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Publication Number
US-11040098-B2
Publication Date
2021-06-22
Expiration Date
Abstract
Disclosed herein are compositions and methods related to mutant viruses, and in particular, mutant influenza viruses. The mutant viruses disclosed herein include a mutant M2 sequence, and are useful in immunogenic compositions, e.g., as vaccines. Also disclosed herein are methods, compositions and cells for propagating the viral mutants, and methods, devices and compositions related to vaccination.
Core Innovation
The patent relates to mutant influenza viruses engineered to include an M gene defect, including M2KO(TM) constructs and influenza A virus nucleotide sequences selected from SEQ ID NOs: 1, 2, and 3. The disclosed mutant viruses fail to express functional M2 protein, or produce truncated or nonfunctional M2 protein.
The described M gene defects include two stop codons at nucleotides 786-791 of SEQ ID NO: 28 (or corresponding positions), a deletion of nucleotides 792-842 of SEQ ID NO: 28 (or corresponding positions), and a G to C substitution at nucleotide 52 of SEQ ID NO: 28 (or corresponding positions). The mutant viruses are described as restricted in replication in normal host cells and stable against reversion over defined passages.
The disclosure further describes propagation using permissive cells and includes immunogenic compositions and vaccine use. Reported outcomes include attenuation and immune responses including humoral and mucosal IgG/IgA responses.
Claims Coverage
The independent claims cover host cells containing influenza A virus configurations, with inventive features centered on specified nucleotide or polypeptide sequences and mutant M genes defined by stop-codon, deletion, and substitution changes relative to SEQ ID NO: 28.
Host cell with specified influenza A virus nucleotide or polypeptide sequences
A host cell comprising a heterologous nucleotide sequence that encodes an influenza A virus comprising a nucleotide sequence selected from SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, or a nucleotide sequence encoding a polypeptide having the amino acid sequence set forth in SEQ ID NO: 6, SEQ ID NO: 7, or SEQ ID NO: 8.
Host cell with an M gene stop-codon and deletion mutant
A host cell comprising a recombinant influenza A virus comprising a mutant M gene, wherein the mutant M gene comprises two stop codons at nucleotides 786-791 of SEQ ID NO: 28 (or a corresponding position) and a deletion of nucleotides 792-842 of SEQ ID NO: 28 (or a corresponding position).
Host cell with an M gene stop-codon and G-to-C substitution mutant
A host cell comprising a recombinant influenza A virus comprising a mutant M gene, wherein the mutant M gene comprises two stop codons at nucleotides 786-791 of SEQ ID NO: 28 (or a corresponding position) and a G to C substitution at nucleotide 52 of SEQ ID NO: 28 (or a corresponding position).
Host cell with an M gene stop-codon, deletion, and substitution mutant
A host cell comprising a recombinant influenza A virus comprising a mutant M gene, wherein the mutant M gene comprises two stop codons at nucleotides 786-791 of SEQ ID NO: 28 (or a corresponding position), a deletion of nucleotides 792-842 of SEQ ID NO: 28 (or a corresponding position), and a G to C substitution at nucleotide 52 of SEQ ID NO: 28 (or a corresponding position).
Collectively, the independent claims define host cells that include recombinant or heterologous influenza A virus configurations, including specified SEQ ID NO-based nucleotide or polypeptide sequences and mutant M genes defined by stop-codon, deletion, and substitution changes.
Stated Advantages
Restricted replication in normal host cells.
Stability against reversion over defined passages.
Attenuation as described in the disclosure.
Induction of immune responses including humoral and mucosal IgG/IgA responses.
Protection against lethal homologous/heterologous challenge as described in the disclosure.
Lack of respiratory/organ dissemination as described in the disclosure.
Lack of transmission in a ferret model as described in the disclosure.
Documented Applications
Use in immunogenic compositions and vaccines.
Immunogenicity and protection studies in mice and ferrets, including reported protection against lethal homologous/heterologous challenge.
Transmission study in a ferret model, reporting lack of transmission as described in the disclosure.
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