Alphavirus replicon encoding chimeric SARS-CoV-2 receptor binding domains
Inventors
Akahata, Wataru • Smith, Jonathan F. • Ueno, Ryuji
Assignees
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Publication Number
US-12280102-B2
Publication Date
2025-04-22
Expiration Date
Abstract
Provided herein is an isolated polynucleotide, which encodes alphavirus non-structural proteins nsp1, nsp2, nsp3 and nsp4 and a polypeptide comprising a coronavirus protein fused to a signal sequence and/or transmembrane domain. The coronavirus protein may be the receptor binding domain of the S1 subunit of coronavirus spike (S) protein. The polynucleotide such as RNA is useful for as a vaccine against coronavirus infection, especially, COVID-19 infection.
Core Innovation
The invention relates to an isolated polynucleotide encoding alphavirus non-structural proteins nsP1, nsP2, nsP3, and nsP4, together with a polypeptide comprising a receptor binding domain (RBD) of an S1 subunit in a spike protein of SARS-CoV-2 fused to a transmembrane domain and optionally to a signal sequence. The alphavirus is Venezuelan Equine Encephalitis Virus or Chikungunya virus, and the transmembrane domain is heterologous to the SARS-CoV-2.
The disclosed platform is described as a coronavirus vaccine platform using alphavirus replicons encoding alphavirus non-structural proteins (nsP1–nsP4) and presenting a single-subunit antigen that includes the SARS-CoV-2 S1 RBD fused to a heterologous transmembrane domain. The document further describes multiple fusion architectures, including different signal sequence and transmembrane domain sources, and includes linker options for the fusion components.
The document states that replicon/single-subunit antigens are intended to induce protective antibody responses while minimizing antibody-dependent enhancement (ADE). It also outlines that the constructs and vectors include replicon/vector elements such as 5′ UTR, 3′ UTR, a subgenomic (SG) promoter, and a polyA tail, and that the system is evaluated for antigen expression and immunogenicity/antibody titers.
Claims Coverage
The independent claim recites an isolated polynucleotide with a specific alphavirus replicon (nsP1–nsP4) combined with a SARS-CoV-2 S1 RBD fused to a heterologous transmembrane domain and optionally to a signal sequence. Across the dependent claims listed, the inventive features further specify alphavirus selection, transmembrane domain sources, expression-cassette components, vaccine compositions with delivery vehicles, and RBD sequence constraint to SEQ ID NO: 19.
Alphavirus replicon encoding nsP1–nsP4 with SARS-CoV-2 S1 RBD polypeptide fusion
An isolated polynucleotide that encodes alphavirus non-structural proteins nsP1, nsP2, nsP3, and nsP4 and a polypeptide comprising a receptor binding domain (RBD) of an S1 subunit in a spike protein of SARS-CoV2 fused to a transmembrane domain and optionally to a signal sequence.
Venezuelan equine encephalitis virus or chikungunya virus selection
The alphavirus is Venezuelan Equine Encephalitis Virus or Chikungunya virus.
Heterologous transmembrane domain relative to SARS-CoV-2
The transmembrane domain is heterologous to the SARS-CoV-2.
Influenza hemagglutinin or CD80 transmembrane domain sources
The polynucleotide specifies that the transmembrane domain is derived from Influenza Hemagglutinin (HA) or CD80.
Vector expression-cassette elements including promoter, UTRs, SG promoter, and polyA
The vector further includes a promoter, 5′ UTR, SG promoter, 3′ UTR, and a poly A tail.
Vaccine composition with pharmaceutically acceptable delivery vehicle
A vaccine composition including a polynucleotide (or an expression vector containing it) together with a pharmaceutically acceptable delivery vehicle.
Delivery vehicle as alphavirus-structural-protein particle or lipid delivery system
The delivery vehicle is either a particle containing one or more alphavirus structural proteins or a lipid delivery system.
SARS-CoV-2 RBD corresponding to SEQ ID NO: 19
The polypeptide comprising the SARS-CoV-2 spike protein S1 subunit has a receptor binding domain (RBD) corresponding to SEQ ID NO: 19.
Overall, the claim set centers on an alphavirus replicon polynucleotide encoding nsP1–nsP4 combined with a SARS-CoV-2 S1 RBD fused to a heterologous transmembrane domain (optionally with a signal sequence), constrained to alphavirus choice and further refined by transmembrane sources, expression-cassette components, vaccine formulations with delivery vehicles, and RBD sequence constraint to SEQ ID NO: 19.
Stated Advantages
Induce protective antibody responses while minimizing antibody-dependent enhancement (ADE).
Documented Applications
Coronavirus vaccine platform using alphavirus replicons encoding alphavirus non-structural proteins (nsP1–nsP4) and a SARS-CoV-2 S1 receptor-binding domain fused to a heterologous transmembrane domain for immunogenicity assessment.
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