Virus-like particles and methods of use
Inventors
Nabel, Gary J. • Rao, Srinivas • Akahata, Wataru
Assignees
US Department of Health and Human Services
Publication Number
US-11718647-B2
Publication Date
2023-08-08
Expiration Date
2032-01-31
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Abstract
The invention features modified alphavirus or flavivirus virus-like particles (VLPs). The invention provides methods, compositions, and kits featuring the modified VLPs. The invention also features methods for enhancing production of modified VLPs for use in the prevention or treatment of alphavirus and flavivirus-mediated diseases. The invention also provides methods for delivering agents to a cell using the modified VLPs.
Core Innovation
The invention features modified alphavirus or flavivirus virus-like particles (VLPs), including methods, compositions, and kits utilizing these modified VLPs. It provides methods for enhancing production of modified VLPs for use in prevention or treatment of diseases mediated by alphaviruses and flaviviruses, and methods for delivering agents to cells using these modified VLPs.
The problem addressed is the public health threat posed by alphaviruses and flaviviruses, which have serious disease outcomes including encephalitis and other severe symptoms, and the lack of effective vaccines or antiviral therapies. Moreover, expression of wild-type alphavirus structural proteins from some strains, such as EEEV and WEEV CBA, does not yield VLPs efficiently, limiting vaccine production.
To solve this, the invention provides virus-like particles having one or more alterations that enhance or allow VLP production, where the alterations reside in the E2 envelope protein or the alphavirus capsid protein Nuclear Localization Signal (NLS). Specific alterations include substitutions at amino acid positions corresponding to 234 and 251 in the Chikungunya virus (CHIKV) E2 protein, which increase VLP yield by affecting budding efficiency and capsid nuclear localization. The invention also extends to flavivirus VLPs with similar principles for enhanced production and vaccine use.
Claims Coverage
The patent contains one independent claim focused on a method of administering modified virus-like particles (VLPs) with specific viral protein alterations to induce an immune response against alphaviruses.
Administration of virus-like particles with alterations in alphavirus E2 protein at specific amino acid positions
A virus-like particle comprising an alphavirus E2 protein having one or more alterations relative to wild-type at one or more amino acid positions selected from positions corresponding to amino acids 170, 200, 233, 234, 251, and 256 in the Chikungunya virus (CHIKV) E2 protein, wherein these alterations enhance VLP production.
Incorporation of alterations in alphavirus capsid protein Nuclear Localization Signal (NLS) charged residues
The alphavirus capsid protein in the VLP includes one or more alterations relative to wild-type in charged amino acid residues within the Nuclear Localization Signal (NLS), contributing to enhanced VLP production.
Use of modified VLPs capable of self-assembly and inducing protective immune response
Virus-like particles comprising at least one altered viral protein as specified, capable of self-assembling into VLPs and administered in an amount effective to induce an immune response in the subject that inhibits alphavirus infection.
Selection of alphavirus types for VLP production and immunization
The alphavirus can be selected from Eastern equine encephalitis virus (EEEV), Western equine encephalitis virus (WEEV), Venezuelan equine encephalitis virus (VEEV), Semliki Forest virus (SFV), Chikungunya virus (CHIKV), O'nyong-nyong virus, Sindbis virus, Mayaro virus, Ross River virus, Barmah Forest virus, and Ockelbo virus.
Specific amino acid regions within capsid protein NLS targeted for alteration
Alterations in charged amino acid residues are located in specific NLS regions, including amino acids 67-70 of EEEV and WEEV capsid proteins, 64-68 of VEEV, 62-69 of CHIKV, 71-74 of Ross River virus, and 64-68 of Barmah Forest virus capsid proteins.
Multivalent immunization through combination of multiple altered VLPs
Administration of a combination of VLPs comprising at least one altered viral protein from multiple alphaviruses, e.g., EEEV, WEEV, and VEEV, to induce broad immune response.
The claim covers methods utilizing virus-like particles with specific amino acid alterations in alphavirus E2 proteins and capsid protein NLS regions to enhance VLP production and immunogenicity, protecting subjects against alphavirus infection, including use of multivalent combinations and effective immunization regimens.
Stated Advantages
Enhanced production of virus-like particles allows for efficient vaccine and delivery vehicle manufacturing.
Use of VLP vaccines provides better safety and higher immunogenicity compared to other vaccine types.
Alterations in E2 protein and capsid protein NLS increase VLP yields, reducing production costs.
Modified VLPs induce potent neutralizing antibody responses protecting against homologous and heterologous alphavirus strains.
Multivalent VLP vaccines can elicit immune responses against multiple alphavirus strains without immunologic interference.
Documented Applications
Prevention or treatment of diseases or disorders mediated by alphaviruses, including Chikungunya virus, Western equine encephalitis virus, Eastern equine encephalitis virus, Venezuelan equine encephalitis virus, Ross River virus, and Barmah Forest virus.
Prevention or treatment of flavivirus-mediated diseases, including those caused by Yellow Fever Virus, Dengue Virus, Japanese Encephalitis Virus, Tick-Borne Encephalitis Virus, and West Nile Virus.
Delivery of agents such as small molecule compounds, antibodies, nucleic acids, or polypeptides into cells using modified virus-like particles.
Use of modified VLPs as vaccines or immunogenic compositions to induce immune responses, including neutralizing antibodies, in humans and animals.
Adoptive immunotherapy by passive transfer of immunoglobulin from immunized subjects to protect susceptible hosts.
Screening or identifying inhibitors of alphavirus or flavivirus entry using pseudotyped lentiviral vectors and reporter gene assays.
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