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Publication Number
US-10272150-B2
Publication Date
2019-04-30
Expiration Date
Abstract
The disclosure relates to respiratory virus ribonucleic acid (RNA) vaccines and combination vaccines, as well as methods of using the vaccines and compositions comprising the vaccines.
Core Innovation
The invention relates to a respiratory virus vaccine administered to a subject. The vaccine comprises at least one lipid nanoparticle formulated with isolated non-self-replicating mRNA polynucleotides encoding antigenic human parainfluenza virus type 3 (hPIV3) Fusion (F) protein and antigenic human metapneumovirus (hMPV) F protein, and is administered in an effective amount to induce an immune response.
The lipid nanoparticle comprises a defined molar ratio of lipids: 20-60% ionizable cationic lipid, 5-25% non-cationic lipid, 25-55% sterol, and 0.5-15% PEG-modified lipid. The disclosure further references open reading frames, 5' cap, 5′ UTR, 3′ UTR, and poly(A) tail, together with codon optimized sequences and optional structural and stability elements.
The described vaccine framework also includes uracil chemical modifications including pseudouridine, N1-methylpseudouridine, and N1-ethylpseudouridine, and broader respiratory virus combination vaccine concepts using RNA encoding antigenic proteins from multiple respiratory viruses. The mRNA polynucleotides are not self-replicating RNA, and may be co-formulated in a single or separate lipid nanoparticle formulations.
Claims Coverage
The document presents independent claim coverage directed to administering a respiratory virus mRNA vaccine containing two non-self-replicating mRNAs encoding antigenic hPIV3 F and hMPV F proteins, formulated in at least one LNP with a defined lipid molar ratio. Dependent claim coverage adds immune readouts, timing, absence of antibody-dependent enhancement, mRNA modification, and antigen sequence identity.
Non-self-replicating dual mRNA encoding antigenic hPIV3 F and antigenic hMPV F
Administering to a subject a respiratory virus vaccine comprising isolated mRNA polynucleotides that are not self-replicating RNA, including an isolated mRNA polynucleotide encoding an antigenic hPIV3 Fusion (F) protein and an isolated mRNA polynucleotide encoding an antigenic hMPV F protein, formulated to induce an immune response in an effective amount.
Lipid nanoparticle with defined molar ratio composition
Formulating the vaccine in at least one lipid nanoparticle comprising a molar ratio of 20-60% ionizable cationic lipid, 5-25% non-cationic lipid, 25-55% sterol, and 0.5-15% PEG-modified lipid.
Immune response quantified by neutralization titer
Producing a 1,000-10,000 neutralization titer against antigenic hPIV3 F and/or antigenic hMPV F measured in serum 1-72 hours post administration.
Neutralization without antibody-dependent enhancement
Producing the 1,000-10,000 neutralization titer in the absence of antibody-dependent enhancement (ADE) of hPIV3-associated and/or hMPV-associated disease.
Chemically modified uracil in the mRNA open reading frame
At least 80% of the uracil in the open reading frame of (a) and/or (b) is chemically modified with N1-methyl-pseudouridine or N1-ethyl-pseudouridine.
Antigen sequence identity constraint for antigenic hPIV3 F
The antigenic hPIV3 F protein amino acid sequence has at least 90% identity to the sequence identified by SEQ ID NO: 13.
Overall, the claims center on administering non-self-replicating mRNA encoding antigenic hPIV3 F and hMPV F formulated in an LNP having a defined lipid molar ratio. The dependent claim coverage adds neutralization titer and timing features, an ADE-absence qualifier, uracil modification constraints in the open reading frame, and an antigen sequence identity constraint.
Stated Advantages
Superior, sometimes synergistic immune responses without additional adjuvants, including rapid and high neutralizing antibody generation at lower mRNA doses.
Neutralizing antibody generation and viral load reduction outcomes reported in vivo, including reduction in viral titer after challenge.
Improved neutralization metrics reported for MERS-CoV, including an improved EC50 range and higher antibody titers compared with other vaccines.
Induces an immune response in the subject.
Neutralization titers can be achieved as quantified in dependent claims, including 1,000-10,000 neutralization titer.
Neutralization is produced in the absence of antibody-dependent enhancement (ADE) of hPIV3-associated and/or hMPV-associated disease.
Documented Applications
Respiratory virus vaccination delivering an mRNA vaccine that encodes antigenic hPIV3 F protein and antigenic hMPV F protein using lipid nanoparticle formulations, with in vivo evaluation including neutralizing antibodies and challenge outcomes.
Respiratory virus vaccination outcomes reported for hMPV/PIV3 and for MERS-CoV, including viral load reduction and neutralizing antibody responses.
Respiratory virus vaccination by administering a vaccine to induce an immune response in a subject, including combination vaccine concepts using mRNAs encoding respiratory virus F proteins.
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