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AssigneeThe Scripps Research Institute
InventorsLinling HE, Jiang ZHU, Ian WILSON, Yi-Zong LEE
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The present invention provides engineered soluble F proteins of paramyxoviruses such as respiratory syncytial viruses (RSVs), human metapneumoviruses (hMPVs), and human parainfluenza viruses (hPIVs). These engineered proteins are stabilized via specific modifications in the wildtype soluble F sequences, e.g., substitutions in the 023 strand and/or introducing an engineered disulfide bond in a 0 hairpin in the F1 subunit. Also provided in the invention are nanoparticle vaccines that contain the engineered soluble F immunogens displayed on self-assembling nanoparticles. The invention also provides methods of using such vaccine compositions in various therapeutic applications, e.g., for preventing or treating viral infections such as RSV, MPV and PIV infections.
An engineered soluble fusion (F) protein of a paramyxovirus, comprising an altered soluble F sequence that has modifications relative to wildtype soluble F sequence of the paramyxovirus, wherein the modifications comprise (1) substitutions of two or more negatively charged residues around the β23 strand (D486-A490) with polar or hydrophobic residues, (2) deletion of the P27 peptide (E110-R136), and (3) an engineered intra-protomer disulfide bond that is either within the F1 subunit or links the F2 and F1 subunits;
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An engineered soluble fusion (F) protein of a paramyxovirus, comprising an altered soluble F sequence that has modifications relative to wildtype soluble F sequence of the paramyxovirus, wherein the modifications comprise an engineered disulfide bond that links a pair of β-sheet-forming amino acids in the β3/β4 hairpin or equivalent hairpin in the F1 subunit, wherein numbering of the hairpin is based on respiratory syncytial virus (RSV).
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An engineered soluble F protein of a respiratory syncytial virus (RSV), comprising a soluble RSV F sequence that is altered by (1) deletion of the P27 peptide (residues E110-R136), (2) a modification in the unstructured C-terminus of the F2 subunit (residues Q98-R109), and (3) a truncation of the N-terminus of the fusion peptide (residues F137-V157), wherein the amino acid numbering is based on human RSV strain A2 having UniProt ID P03420.
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Dependencies are inferred from the claim text.