Chikungunya virus (CHIKV) virus-like particles (VLPS) comprising the C, E1, and E2 structural proteins
Inventors
Nabel, Gary J. • Akahata, Wataru • Rao, Srinivas
Assignees
US Department of Health and Human Services
Publication Number
US-12281336-B2
Publication Date
2025-04-22
Expiration Date
2029-11-24
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Abstract
The invention features compositions and methods for the prevention or treatment of one or more strains of Chikungunya virus, as well as other alphavirus-mediated diseases.
Core Innovation
The invention provides compositions and methods for the prevention or treatment of one or more strains of Chikungunya virus (CHIKV), as well as other alphavirus-mediated diseases. The core aspect of the invention includes virus-like particles (VLPs) containing one or more CHIKV structural polypeptides, including capsid and envelope proteins such as E3, E2, 6K, and E1. Polynucleotides encoding these VLPs, expression vectors, and host cells for producing VLPs are also described. Immunogenic compositions and vaccines comprising such VLPs or nucleic acids, including DNA vaccines, are provided, and methods of inducing immune responses using these compositions are disclosed.
The problem addressed by the invention is the significant public health threat posed by CHIKV infections, which cause severe arthritis and have spread widely without available vaccines or antiviral therapies. Since CHIKV has different genotypes and considerable antigenic variability, therapeutic and prophylactic strategies that can effectively prevent or treat infections across strains are urgently needed. Prior attempts at vaccines have limitations in safety and efficacy, underscoring the need for improved vaccine candidates.
The invention develops recombinant VLP vaccines that authentically mimic the morphology and antigenic structure of native CHIKV, inducing potent neutralizing antibody responses against both homologous and heterologous strains. Immunization with these VLPs protects against viremia and inflammatory consequences of infection in non-human primates and confers protection in lethal challenge models via antibody-mediated mechanisms. The methods also encompass prime-boost vaccination regimens and kits comprising VLPs and immunostimulatory adjuvants for enhanced efficacy.
Claims Coverage
The patent includes five independent inventive features relating to kits, VLP composition, nucleic acid constructs, methods of immunization, and methods of identifying inhibitors of CHIKV entry.
Kit containing CHIKV virus-like particles comprising structural proteins
The invention provides a kit comprising a virus-like particle (VLP) comprising CHIKV strain 37997 structural proteins including capsid (C), E2, and E1 proteins, wherein the VLP does not carry genetic information encoding the VLP proteins. The structural proteins may include any combination from capsid (C), E3, E2, 6K, and E1, and the VLP may include a polyprotein comprising C-E3-E2-6K-E1.
Virus-like particle comprising alphavirus structural polypeptides
The invention covers virus-like particles comprising one or more alphavirus structural polypeptides selected from the group consisting of Chikungunya virus, Sindbis virus, Eastern equine encephalitis virus, Western equine encephalitis virus, and Venezuelan equine encephalitis virus, including capsid and envelope proteins E3, E2, 6K, and E1, capable of eliciting an immune response.
Isolated polynucleotide encoding virus-like particle structural polypeptides
The invention provides isolated polynucleotides encoding one or more structural polypeptides of Chikungunya or other alphaviruses as described, including sequences encoding polyproteins comprising C-E3-E2-6K-E1, operably linked to expression control sequences such as the CMV/R promoter.
Methods of inducing an immune response against Chikungunya or alphavirus infections
Methods involve administering an effective amount of immunogenic compositions comprising virus-like particles or expression vectors encoding one or more Chikungunya virus structural polypeptides to induce protective humoral and cellular immune responses in a subject, for prevention or treatment of infection.
Assays for identifying inhibitors of Chikungunya virus entry
Methods for identifying inhibitors of CHIKV entry involve contacting a cell expressing a CHIKV receptor with Chikungunya polypeptides or pseudotyped viruses and candidate compounds, and assessing viral entry or reporter gene expression to detect compounds that inhibit viral entry, including antibodies or small molecules.
The claims collectively cover kits containing VLPs with defined CHIKV structural proteins, compositions comprising such VLPs or nucleic acids encoding them, methods for immunization to prevent or treat alphavirus infections, and screening methods to identify entry inhibitors, demonstrating broad coverage of both prophylactic and therapeutic aspects for Chikungunya virus.
Stated Advantages
VLPs elicit higher titer neutralizing antibody responses than DNA vaccines, inducing potent immunity.
Immunization with VLPs protects against viremia and inflammatory consequences of CHIKV infection in non-human primates.
Passive transfer of antibodies generated by VLP immunization confers protection against lethal CHIKV challenge in mouse models, demonstrating the role of humoral immunity.
VLP vaccines provide cross-strain reactivity against homologous and heterologous strains of CHIKV.
The approach is applicable to other alphaviruses, potentially supporting broad vaccine development for emerging alphavirus threats.
Documented Applications
Prevention or treatment of Chikungunya virus infection in humans or other mammals by vaccination with VLPs comprising CHIKV structural proteins.
Use of VLPs or DNA vaccines to induce protective immune responses, including neutralizing antibody production against CHIKV and related alphaviruses.
Development of kits containing VLPs and adjuvants for immunization protocols.
Screening assays for identifying inhibitors of Chikungunya virus entry into cells using labeled pseudotyped viruses or recombinant polypeptides.
Therapeutic administration of neutralizing antibodies generated by VLP immunization to treat or prevent CHIKV infection.
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