Influenza B virus mutants and uses therefor
Inventors
Moser, Michael J. • Hatta, Yasuko • Bilsel, Pamuk
Assignees
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Publication Number
US-11529409-B2
Publication Date
2022-12-20
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 BM2 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 disclosure describes recombinant influenza B virus vaccine candidates carrying mutant BM2 genes comprising SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5. The mutant BM2 genes disrupt or abrogate BM2 expression, including complete BM2 ORF deletion or insertion of stop codons, and can yield truncated BM2 protein or prevent expression of BM2.
A key element is the genetic stability of the mutant BM2 genes during propagation. The disclosure states that mutant viruses are genetically stable, including no reversion to functional BM2-encoding sequences through at least 10 in vitro passages, when propagated in BM2-supplying cells in trans. In this context, a functional BM2 gene product is provided to the virus in trans by a modified host-cell system.
The recombinant influenza B virus mutants are immunogenic in mammals and may be non-pathogenic or attenuated in vivo. Vaccine compositions are described, and the disclosure supports multivalent ferret models, including use of immunological endpoints such as anti-HA IgG and hemagglutination inhibition (HAI).
Claims Coverage
The document includes three independent claims directed to a recombinant influenza B virus with a mutant BM2 gene, a composition comprising such a recombinant influenza B virus, and a method for propagating the recombinant influenza B virus using a host cell modified to provide a functional BM2 gene product in trans. Across these independent claims, three main inventive features are emphasized: mutant BM2 gene sequence identity (SEQ ID NOs 1–5), functional BM2-gene-product provision in trans during propagation, and optional phenotypic/immunological refinements such as eliciting an immune response and being non-pathogenic.
Mutant BM2 gene defined by SEQ ID NOs 1–5
A recombinant influenza B virus having a mutant BM2 gene comprising SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5.
Composition comprising recombinant influenza B virus with mutant BM2 gene defined by SEQ ID NOs 1–5
A composition comprising a recombinant influenza B virus having a mutant BM2 gene comprising SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5.
Host-cell modified to provide functional BM2 gene product in trans during propagation
A method for propagating a recombinant influenza B virus, contacting a host cell with a recombinant influenza virus comprising SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5; and incubating the host cell for a sufficient time and under conditions suitable for viral replication, wherein the host cell is modified to produce a functional version of the influenza BM2 gene, thereby providing the gene product to the virus in trans.
Overall, the independent claims anchor the invention on recombinant influenza B virus candidates carrying mutant BM2 genes defined by SEQ ID NOs 1–5, and on propagation using a host cell modified to provide a functional BM2 gene product in trans.
Stated Advantages
The mutant BM2 genes are genetically stable, including no reversion to functional BM2-encoding sequences through at least 10 in vitro passages when propagated in BM2-supplying cells in trans.
The recombinant influenza B virus mutants are immunogenic in mammals.
The recombinant viruses can be non-pathogenic or attenuated in vivo.
Documented Applications
Vaccine candidates and vaccine compositions comprising recombinant influenza B viruses with mutant BM2 genes (SEQ ID NOs 1–5), including multivalent ferret vaccination models.
In vivo use in mammals for eliciting an immune response following infection with the recombinant influenza B virus.
Nonclinical evaluation in mouse and ferret models, including immune-response measurements such as anti-HA IgG ELISA and hemagglutination inhibition (HAI).
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