Vectors for eliciting immune responses to non-dominant epitopes in the hemagglutinin (HA) protein
AssigneeWisconsin Alumni Research Foundation (WARF)
InventorsYoshihiro Kawaoka, Gabriele Neumann, Huihui Kong
Life of this patent
Estimating the term…
Abstract
Methods of preparing influenza viruses having altered immunodominant epitopes in HA, e.g., having one or more residues in one or more of antigenic sites A-E in HA altered, and viral vectors, e.g., influenza virus VLPs or non-influenza viruses or VLPs thereof expressing or having influenza HAs with altered immunogenicity as a result of altered immunodominant epitopes therein are provided.
Claims19
A method to prepare a plurality of influenza virus nucleic acid molecules encoding a H3 or H5 hemagglutinin (HA) having a reduced number of immune dominant epitopes, comprising:
- introducing random mutations at a plurality of codons in one or more immune dominant epitopes in an isolated parental influenza virus nucleic acid molecule encoding an influenza virus H3 or H5 hemagglutinin having at least two immune dominant epitopes, thereby providing a library of influenza virus nucleic acid molecules encoding a mutant H3 or H5 influenza virus hemagglutinin;
- introducing the library into cells so as to provide a library of cells that express the mutant hemagglutinins;
- and identifying a mutant hemagglutinin encoded by the library with a reduced number of the immune dominant epitopes relative to the parental hemagglutinin as a result of one or more substitutions and/or deletions at residues that form the one or more immune dominant epitopes, wherein if the mutant H3 hemagglutinin has substitutions, the mutant H3 hemagglutinin has more than five substitutions relative to the parental H3 hemagglutinin.
A method to prepare an influenza virus encoding a mutant hemagglutinin that has fewer immune dominant epitopes relative to a parental influenza virus, comprising:
- introducing a mutation in a parental H3 HA nucleic acid molecule at two or more codons for residue 121, 131, 135, 138, 140, 142, 144, 145, 155, 156, 157, 158, 171, 189, 193, 212, or 225, wherein the mutation encodes a residue that is not an immune dominant epitope residue in the parent H3 HA or introducing a mutation in a parental H5 HA nucleic acid molecule at two or more codons for residue 119, 123, 125, 126, 127, 129, 138, 140, 141, 151, 152, 153, 154, 155, 156, 185, or 189, wherein the mutation encodes a residue that is not an immune dominant epitope residue in the parent H5 HA;
- and isolating or preparing one or more influenza viruses with the mutated H3 or H5 HA, wherein the mutated H3 nucleic acid has more than five of the codons mutated, and wherein numbering for H3 is H3 numbering.
A composition comprising a plurality of distinct isolated recombinant influenza viruses each encoding a H3 or H5 hemagglutinin comprising a plurality of antigenically distinct residues relative to residues that form an immune dominant epitope in a parent virus, wherein each of the plurality of influenza viruses comprises substitutions at two or more of positions 121, 131, 135, 138, 140, 142, 144, 145, 155, 156, 157, 158, 171, 189, 193, 212, or 225, or one or more deletions of positions 121, 131, 135, 138, 140, 142, 144, 145, 155, 156, 157, 158, 171, 189, 193, 212, or 225, in H3, or any combination thereof, relative to the parent virus H3 hemagglutinin;
- or wherein each of the plurality of influenza viruses comprises a substitution at two or more of positions 119, 123, 125, 126, 127, 129, 138, 140, 141, 151, 152, 153, 154, 155, 156, 185, or 189, or a deletion in one or more of positions 119, 123, 125, 126, 127, 129, 138, 140, 141, 151, 152, 153, 154, 155, 156, 185, or 189, in H5, or any combination thereof, relative to the parent virus H5 hemagglutinin vims, wherein at least one of the plurality of distinct recombinant H3 viruses has a H3 hemagglutinin with more than five substitutions relative to the parental virus H3 hemagglutinin.
A method to immunize an animal, comprising:
- administering an effective amount of a composition comprising a plurality of distinct isolated recombinant influenza viruses each encoding a H3 or H5 hemagglutinin comprising a plurality of antigenically distinct residues relative to residues that form an immune dominant epitope in a parent virus, wherein each of the plurality of influenza viruses comprises substitutions at two or more of positions 121, 131, 135, 138, 140, 142, 144, 145, 155, 156, 157, 158, 171, 189, 193, 212, or 225, or one or more deletions of positions 121, 131, 135, 138, 140, 142, 144, 145, 155, 156, 157, 158, 171, 189, 193, 212, or 225, in H3, or any combination thereof relative to the parent virus H3 hemagglutinin;
- or wherein each of the plurality of influenza viruses comprises a substitution at two or more of positions 119, 123, 125, 126, 127, 129, 138, 140, 141, 151, 152, 153, 154, 155, 156, 185, or 189, or a deletion in one or more of positions 119, 123, 125, 126, 127, 129, 138, 140, 141, 151, 152, 153, 154, 155, 156, 185, or 189, in H5, or any combination thereof, relative to the parent virus H5 hemagglutinin to an animal.
Dependencies are inferred from the claim text.