophylactically or therapeutically effective amount of the genetically modified alphavirus having a capsid with decreased phosphorylation at T93, T108, S124, and/or T127, or equivalent positions.
Method of preparing live, attenuated VEEV alphavirus with modified capsid protein
A method that includes providing a modified alphavirus genome capable of expressing a capsid protein with substitutions that decrease phosphorylation compared to nonmodified capsid, specifically at the identified positions.
The inventive features are directed to modified, live, attenuated alphaviruses with capsid proteins engineered to lack phosphorylation at select residues, as well as compositions, host cells, kits, methods of use for immune response, and methods for preparing such alphaviruses.
Stated Advantages
Provides new and effective alphavirus vaccines addressing the lack of available FDA-approved therapeutics or vaccines for alphavirus infection.
The modified virus elicits an immune response without causing disease, offering an attenuated virus suitable for vaccine use.
The modification reduces virulence while maintaining the ability to replicate and induce immunity.
Documented Applications
Eliciting an immune response to an alphavirus in a subject, including humans and animals, for prophylactic or therapeutic purposes.
Prevention of alphavirus-associated disease by administration of the modified virus as a vaccine.
Delaying onset or slowing progression of alphavirus-associated disease in infected subjects by therapeutic administration.
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