Protein-based nanoparticle vaccine for metapneumovirus
Inventors
Feldhaus, Andrew Lawrence • Holtzman, Douglas Andrew • Wolf, Clancey Buchanan
Assignees
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Publication Number
US-12343391-B2
Publication Date
2025-07-01
Expiration Date
Abstract
Provided are virus-like particle vaccines for human metapneumovirus (hMPV) in which the ectodomain of hMPV F protein is linked to, and thereby displayed on, a symmetric protein-based virus-like particle. For example, the vaccine antigen may be a N-terminal fusion of the ectodomain of hMPV F protein to a protein having a multimerization domain for a one- or two-component virus-like particle, such as a two-component icosahedral virus-like particle. Further provided are vaccine compositions, methods of manufacturing, and methods of use, e.g., immunizing a subject to generate a protective immune response to hMPV.
Core Innovation
The invention relates to protein-based virus-like particles for human metapneumovirus vaccination. The VLP includes a first component and optionally a second component, where the first component comprises a fusion protein with an hMPV F protein ectodomain or an antigenic variant thereof displayed in a symmetric, designed, protein-only VLP core. The ectodomain presentation is coupled to a first multimerization domain to drive multimerization and assembly of the VLP.
When a second component is present, it comprises a second multimerization domain configured to work with the first multimerization domain to form the overall symmetric particle. The construction includes one-component or two-component VLP formats, including symmetric icosahedral or tetrahedral particle concepts. The disclosed designs support antigen display and assembly rationale.
The disclosure describes structural and building principles for forming assembled hMPV virus-like particles, including controlling valency and presenting conformationally defined antigenic surfaces. The hMPV F ectodomain is described with furin-cleavage-site modifications and antigenic variants, and specific linker designs connect the hMPV F ectodomain to multimerization domains, including a foldon sequence and Gly-Ser linker options.
Claims Coverage
The independent claim set includes one independent claim. It covers VLP constructs built from a fusion protein first component displaying an hMPV F ectodomain or antigenic variant and containing a first multimerization domain selected from specified SEQ ID NOS, with an optional second component containing a second multimerization domain. Across the provided material, the inventive coverage is further refined by multimerization-domain type and sequence identity, linker and foldon definition, hMPV F ectodomain substitutions and deletions, and antibody binding selectivity.
Fusion protein first component with hMPV F ectodomain and first multimerization domain
A VLP comprising a first component that is a fusion protein, wherein the fusion protein comprises a human metapneumovirus (hMPV) F protein ectodomain or an antigenic variant thereof and a first multimerization domain selected from specified SEQ ID NOS or functional variants thereof.
Optional second component with second multimerization domain
The VLP optionally comprises a second component, if present, where the second component is a protein comprising a second multimerization domain.
Trimerization multimerization domain
The first multimerization domain is a trimerization domain.
Multimerization domain sequence identity thresholds
The first multimerization domain is at least 70%, 80%, 90%, 95%, 98%, 99%, or 100% identical to one of two provided sequence variants (SEQ ID NO: 144 or SEQ ID NO: 145).
Foldon-defined linker sequence
A linker sequence containing a foldon sequence defined as EKAAKAEEAARK (SEQ ID NO: 125).
Constrained hMPV F ectodomain substitutions and/or deletions
The hMPV F protein ectodomain or antigenic variant includes one or more specified amino-acid substitutions and/or a specified deletion.
Low or no binding to postfusion-preferring antibody
The hMPV F protein ectodomain or antigenic variant exhibits no or low binding to an antibody that preferentially binds the postfusion form of the hMPV F protein ectodomain.
Overall claim coverage centers on a multicomponent hMPV F ectodomain virus-like particle in which the hMPV F ectodomain or antigenic variant is fused to a selected first multimerization domain, optionally with a second multimerization domain, and is further constrained by multimerization-domain identity and type, defined linker and foldon content, specific hMPV F ectodomain substitutions and deletions, and antibody-binding selectivity.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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