VIRUS-LIKE PARTICLE VACCINES

摘要

The invention is directed to dimeric fusion proteins and virus-like particles comprising such dimeric fusion proteins. These dimeric fusion proteins comprise an antigen or antigenic fragment carried between two viral structural proteins or fragments thereof, with or without linkers, in a manner that, relative to traditional monomeric platforms, minimizes steric hindrance among the antigen or antigenic fragment and the viral structural proteins or fragments thereof. This novel design provides for multivalent vaccines and enhanced immunogenicity. The invention also relates to nucleic acids encoding such dimeric fusion proteins and host cells comprising such nucleic acids. The invention further relates to pharmaceutical compositions comprising the dimeric fusion proteins and/or virus-like particles of the invention, and methods of prevention or treatment using such compositions.

主权项

1. A fusion protein comprising:
(a) V1-L1-Ag-L2-V2, wherein
V1 is an N-terminal viral structural protein,L1 is an N-terminal linker,Ag is an antigen or antigenic fragment of a pathogen,L2 is a C-terminal linker, andV2 is a C-terminal viral structural protein, andwherein each of V1 and V2 is, independently or together, capable of forming a virus-like particle; (b) V1-L1-Ag-V2 or V1-Ag-L2-V2, wherein
V1 is an N-terminal viral structural protein,L1 is an N-terminal linker,Ag is an antigen or antigenic fragment of a pathogen,L2 is a C-terminal linker, andV2 is a C-terminal viral structural protein, andwherein each of V1 and V2 is, independently or together, capable of forming a virus-like particle; (c) V1-Ag-V2, wherein
V1 is an N-terminal viral structural protein,Ag is an antigen or antigenic fragment of a pathogen,V2 is a C-terminal viral structural protein, andwherein each of V1 and V2 is, independently or together, capable of forming a virus-like particle; (d) V1-L1-Ag-L2-V2, wherein
V1 is a fragment of an N-terminal viral structural protein,L1 is an N-terminal linker,Ag is an antigen or antigenic fragment of a pathogen,L2 is a C-terminal linker, andV2 is a fragment of a C-terminal viral structural protein, andwherein each of V1 and V2 is, independently or together, capable of forming a virus-like particle, and wherein V1 and V2 are the same; (e) V1-L1-Ag-V2 or V1-Ag-L2-V2, wherein
V1 is a fragment of an N-terminal viral structural protein,L1 is an N-terminal linker,Ag is an antigen or antigenic fragment of a pathogen,L2 is a C-terminal linker, andV2 is a fragment of a C-terminal viral structural protein, andwherein each of V1 and V2 is, independently or together, capable of forming a virus-like particle, and wherein V1 and V2 are the same; (f) V1-Ag-V2, wherein
V1 is a fragment of an N-terminal viral structural protein,Ag is an antigen or antigenic fragment of a pathogen,V2 is a fragment of a C-terminal viral structural protein, andwherein each of V1 and V2 is, independently or together, capable of forming a virus-like particle, and wherein V1 and V2 are the same; (g) V1-L1-Ag-L2-V2, wherein
V1 is a fragment of an N-terminal viral structural protein,L1 is an N-terminal linker,Ag is an antigen or antigenic fragment of a pathogen,L2 is a C-terminal linker, andV2 is a fragment of a C-terminal viral structural protein, andwherein each of V1 and V2 is, independently or together, capable of forming a virus-like particle, andwherein V1 and V2 are from different proteins from the same virus; (h) V1-L1-Ag-V2 or V1-Ag-L2-V2, wherein
V1 is a fragment of an N-terminal viral structural protein,L1 is an N-terminal linker,Ag is an antigen or antigenic fragment of a pathogen,L2 is a C-terminal linker, andV2 is a fragment of a C-terminal viral structural protein, andwherein each of V1 and V2 is, independently or together, capable of forming a virus-like particle, andwherein V1 and V2 are from different proteins from the same virus; (i) V1-Ag-V2, wherein
V1 is a fragment of an N-terminal viral structural protein,Ag is an antigen or antigenic fragment of a pathogen,V2 is a fragment of a C-terminal viral structural protein, andwherein each of V1 and V2 is, independently or together, capable of forming a virus-like particle, andwherein V1 and V2 are from different proteins from the same virus; (j) V1-L1-Ag-L2-V2, wherein
V1 is a fragment of an N-terminal viral structural protein,L1 is an N-terminal linker,Ag is an antigen or antigenic fragment of a pathogen,L2 is a C-terminal linker, andV2 is a fragment of a C-terminal viral structural protein, andwherein each of V1 and V2 is, independently or together, capable of forming a virus-like particle, andwherein V1 and V2 are from proteins of different viruses; (k) V1-L1-Ag-V2 or V1-Ag-L2-V2, wherein
