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Publication Number
US-11207399-B2
Publication Date
2021-12-28
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 invention relates to a recombinant influenza A virus comprising a mutant influenza M gene. The mutant M gene includes two stop codons at a position corresponding to nucleotides 786-791 of SEQ ID NO: 28 with respect to the M gene coding sequence, and may further include a deletion at a position corresponding to nucleotides 792-842 of SEQ ID NO: 28 and a G to C substitution at a position corresponding to nucleotide 52 of SEQ ID NO: 28.
The disclosed viruses are described as eliminating functional M2 expression, including failure to express the M2 protein or expression of a truncated M2. The content states that the viruses maintain stability by avoiding reversion of the mutant M gene back toward a sequence that encodes functional M2 protein, and are characterized by non-reversion behavior for M2KO variants.
The disclosed study context addresses intranasal influenza vaccination by linking the recombinant influenza A virus to safety and minimal transmission risk while still eliciting immune responses and protection. In ferrets, M2KO(ΔTM) intranasal vaccination does not cause clinical disease or detectable viral shedding in contact ferrets, including direct or aerosol contact, and mouse examples describe humoral and mucosal immune responses and protection against lethal homologous and heterologous challenge.
Claims Coverage
The document includes three independent claims directed to recombinant influenza A viruses with defined influenza M gene mutations. Across the independent claims, the main inventive features are the specific placement of two stop codons and the additional structural change comprising a deletion, a G to C substitution, or both.
Two stop codons and a deletion in the mutant influenza M gene
A recombinant influenza A virus comprising a mutant influenza M gene, wherein the mutant M gene comprises two stop codons and a deletion, wherein the two stop codons are at a position corresponding to nucleotides 786-791 of SEQ ID NO: 28 with respect to the M gene coding sequence, and wherein the deletion is at a position corresponding to nucleotides 792-842 of SEQ ID NO: 28 with respect to the M gene coding sequence.
Two stop codons and a G to C substitution in the mutant influenza M gene
A recombinant influenza A virus comprising a mutant influenza M gene, wherein the mutant M gene comprises two stop codons and a G to C substitution, wherein the two stop codons are at a position corresponding to nucleotides 786-791 of SEQ ID NO: 28 with respect to the M gene coding sequence, and wherein the G to C substitution is at a position corresponding to nucleotide 52 of SEQ ID NO: 28 with respect to the M gene coding sequence.
Two stop codons and a deletion plus a G to C substitution in the mutant influenza M gene
A recombinant influenza A virus comprising a mutant influenza M gene, wherein the mutant M gene comprises two stop codons, a deletion, and a G to C substitution, wherein the two stop codons are at a position corresponding to nucleotides 786-791 of SEQ ID NO: 28 with respect to the M gene coding sequence, wherein the deletion is at a position corresponding to nucleotides 792-842 of SEQ ID NO: 28, and wherein the G to C substitution is at a position corresponding to nucleotide 52 of SEQ ID NO: 28 with respect to the M gene coding sequence.
Together, the independent claims define recombinant influenza A viruses with mutant influenza M genes characterized by precisely positioned two stop codons, with further structural modifications including a deletion and/or a G to C substitution relative to SEQ ID NO: 28. The exemplified context links the constructs to intranasal vaccination and vaccine-related immune outcomes.
Stated Advantages
Non-pathogenicity in a mammal infected with the virus.
Restricted replication in normal cells.
Antigen expression without M2.
Attenuation in mice and ferrets.
Induction of humoral and mucosal immune responses including IgG and IgA.
Protection against lethal homo- and heterosubtypic challenge.
Lack of transmission in ferret models.
Documented Applications
Vaccine use as an immunogenic composition based on the recombinant influenza A viruses described in the document.
Intranasal influenza vaccination with M2KO(ΔTM), including ferret studies assessing clinical disease and detectable viral shedding in contact ferrets after direct or aerosol contact.
Mouse immunogenicity and efficacy use, including humoral and mucosal immune responses and protection against lethal homologous and heterologous challenge.
Administration and delivery including intradermal microneedle delivery and other described administration routes for the vaccine.
Cell-based vaccine propagation and manufacturing using permissive/receptor-sialylated or M2-expressing producer cells and bioreactor-based vaccine production.
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