Recombinant mumps virus vaccine
Inventors
Assignees
United States, Health And Human Services Food And Drug Administration, Secretary of, Department of • University of Georgia Research Foundation Inc UGARF • US Department of Health and Human Services
Publication Number
US-11027008-B2
Publication Date
2021-06-08
Expiration Date
2032-02-24
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Abstract
The present invention provides the complete genomic sequence of the epidemic mumps virus (MuV) strain MuVIowa/US/06. Further, a reverse genetics system was constructed and used to rescue recombinant viral constructs that are attenuated compared to rMuVIowa/US/06 and JL vaccine viruses. Such constructs include viral constructs lacking the open reading frame (ORF) of the SH gene (rMuVΔSH) and/or incapable of expressing the V protein (rMuVΔV).
Core Innovation
The invention provides the complete genomic sequence of the epidemic mumps virus strain MuVIowa/US/06 (MuV-IA), a genotype G virus associated with recent outbreaks, and constructs a reverse genetics system to rescue recombinant viral constructs. These recombinant viruses include variants lacking expression of the small hydrophobic (SH) protein gene (rMuVΔSH) and/or incapable of expressing the V protein (rMuVΔV). Such constructs are attenuated compared to the recombinant wild type virus and the JL vaccine virus, showing lower neurotoxicity and suitability as new vaccine candidates.
The background addresses the problem that, despite widespread use of the Jeryl Lynn (JL) mumps vaccine derived from genotype A, mumps outbreaks have occurred in highly vaccinated populations. This is potentially due to waning immunity, high infection velocity, or vaccine failure due to emergence of genotype G mumps virus strains distinct from the vaccine strain. Current live attenuated vaccines are derived from serial passages in eggs or cells, a time-consuming process with a poor record of generating safe vaccines. Therefore, there is a need for new and improved mumps vaccines targeted at the outbreak-associated genotype G and for new methods of developing such vaccines.
The invention’s approach includes producing isolated nucleotide sequences comprising cDNA encoding full-length RNA genomes of mumps virus unable to express the SH protein and/or V protein by deletions or mutations of the respective open reading frames. Recombinant viruses rescued using this approach grow efficiently in WHO-approved Vero cells but are attenuated in animal models, demonstrating lower neurotoxicity than current JL vaccines. The invention also provides vectors, plasmids, viral particles, and compositions, and methods for vaccination and induction of immune responses using these recombinant viruses or their derivatives, enabling the development of safer, genotype G-directed mumps vaccines.
Claims Coverage
The patent includes 17 claims with one independent claim. The claims cover live-attenuated recombinant mumps viruses with specific genetic mutations, corresponding nucleotide sequences and plasmids, methods of inducing immune responses, and compositions comprising these sequences. The main inventive features relate to the mutations abrogating V protein expression, additional mutations including SH protein deletions, and vaccination methods.
Mutation abrogating V protein expression
A live-attenuated recombinant mumps virus comprising one or more mutations in the V/I/P gene that abrogate expression of the V protein compared to the parent mumps virus strain from which it is derived.
Isolated nucleotide sequence encoding mutated mumps virus genome
An isolated nucleotide sequence comprising a cDNA sequence encoding the full-length RNA genome of the recombinant mumps virus that has mutations abrogating V protein expression, where only the P protein transcript is generated from the P/V transcript.
Additional mutation or deletion of SH protein ORF
The full-length recombinant mumps virus genome may include further mutations or deletions, specifically including deletion of the open reading frame encoding the small hydrophobic (SH) protein, comprising a deletion of approximately 156 nucleotides.
Mutations affecting phosphorylation of P protein
Further mutations or deletions affecting phosphorylation sites in the P protein, specifically mutations encoding amino acid residues at positions 147 and/or 307 of the P protein.
Encoding of heterologous polypeptide
The recombinant mumps virus genome may further encode a heterologous polypeptide, adding non-mumps antigenic determinants or markers.
Parental virus details and growth characteristics
The parent virus may be MuV/IowaUS/2006 (MuV-IA) or genotype A or G. The recombinant live-attenuated virus grows to titers in Vero cells similar to wild type mumps virus.
Plasmid encoding full-length recombinant virus genome
A plasmid comprising the isolated nucleotide sequence encoding the full-length RNA genome of the recombinant live-attenuated mumps virus.
Methods of inducing immune response and vaccination
Methods for inducing an immune response or vaccinating a subject by administering an effective amount of the isolated nucleotide sequence encoding the recombinant virus.
Compositions including recombinant virus sequences and antigenic determinants
Compositions including the isolated nucleotide sequence or plasmid of the recombinant virus, which may further include rubella and/or measles antigenic determinants.
The claims cover live-attenuated recombinant mumps viruses with mutations that abolish V protein expression, optionally combined with SH protein ORF deletions and mutations affecting P protein phosphorylation, nucleotide sequences and plasmids encoding these viruses, methods of immunization with these constructs, and compositions including the sequences and additional antigenic determinants. The recombinant viruses are characterized by growth in Vero cells to titers comparable to wild type strains.
Stated Advantages
The recombinant mumps viruses are attenuated relative to wild type and current vaccine strains, demonstrating lower neurotoxicity in animal models.
Such recombinant viruses grow efficiently in WHO-approved Vero cells, facilitating vaccine production.
Recombinants lacking SH or V proteins induce increased immune responses and are suitable for development as improved vaccines against outbreak-associated genotype G strains.
Documented Applications
The recombinant mumps viruses and their derivatives are useful as new-generation mumps vaccines, including vaccines directed against genotype G strains causing recent outbreaks.
Methods of vaccinating subjects against mumps using the recombinant virus or compositions thereof, including intranasal, oral, intradermal, or intramuscular administration.
Using recombinant mumps viruses as vectors to express heterologous antigens such as those for respiratory syncytial virus (RSV), enabling development of vaccines against other pathogens.
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