PR13.5 promoter for robust T-cell and antibody responses

Inventors

Steigerwald, Robin • Brinkmann, Kay

Assignees

Bavarian Nordic AS

Abstract

The invention encompasses recombinant poxviruses, preferably modified Vaccinia Ankara (MVA) viruses, comprising a Pr13.5 promoter operably linked to a nucleotide sequence encoding an antigen and uses thereof. The invention is drawn to compositions and methods for the induction of strong CD8 T cell and antibody responses to a specific antigen(s) by administering one or more immunizations of the recombinant MVA to a mammal, preferably a human.

Core Innovation

The document describes recombinant modified Vaccinia Ankara (MVA) viruses that comprise a Pr13.5 promoter operably linked to a nucleotide sequence encoding a neoantigen, for inducing immune responses in a human. The Pr13.5 promoter is defined by a promoter architecture that includes at least 1 copy of a first nucleotide sequence set forth in SEQ ID NOs:8-27 and at least 1 copy of a second nucleotide sequence set forth in SEQ ID NOs:8-27, separated by 20-80 nucleotides.

In the described embodiments, the Pr13.5 promoter architecture is provided in specific repeat configurations associated with stronger early neoantigen expression and altered immune response features. The document reports that Pr13.5-long, including two repeat copies, produces stronger early OVA expression and changes the CD8 T-cell immunodominance hierarchy, reversing OVA-specific CD8 T cells versus B8R (TSYKFESV) CD8 T-cell responses.

The document further describes that the recombinant MVA using the Pr13.5 promoter architecture yields substantially higher antibody titers than other promoters, including PrS. It also characterizes MVA-BN attenuation and provides rationale involving vector immunodominance and timing of early promoter-driven antigen expression, with immunogenicity endpoints described using CD8 T-cell and antibody measurements.

Claims Coverage

The claims cover methods of inducing an antibody response and/or a CD8 T-cell response against a neoantigen, methods of inducing an immunodominant T cell response, and the recombinant MVA virus itself. The core inventive feature across the independent claims is the Pr13.5 promoter operably linked to a neoantigen, with at least one first sequence copy and at least one second sequence copy separated by 20-80 nucleotides.

The claims are centered on recombinant MVA viruses and administration methods in which a Pr13.5 promoter drives expression of a neoantigen. The promoter is defined by at least one first repeat sequence and at least one second repeat sequence with a separation distance of 20-80 nucleotides, and the immunodominant-response method further requires that the neoantigen-specific immunodominant T cell response is greater than a T cell response to a poxviral antigen.

Stated Advantages

Documented Applications