Methods and compositions for intra-nasal immunization with recombinant MVA encoding flagellin
Inventors
Lauterbach, Henning • Hochrein, Hubertus • Sanos, Stephanie
Assignees
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Publication Number
US-10512684-B2
Publication Date
2019-12-24
Expiration Date
Abstract
Provided herein are immunogenic compositions comprising a recombinant modified vaccinia virus Ankara (MVA) comprising a nucleic acid sequence encoding a flagellin, and a nucleic acid sequence encoding a heterologous disease-associated antigen, wherein the immunogenic composition induces increased T-cell and antibody mediated immune responses specific for the heterologous disease-associated antigen when administered to a subject, e.g. a human subject, and related methods and uses.
Core Innovation
The invention relates to an immunogenic composition comprising a recombinant modified vaccinia virus Ankara (MVA) engineered to comprise a nucleic acid sequence encoding a flagellin and a nucleic acid sequence encoding a heterologous disease-associated antigen. The composition is defined such that administration induces increased T-cell and/or B-cell immune responses specific for the heterologous disease-associated antigen and increased innate immune responses, as compared to a recombinant MVA comprising the heterologous disease-associated antigen but lacking a nucleic acid sequence encoding a flagellin.
The approach integrates flagellin expression into a recombinant MVA vaccination construct that also expresses a heterologous disease-associated antigen, with the aim of increasing both adaptive antigen-specific responses and innate immune responses. The recombinant MVA is further specified as capable of reproductive replication in chicken embryo fibroblasts.
In the described findings, intra-nasal administration of rMVA engineered to express flagellin together with a disease-associated antigen is associated with enhanced antigen-specific CD8+ CTL responses and increased IFN-γ and TNF-α producing CTLs. The document also reports Th1-biased antibody isotypes, including IgG2c, mucosal IgA responses, gastro-intestinal immunity including IgA and homing to mesenteric lymph nodes, and increased innate cytokines in BAL, including IL-1β, IL-18, and TNF-α.
Claims Coverage
The independent claims cover two aspects: an immunogenic composition and a method of inducing an antigen-specific immune response. Across the independent claims, the inventive features include a recombinant MVA expressing both flagellin and a heterologous disease-associated antigen, increased antigen-specific T-cell and/or B-cell responses and increased innate immune responses versus a comparator recombinant MVA lacking flagellin, and reproductive replication in chicken embryo fibroblasts.
Recombinant MVA expressing flagellin and a heterologous disease-associated antigen
A recombinant modified vaccinia virus Ankara (MVA) comprising a nucleic acid sequence encoding a flagellin and further comprising a nucleic acid sequence encoding a heterologous disease-associated antigen.
Increased antigen-specific T-cell and/or B-cell immune responses and increased innate immune responses versus flagellin-lacking MVA
The immunogenic composition induces increased T-cell and/or B-cell immune responses specific for the heterologous disease-associated antigen and increased innate immune responses when administered to a subject as compared to administration of a recombinant MVA comprising the heterologous disease-associated antigen but not a nucleic acid sequence encoding a flagellin.
Reproductive replication capability in chicken embryo fibroblasts
The recombinant modified vaccinia virus Ankara (MVA) is capable of reproductive replication in chicken embryo fibroblasts.
Administering the flagellin-and-antigen immunogenic composition to induce an antigen-specific immune response
A method of inducing an antigen-specific immune response to a disease-associated antigen in a subject comprising administering an immunogenic composition comprising a nucleic acid sequence encoding a flagellin and further comprising a nucleic acid sequence encoding a heterologous disease-associated antigen.
The independent claims require a recombinant MVA that expresses both a flagellin and a heterologous disease-associated antigen, where administration increases antigen-specific T-cell/B-cell responses and also increases innate immune responses relative to the same MVA lacking flagellin, with the additional specification that the recombinant MVA is capable of reproductive replication in chicken embryo fibroblasts.
Stated Advantages
Increased T-cell and/or B-cell immune responses specific for the heterologous disease-associated antigen.
Increased innate immune responses when administered to a subject compared to an MVA lacking a nucleic acid sequence encoding flagellin.
Enhanced antigen-specific CD8+ CTL responses associated with increased IFN-γ and TNF-α producing CTLs.
Th1-biased antibody isotypes, including IgG2c, and induction of mucosal IgA responses.
Induction of gastro-intestinal immunity including IgA and intestinal homing to mesenteric lymph nodes.
Increased innate cytokines in BAL including IL-1β, IL-18, and TNF-α.
Documented Applications
Intra-nasal mucosal immunization using rMVA engineered to express flagellin and a heterologous disease-associated antigen to increase antigen-specific T-cell and antibody responses.
Induction of gastro-intestinal immunity after rMVA-flagellin mucosal immunization, including intestinal IgA and homing to mesenteric lymph nodes.
Use in a kit format comprising the immunogenic composition in a first vial or container for a first administration and in a second vial or container for a second administration.
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