Method for producing chikungunya virus (CHIKV) virus-like particles comprising the C, E2, and E1 structural proteins
Inventors
Nabel, Gary J. • Akahata, Wataru • Rao, Srinivas
Assignees
US Department of Health and Human Services
Publication Number
US-11992523-B2
Publication Date
2024-05-28
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
Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that causes human disease characterized by rash, high fever, and severe arthritis that can persist for years. Since its re-emergence in 2004, CHIKV has spread across Africa, Europe, and Asia, posing a serious public health threat due to the absence of vaccines or anti-viral therapies. The virus has three genotypes with varying degrees of similarity, underscoring the urgent need for therapeutic and prophylactic methods to treat or prevent Chikungunya viral disease.
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. It provides virus-like particles (VLPs) containing one or more Chikungunya virus structural polypeptides including capsid (C) and envelope proteins E3, E2, 6K, and E1, either individually or as a polyprotein. The invention also includes isolated polynucleotides encoding these VLPs, expression vectors containing such polynucleotides, prokaryotic or eukaryotic cells containing these vectors, and immunogenic compositions—including vaccines—containing effective amounts of these VLPs or vectors.
The invention addresses the challenge of inducing protective immunity against CHIKV by producing recombinant VLP vaccines that self-assemble from structural proteins, mimicking the morphology and buoyant density of the native virus. Immunization with these VLPs elicits neutralizing antibodies effective against homologous and heterologous strains, providing protection in non-human primates against high-dose CHIKV challenge. This strategy holds promise for preventing infection and spread of CHIKV and related alphaviruses in humans.
Claims Coverage
The patent includes one independent claim that defines a method for producing CHIKV virus-like particles, focusing on the expression of specific structural proteins from strain 37997 and their self-assembly into VLPs.
Production of CHIKV virus-like particles by expression of structural proteins
The method involves expressing in a cell one or more polynucleotides encoding CHIKV strain 37997 structural proteins under conditions allowing self-assembly into a virus-like particle, wherein the structural proteins include at least capsid (C), E2, and E1 proteins, and wherein the cell does not express polynucleotides encoding non-structural CHIKV proteins.
Inclusion of additional structural proteins to form VLPs
The structural proteins expressed can further include at least E3 protein and 6K protein, in addition to capsid (C), E2, and E1 proteins.
Encoding structural proteins as a polyprotein
The polynucleotides expressed may encode a polyprotein comprising capsid (C), E3, E2, 6K, and E1 proteins from CHIKV strain 37997.
Isolation of the assembled virus-like particles
The method may further encompass isolating the virus-like particles after expression and self-assembly.
Overall, the claims cover a method of producing CHIKV virus-like particles by expressing CHIKV 37997 structural proteins in a cell devoid of non-structural protein expression, including the specific structural components necessary for VLP formation, possibly as a polyprotein, with an optional isolation step.
Stated Advantages
The VLP vaccines elicit high titer neutralizing antibodies against multiple CHIKV strains, providing cross-strain reactivity.
Immunization with VLPs protects non-human primates against CHIKV viremia and inflammation following high-dose viral challenge.
Passive transfer of antibodies generated by VLP immunization confers protection against lethal CHIKV challenge in an immunodeficient mouse model, demonstrating protective humoral immunity.
VLPs mimic native virus morphology and structure, enhancing their immunogenicity relative to DNA vaccine approaches.
Documented Applications
Vaccination of mammals, including humans, to induce protective immunity against Chikungunya virus infection.
Use of VLP vaccines for prophylactic and therapeutic treatment of CHIKV infection in subjects at risk of or suffering from such infection.
Immunogenic compositions containing CHIKV VLPs or DNA vaccines to prevent or treat alphavirus-mediated diseases.
Screening for inhibitors of CHIKV viral entry using cells expressing CHIKV receptors and pseudotyped viruses containing CHIKV envelope proteins.
Administration of VLPs or antibodies generated against VLPs for protection against CHIKV infection and its symptoms in animal models and potentially humans.
Prime-boost immunization regimens combining DNA vaccines and VLPs to enhance immune responses against CHIKV.
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