Multivalent recombinant modified vaccinia virus ankara (MVA) vector encoding filovirus immunogens
Inventors
VOLKMANN, Ariane • Steigerwald, Robin • Hochrein, Hubertus • Dirmeier, Ulrike • Lauterbach, Henning • HAUSMANN, JÜRGEN
Assignees
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Publication Number
US-11338030-B2
Publication Date
2022-05-24
Expiration Date
Abstract
The present invention relates to an improved filovirus vaccine comprising a recombinant modified vaccinia virus Ankara-based (MVA-based) vaccine against filovirus infection and to related products, methods and uses. Specifically, the present invention relates to genetically engineered (recombinant) MVA and FPV vectors comprising at least one heterologous nucleotide sequence encoding an antigenic determinant of a Marburg virus (MARV) or Ebola virus glycoprotein. Specifically, the invention relates to recombinant MVA comprising Ebola virus glycoprotein and virion protein 40. The invention also relates to products, methods and uses thereof as well as prime/boost regimens of MVA and genetically engineered (recombinant) FPV, e.g., suitable to induce a protective immune response in a subject.
Core Innovation
The invention relates to an improved multivalent filovirus vaccine in the form of a recombinant, replication-deficient MVA vector (MVA-BN). The recombinant vector expresses filovirus antigenic determinants, including MARV envelope glycoprotein (GP) and Zaire Ebola virus (ZEBOV) envelope glycoprotein, as well as a Sudan Ebola virus (SEBOV) envelope glycoprotein and an Ebola virus Ivory Coast nucleoprotein.
The invention further addresses heterologous prime/boost regimens by incorporating recombinant fowlpox (FPV) for boosting after an MVA prime. The described regimens include MVA prime/FPV boost and report enhanced immune outcomes, including CD8 T-cell responses and neutralizing antibodies.
The construct design includes expression of multiple specified antigens, including Ebola virus glycoprotein and nucleoprotein, and additionally indicates that inclusion of VP40 in the MVA component is associated with enhanced neutralizing antibodies in the multivalent prime-boost context. The document also reports that expression of selected antigen combinations can lead to formation of filovirus-like particles (VLPs) in cells when GP plus VP40 is expressed.
Claims Coverage
The independent claim recites a recombinant MVA vector containing four nucleic acids encoding MARV and Ebola-family immunogenic envelope glycoproteins and an Ebola nucleoprotein, i.e., a multi-antigen Ebola/MARV construct. The independent claim includes several inventive features, with dependent claims further refining antigen selection and optional immune-modulating components, while at least one dependent claim frames administration as providing protective immunity or a protective immune response.
Multi-antigen recombinant MVA expressing MARV and Ebola envelope glycoproteins plus Ebola nucleoprotein
A recombinant MVA vector comprising a first nucleic acid encoding at least one immunogenic protein of a MARV envelope glycoprotein (GP), a second nucleic acid encoding an immunogenic protein of Zaire Ebola virus (ZEBOV) envelope glycoprotein, a third nucleic acid encoding an immunogenic protein of Sudan Ebola virus (SEBOV) envelope glycoprotein, and a fourth nucleic acid encoding an immunogenic protein of Ebola virus Ivory Coast nucleoprotein.
Inclusion of CD40L nucleic acid in the recombinant MVA
A recombinant MVA vector further comprising a nucleic acid encoding an immunogenic protein of CD40L.
CD40L defined by an amino acid sequence reference
The recombinant MVA vector having CD40L that includes the amino acid sequence of SEQ ID NO:10.
Full-length MARV-Musoke envelope glycoprotein in the recombinant MVA
A recombinant MVA vector in which the MARV envelope glycoprotein is the full-length MARV-Musoke envelope glycoprotein.
Immunogenic protein sequences constrained to defined SEQ ID sets
A recombinant MVA vector that includes a nucleic acid encoding an immunogenic protein with a sequence chosen from the group consisting of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:20, SEQ ID NO:29, SEQ ID NO:31, and SEQ ID NO:37.
Administration providing protective immunity or a protective immune response
Administration of the recombinant MVA vector to provide protective immunity or a protective immune response in the subject.
Across the independent claim and dependent claims, the core claim coverage is a recombinant MVA multi-antigen design encoding MARV GP, ZEBOV GP, SEBOV GP, and Ebola virus Ivory Coast nucleoprotein, with refinements specifying a full-length MARV-Musoke GP, constraining certain antigen sequences by SEQ ID sets, and optionally adding CD40L (including a defined SEQ ID NO:10 amino acid sequence). Claim coverage also includes framing administration as providing protective immunity or a protective immune response.
Stated Advantages
Enhanced CD8 T-cell responses.
Neutralizing antibodies, including in MVA/FPV prime-boost regimens.
Formation of filovirus-like particles (VLPs) in cells upon expression of GP plus VP40.
Documented Applications
Heterologous prime/boost vaccination using MVA prime/FPV boost regimens, including multivalent Ebola/MARV vaccination contexts.
Protective vaccination outcomes in non-human primates, including protective efficacy against MARV-Musoke and MARV-Angola.
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