V1 is a fragment of an N-terminal viral structural protein,L1 is an N-terminal linker,Ag is an antigen or antigenic fragment of a pathogen,L2 is a C-terminal linker, andV2 is a fragment of a C-terminal viral structural protein, andwherein each of V1 and V2 is, independently or together, capable of forming a virus-like particle, andwherein V1 and V2 are from proteins from different viruses; (l) V1-Ag-V2, wherein
V1 is a fragment of an N-terminal viral structural protein,Ag is an antigen or antigenic fragment of a pathogen,V2 is a fragment of a C-terminal viral structural protein, andwherein each of V1 and V2 is, independently or together, capable of forming a virus-like particle, andwherein V1 and V2 are from proteins from different viruses; (m) V1-L1-Ag-L2-V2, wherein
V1 is a fragment of an N-terminal viral structural protein,L1 is an N-terminal linker,Ag is an antigen or antigenic fragment of a pathogen,L2 is a C-terminal linker, andV2 is a fragment of a C-terminal viral structural protein, andwherein each of V1 and V2 is, independently or together, capable of forming a virus-like particle, andwherein the fragments are from different portions of the same parent viral structural protein, andwherein the combined amino acid sequence of V1 and V2 comprises less than the complete amino acid sequence of the parent viral structural protein; (n) V1-L1-Ag-V2 or V1-Ag-L2-V2, wherein
V1 is a fragment of an N-terminal viral structural protein,L1 is an N-terminal linker,Ag is an antigen or antigenic fragment of a pathogen,L2 is a C-terminal linker, andV2 is a fragment of a C-terminal viral structural protein, andwherein each of V1 and V2 is, independently or together, capable of forming a virus-like particle, andwherein the fragments are from different portions of the same parent viral structural protein, andwherein the combined amino acid sequence of V1 and V2 comprises less than the complete amino acid sequence of the parent viral structural protein; (o) V1-Ag-V2, wherein
V1 is a fragment of an N-terminal viral structural protein,Ag is an antigen or antigenic fragment of a pathogen,V2 is a fragment of a C-terminal viral structural protein, andwherein each of V1 and V2 is, independently or together, capable of forming a virus-like particle, andwherein the fragments are from different portions of the same parent viral structural protein, andwherein the combined amino acid sequence of V1 and V2 comprises less than the complete amino acid sequence of the parent viral structural protein; (p) V1-L1-Ag-L2-V2, wherein
V1 is an N-terminal viral structural protein,L1 is an N-terminal linker,Ag is an antigen or antigenic fragment of a pathogen,L2 is a C-terminal linker, andV2 is a fragment of a C-terminal viral structural protein, andwherein each of V1 and V2 is, independently or together, capable of forming a virus-like particle, andwherein V2 is a fragment of V1; (q) V1-L1-Ag-L2-V2, wherein
V1 is a fragment of an N-terminal viral structural protein,L1 is an N-terminal linker,Ag is an antigen or antigenic fragment of a pathogen,L2 is a C-terminal linker, andV2 is a C-terminal viral structural protein, andwherein each of V1 and V2 is, independently or together, capable of forming a virus-like particle, andwherein V1 is a fragment of V2; (r) V1-L1-Ag-V2 or V1-Ag-L2-V2, wherein
V1 is an N-terminal viral structural protein,L1 is an N-terminal linker,Ag is an antigen or antigenic fragment of a pathogen,L2 is a C-terminal linker, andV2 is a fragment of a C-terminal viral structural protein, andwherein each of V1 and V2 is, independently or together, capable of forming a virus-like particle, andwherein V2 is a fragment of V1; (s) V1-L1-Ag-V2 or V1-Ag-L2-V2, wherein
V1 is a fragment of an N-terminal viral structural proteinL1 is an N-terminal linker,Ag is an antigen or antigenic fragment of a pathogen,L2 is a C-terminal linker, andV2 is a C-terminal viral structural protein, andwherein each of V1 and V2 is, independently or together, capable of forming a virus-like particle, andwherein V1 is a fragment of V2; (t) V1-Ag-V2, wherein
V1 is an N-terminal viral structural protein,Ag is an antigen or antigenic fragment of a pathogen,V2 is a fragment of a C-terminal viral structural protein, andwherein each of V1 and V2 is, independently or together, capable of forming a virus-like particle, andwherein V2 is a fragment of V1; (u) V1-Ag-V2, wherein
V1 is a fragment of an N-terminal viral structural protein,Ag is an antigen or antigenic fragment of a pathogen,V2 is a C-terminal viral structural protein, andwherein each of V1 and V2 is, independently or together, capable of forming a virus-like particle, andwherein V1 is a fragment of V2; (v) V1-L1-Ag-L2-V2, wherein
