Protein-based nanoparticle vaccine for metapneumovirus
Inventors
Feldhaus, Andrew Lawrence • Holtzman, Douglas Andrew • Wolf, Clancey Buchanan
Assignees
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Publication Number
US-11806394-B2
Publication Date
2023-11-07
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 (VLP) for human metapneumovirus (hMPV), where a human metapneumovirus (hMPV) F protein ectodomain is linked to a symmetric, protein-designed, self-assembling VLP core. The VLP is built from a first component and a second component, and the first component includes a first fusion protein comprising the hMPV F protein ectodomain and a first multimerization domain sharing at least 90% identity to SEQ ID NO: 7.
The second component includes a second protein having a second multimerization domain sharing at least 90% identity to SEQ ID NO: 8. The description further specifies linker sequences between the hMPV F ectodomain and the multimerization domain, with linker examples including Foldon and GSGGSGSGSGGS and other Gly-Ser linkers, and the VLP examples include multimer display stoichiometry such as 20 trimers and 12 pentamers.
The disclosure further supports the immunogenicity and protective function of the prefusion-focused VLP designs. Antibody binding and EC50 trends are described for prefusion versus postfusion recognition, neutralizing antibody induction is reported in mice with adjuvants, and in vivo performance is reported in cotton rats after hMPV challenge, including viral-load reduction.
Claims Coverage
The provided claims include three independent claims: a VLP, a polynucleotide encoding the VLP, and a method of immunizing against hMPV infection. Across these independent claims, the core inventive features are a two-component symmetric VLP architecture using fusion of the hMPV F ectodomain to a first multimerization domain, and a second multimerization domain supplied by a second protein, each constrained by at least 90% identity to specified SEQ ID sequences.
Two-component protein-based VLP with hMPV F ectodomain fusion to multimerization domains
A protein-based virus-like particle (VLP) comprising a first component and a second component, wherein the first component includes a first fusion protein comprising a human metapneumovirus (hMPV) F protein ectodomain and a first multimerization domain sharing at least 90% identity to SEQ ID NO: 7, and the second component includes a second protein having a second multimerization domain sharing at least 90% identity to SEQ ID NO: 8.
Polynucleotide encoding the two-component multimerization-domain VLP
A polynucleotide encoding a protein-based virus-like particle (VLP) comprising a first component and a second component, wherein the first component includes a first fusion protein comprising a human metapneumovirus (hMPV) F protein ectodomain and a first multimerization domain sharing at least 90% identity to SEQ ID NO: 7, and the second component includes a second protein having a second multimerization domain sharing at least 90% identity to SEQ ID NO: 8.
Immunizing a subject with the two-component VLP against hMPV infection
A method of immunizing a subject against infection by human metapneumovirus, comprising administering a protein-based virus-like particle (VLP) comprising a first component and a second component, wherein the first component includes a first fusion protein comprising a human metapneumovirus (hMPV) F protein ectodomain and a first multimerization domain sharing at least 90% identity to SEQ ID NO: 7, and the second component includes a second protein having a second multimerization domain sharing at least 90% identity to SEQ ID NO: 8.
Across the independent claims, coverage centers on a two-component protein-based VLP in which the hMPV F protein ectodomain is fused to a first multimerization domain (SEQ ID NO: 7) and assembled with a second multimerization domain provided by a second protein (SEQ ID NO: 8), each constrained by at least 90% identity. The same VLP architecture is covered as a polynucleotide encoding the components and as a method for immunizing a subject against hMPV infection.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Inducing neutralizing antibody responses in mice using hMPV F ectodomain VLPs with adjuvants (Addavax/Alhydrogel).
Protecting against hMPV challenge in cotton rats and reducing viral load after hMPV challenge (hMPV033).
Immunizing a subject against infection by human metapneumovirus using the defined protein-based VLP.
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