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Publication Number
US-10300125-B2
Publication Date
2019-05-28
Expiration Date
Abstract
Novel compositions useful as influenza immunogens are provided. The compositions enable a host response to immunogen sites normally not recognized by a host.
Core Innovation
The invention relates to influenza immune-refocusing vaccine compositions that include a cross reactive epitope and an immunodominant surface epitope of influenza virus hemagglutinin that is immunodampened. The concept defines immunodominant epitopes as normally strongly recognized and immunodampened epitopes as engineered to be less immunodominant than the corresponding epitope in a wild type influenza virus.
A central mechanism described is immunodampening of the hemagglutinin immunodominant surface epitope, including immunodampening via N-linked glycosylation-site addition or removal and via amino-acid substitutions, insertions, or deletions. The document frames these changes as engineered HA site modification schemes, including HA epitopes A–E and selected CD4 T-cell epitope changes.
This immunodampening is intended to redirect immune responses away from immunodominant non-protective epitopes toward cross-reactive and subdominant sites. The partial content further describes engineered hemagglutinin candidates and modification designs that are reported to yield high-titer and broadened cross-subtype/heterologous neutralization and hemagglutination-inhibition responses in mice/serology assays.
Claims Coverage
The document provides one independent claim covering an isolated composition with two epitope roles and defined dominance relationships. The dependent claims refine the hemagglutinin epitope identity, specify immunodampening by glycosylation-site changes and by particular amino-acid mutation types, and extend the concept to recombinant virus.
Isolated composition with cross reactive subdominant epitope and immunodampened hemagglutinin immunodominant surface epitope
An isolated composition comprising a cross reactive epitope that stimulates an immune response to influenza virus and an immunodominant surface epitope of influenza virus hemagglutinin that is immunodampened, wherein the dampened epitope is not as immunodominant as in a wild type influenza virus and the cross reactive epitope is subdominant in a wild type influenza virus.
Hemagglutinin surface epitope defined as epitopes A–E
The composition includes a surface epitope made up of hemagglutinin epitopes A–E.
Immunodampening via addition or removal of a glycosylation site
The immunodampened surface epitope includes addition or removal of a glycosylation site.
Immunodampening by amino-acid addition, substitution, or deletion
The immunodampened epitope contains one or more mutations selected from amino acid addition, amino acid substitution, or an amino acid deletion.
Sequence-defined immunodampened epitope with specified residue-level substitutions and glycosylation-site option
The composition is defined by specific amino-acid substitutions and sequence edits to an immunodampened epitope, including multiple epitope modifications and an option for addition of a glycosylation site at position 159 in epitope B, with specified deletions and combinations of listed changes.
Recombinant virus including the claimed epitope composition
A recombinant virus includes one or more of the compositions described in the claim.
Claim coverage centers on an epitope-role rearrangement where an immunodominant hemagglutinin surface epitope is engineered to be immunodampened, while a cross reactive epitope is subdominant in wild type yet included to stimulate an immune response to influenza virus. Dependent features specify hemagglutinin epitopes A–E, immunodampening by glycosylation-site alteration and by amino-acid addition, substitution, or deletion, and extend the concept to recombinant virus formats.
Stated Advantages
Redirection of immune responses away from immunodominant non-protective epitopes toward cross-reactive and subdominant sites.
High-titer and broadened cross-subtype/heterologous neutralization and hemagglutination-inhibition responses in mice/serology assays.
Documented Applications
Influenza immune-refocusing vaccine compositions.
Nonclinical safety/toxicity evaluation concepts in connection with the engineered candidates.
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