V1 is an N-terminal viral structural protein,L1 is an N-terminal linker,Ag is an antigen or antigenic fragment of a pathogen,L2 is a C-terminal linker, andV2 is a fragment of a C-terminal viral structural protein, andwherein each of V1 and V2 is, independently or together, capable of forming a virus-like particle, andwherein V2 is a fragment of a different protein from the same virus as V1; (w) V1-L1-Ag-L2-V2, wherein
V1 is a fragment of an N-terminal viral structural protein,L1 is an N-terminal linker,Ag is an antigen or antigenic fragment of a pathogen,L2 is a C-terminal linker, andV2 is a C-terminal viral structural protein, andwherein each of V1 and V2 is, independently or together, capable of forming a virus-like particle, andwherein V1 is a fragment of a different protein from the same virus as V2; (x) V1-L1-Ag-V2 or V1-Ag-L2-V2, wherein
V1 is an N-terminal viral structural protein,L1 is an N-terminal linker,Ag is an antigen or antigenic fragment of a pathogen,L2 is a C-terminal linker, andV2 is a fragment of a C-terminal viral structural protein, andwherein each of V1 and V2 is, independently or together, capable of forming a virus-like particle, andwherein V2 is a fragment of a different protein from the same virus as V1; (y) V1-L1-Ag-V2 or V1-Ag-L2-V2, wherein
V1 is a fragment of an N-terminal viral structural protein,L1 is an N-terminal linker,Ag is an antigen or antigenic fragment of a pathogen,L2 is a C-terminal linker, andV2 is a C-terminal viral structural protein, andwherein each of V1 and V2 is, independently or together, capable of forming a virus-like particle, andwherein V1 and V2 are from different proteins from the same virus; (z) V1-Ag-V2, wherein
V1 is an N-terminal viral structural protein,Ag is an antigen or antigenic fragment of a pathogen,V2 is a fragment of a C-terminal viral structural protein, andwherein each of V1 and V2 is, independently or together, capable of forming a virus-like particle, andwherein V2 is a fragment of a different protein from the same virus as V1; (aa) V1-Ag-V2, wherein
V1 is a fragment of an N-terminal viral structural protein,Ag is an antigen or antigenic fragment of a pathogen,V2 is a C-terminal viral structural protein, andwherein each of V1 and V2 is, independently or together, capable of forming a virus-like particle, andwherein V1 is a fragment of a different protein from the same virus as V2; (bb) V1-L1-Ag-L2-V2, wherein
V1 is an N-terminal viral structural protein,L1 is an N-terminal linker,Ag is an antigen or antigenic fragment of a pathogen,L2 is a C-terminal linker, andV2 is a fragment of a C-terminal viral structural protein, andwherein each of V1 and V2 is, independently or together, capable of forming a virus-like particle, andwherein V2 is a fragment of a protein from a different virus than V1; (cc) V1-L1-Ag-L2-V2, wherein
V1 is a fragment of an N-terminal viral structural protein,L1 is an N-terminal linker,Ag is an antigen or antigenic fragment of a pathogen,L2 is a C-terminal linker, andV2 is a C-terminal viral structural protein, andwherein each of V1 and V2 is, independently or together, capable of forming a virus-like particle, andwherein V1 is a fragment of a protein from a different virus than V2; (dd) V1-L1-Ag-V2 or V1-Ag-L2-V2, wherein
V1 is an N-terminal viral structural protein,L1 is an N-terminal linker,Ag is an antigen or antigenic fragment of a pathogen,L2 is a C-terminal linker, andV2 is a fragment of a C-terminal viral structural protein, andwherein each of V1 and V2 is, independently or together, capable of forming a virus-like particle, andwherein V2 is a fragment of a protein from a different virus than V1; (ee) V1-L1-Ag-V2 or V1-Ag-L2-V2, wherein
V1 is a fragment of an N-terminal viral structural protein,L1 is an N-terminal linker,Ag is an antigen or antigenic fragment of a pathogen,L2 is a C-terminal linker, andV2 is a C-terminal viral structural protein, andwherein each of V1 and V2 is, independently or together, capable of forming a virus-like particle, andwherein V1 is a fragment of a protein from a different virus than V2; (ff) V1-Ag-V2, wherein
V1 is an N-terminal viral structural protein,Ag is an antigen or antigenic fragment of a pathogen,V2 is a fragment of a C-terminal viral structural protein, andwherein each of V1 and V2 is, independently or together, capable of forming a virus-like particle, andwherein V2 is a fragment of a protein from a different virus than V1; or (gg) V1-Ag-V2, wherein
V1 is a fragment of an N-terminal viral structural protein,Ag is an antigen or antigenic fragment of a pathogen,V2 is a C-terminal viral structural protein, andwherein each of V1 and V2 is, independently or together, capable of forming a virus-like particle, andwherein V1 is a fragment of a protein from a different virus than V2.