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-12168675-B2
Publication Date
2024-12-17
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). It provides methods, compositions, and kits featuring the modified VLPs, including 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 cells using the modified VLPs.
The problem being solved is that alphaviruses and flaviviruses pose serious public health issues due to their evolution and spread into new geographic areas, and the severity of diseases resulting from their infection presents challenges in the absence of vaccines or antiviral therapies.
The invention addresses the difficulty in producing VLPs from wild-type alphavirus proteins that do not naturally form VLPs efficiently, such as certain strains of Eastern equine encephalitis virus (EEEV) and Western equine encephalitis virus (WEEV). It solves this by introducing one or more alterations in alphavirus E2 proteins and/or alphavirus capsid protein Nuclear Localization Signal (NLS) that allow or enhance VLP production. It also applies this strategy to flavivirus envelope proteins.
The invention demonstrates that expression of alphavirus structural proteins with these alterations yields VLPs that resemble replication-competent alphaviruses and induce potent immune responses in animal models, providing protection against multiple heterologous alphavirus strains. Furthermore, the modified VLPs can be used as delivery vehicles for agents into cells.
Claims Coverage
The patent claims focus on immunogenic compositions comprising modified virus-like particles (VLPs) from Eastern equine encephalitis virus (EEEV), Western equine encephalitis virus (WEEV), and Venezuelan equine encephalitis virus (VEEV) with specific alterations that enhance VLP production and methods of inducing immunity using these compositions.
Virus-like particles with altered E2 protein to enhance production
The invention provides VLPs comprising EEEV, WEEV, or VEEV E2 proteins that include one or more alterations at amino acid positions corresponding to amino acids 170, 200, 233, 234, 251, and 256 of the Chikungunya virus (CHIKV) E2 protein. These alterations enhance VLP production and allow self-assembly into VLPs.
Virus-like particles with altered capsid protein Nuclear Localization Signal (NLS) to enhance production
The invention provides VLPs comprising EEEV, WEEV, or VEEV capsid proteins with one or more alterations at charged amino acid residues within their NLS, specifically in regions at amino acids 67-70 for EEEV and WEEV, and amino acids 64-68 for VEEV. These alterations enhance VLP production and allow self-assembly into VLPs.
Multivalent immunogenic compositions containing multiple altered VLPs
The invention includes immunogenic compositions comprising at least three distinct VLPs, one each comprising altered EEEV, WEEV, and VEEV viral proteins as described, capable of inducing an immune response against EEEV, WEEV, and VEEV.
Use of adjuvants to enhance immunogenicity
The immunogenic compositions may further include adjuvants such as alum to enhance the immune response elicited by the VLPs.
Methods of inducing immune response using the immunogenic compositions
Methods for inducing immune responses against EEEV, WEEV, and VEEV in subjects by administering the described immunogenic compositions in effective amounts, through one or more doses, priming and boosting immunizations to induce neutralizing antibodies and protection against infection and associated symptoms.
Overall, the claims cover modified alphavirus VLPs with specific alterations in the E2 envelope proteins and capsid protein NLS regions that enhance VLP production, immunogenic compositions comprising these VLPs with optional adjuvants, and methods for immunization against alphavirus infections using these compositions.
Stated Advantages
The modified VLP vaccines efficiently induce high-titer neutralizing antibodies against homologous and heterologous alphavirus strains in animal models.
Immunized animals, including non-human primates and mice, show complete protection against high titer heterologous alphavirus challenge.
VLP vaccines have advantages such as safety and high immunogenicity compared to other vaccine types.
Modifications to alphavirus capsid protein NLS increase VLP yield, enabling their use in immunogenic compositions and pan-alphavirus vaccines.
Exposure of VLPs to high pH conditions during production increases VLP yield.
Documented Applications
Prevention or treatment of alphavirus-mediated diseases, including infections by Chikungunya virus (CHIKV), Western equine encephalitis virus (WEEV), Eastern equine encephalitis virus (EEEV), Venezuelan equine encephalitis virus (VEEV), Ross River virus, or Barmah Forest virus.
Prevention or treatment of flavivirus-mediated diseases, including infections by Yellow Fever Virus (YFV), Dengue Virus (DENV), Japanese Encephalitis Virus (JEV), Tick-Borne Encephalitis Virus (TBEV), or West Nile Virus (WNV).
Delivery of agents (small molecules, antibodies, nucleic acids, polypeptides) into cells using modified alphavirus or flavivirus VLPs as delivery vehicles.
Use as immunogenic compositions or vaccines for inducing neutralizing antibodies and protective immunity in mammals against alphaviruses and flaviviruses.
Use in multivalent vaccine formulations for broad protection against multiple alphaviruses, such as EEEV, WEEV, and VEEV.
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