Methods and compositions for enhancing vaccine immune responses
Inventors
Lauterbach, Henning • Hochrein, Hubertus
Assignees
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Publication Number
US-10973892-B2
Publication Date
2021-04-13
Expiration Date
Abstract
Provided herein are immunogenic compositions comprising a recombinant modified vaccinia virus Ankara (MVA) comprising a nucleic acid sequence encoding a CD40 ligand (CD40L) and a nucleic acid sequence encoding a heterologous disease-associated antigen, wherein the immunogenic composition induces increases T-cell immune responses specific for the heterologous disease-associated antigen when administered to a human host, and related methods and uses.
Core Innovation
The invention relates to immunogenic compositions and methods using a recombinant modified vaccinia virus Ankara (MVA) for enhancing T-cell responses specific for a disease-associated antigen in a human. The recombinant MVA is not capable of reproductive replication in the human keratinocyte cell line HaCat and comprises a nucleic acid sequence encoding a CD40 ligand (CD40L) together with a nucleic acid sequence encoding a heterologous disease-associated antigen.
Intravenous administration of the recombinant MVA is stated to induce increased numbers of cytotoxic T-cells (CTLs) specific for the heterologous disease-associated antigen. The method further includes administering one or more boosting injections of the recombinant MVA.
The disclosure further defines CD40L and antigen scope through specified CD40L sequence identity embodiments and heterologous disease-associated antigen classes. CD40L sequence embodiments include murine and human CD40L sequence embodiments, and antigen embodiments encompass infectious disease antigens and tumor-associated antigens, together with pharmaceutically acceptable carriers and prime-boost vaccination regimens involving homologous or heterologous vector boosts.
Claims Coverage
Independent claim coverage describes a human method that enhances T-cell responses for a heterologous disease-associated antigen by intravenous priming with replication-incompetent recombinant MVA encoding CD40L and the antigen, followed by one or more boosting injections. The claim set contains refinement features that constrain antigen class, tumor-associated and infectious antigen selection, the recombinant MVA variant, and CD40L sequence identity or sequence.
Intravenous priming with replication-incompetent recombinant MVA encoding CD40L and a heterologous disease-associated antigen
Administering intravenously to the human a priming injection of a recombinant modified vaccinia virus Ankara (MVA) that is not capable of reproductive replication in the human keratinocyte cell line HaCat and that comprises a nucleic acid sequence encoding a CD40 ligand (CD40L) and a nucleic acid sequence encoding a heterologous disease-associated antigen, wherein the intravenous administration induces increased numbers of cytotoxic T-cells (CTLs) specific for the heterologous disease-associated antigen.
One or more boosting injections with the recombinant MVA
Further comprising administering to the human one or more boosting injections of the recombinant MVA.
Replication-incompetent recombinant MVA backbone as MVA-BN or a derivative
Using modified vaccinia virus Ankara (MVA) that is MVA-BN or a derivative of MVA-BN.
CD40L encoded sequence constrained by identity to SEQ ID NO:2
Using a nucleic acid sequence that encodes a CD40L with at least 95% amino acid sequence identity to SEQ ID NO:2.
CD40L encoded sequence as the amino acid sequence of SEQ ID NO:2
Using a nucleic acid sequence that encodes CD40L with the amino acid sequence of SEQ ID NO:2.
The core inventive concept is to enhance human CTL responses to a heterologous disease-associated antigen by intravenous priming with a recombinant MVA that encodes CD40L and the antigen and is replication-incompetent in HaCat, together with administering one or more boosting injections. The refinement features further constrain the recombinant MVA to MVA-BN or derivatives, and define CD40L encoding through SEQ ID NO:2 identity or exact sequence requirements.
Stated Advantages
Increases numbers of cytotoxic T-cells (CTLs) specific for the heterologous disease-associated antigen.
Induces increased human T-cell responses, including higher CTL numbers.
Enhances cytolytic activity.
Induces memory T-cells.
Improves memory kinetics as stated in the document’s described experimental support.
Documented Applications
Prime-boost vaccination use cases for enhancing CTL responses and memory T-cell induction to a heterologous disease-associated antigen in a human.
Use with infectious disease antigens, including viral, bacterial, fungal, and parasite antigens, as part of the antigen scope described.
Use with tumor-associated antigens, including enumerated tumor antigen selections described in the disclosure.
Use involving CD40L variants and CD40L sequence embodiments to support CD40/CD40L dependence and cross-species CD40L functionality as described by the document’s experiments.
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