Optimized early-late promoter combined with repeated vaccination favors cytotoxic T cell response against recombinant antigen in MVA vaccines
The invention is drawn to compositions and methods for the induction of a strong CD8 T cell response to a specific antigen(s). The combination of an early/late hybrid promoter directing strongly enhanced early expression of a neoantigen with at least three immunization rounds resulted in a highly efficient neoantigen-specific CD8 T cell response. This combination reversed the immunodominance hierarchy and converted a moderately immunogenic and subdominant CD8 T cell epitope into the immunodominant epitope.
1. A method of inducing a CD8 T cell response in a host comprising administering at least three immunizations of a recombinant modified vaccinia Ankara virus (MVA) to the host;
wherein the recombinant MVA comprises a Vaccinia virus (VACV) early/late hybrid promoter linked to a nucleotide sequence encoding an antigen;
wherein, after the third immunization, the recombinant MVA induces a CD8 T cell response in the host against the encoded antigen that is at least 15% of total CD8 T cells.
2. The method of claim 1 , wherein the host is a human.
3. The method of claim 1 , wherein the recombinant MVA expresses in HeLa cells a level of the encoded antigen from the VACV early/late hybrid promoter in the presence of 40 μg/ml AraC that is greater than the level of the encoded antigen in the absence of AraC.
4. The method of claim 3 , wherein the host is a human.
5. The method of claim 1 , wherein the early/late hybrid promoter comprises at least 5 copies of an optimized p7.5 early promoter element.
6. The method of claim 5 , wherein the host is a human.
7. The method of claim 1 , wherein, after the third immunization, the recombinant MVA induces a CD8 T cell response in the host against the encoded antigen that is at least 25% of total CD8 T cells.
8. The method of claim 7 , wherein the host is a human.
9. The method of claim 1 , wherein, after the third immunization, the recombinant MVA induces a CD8 T cell response in the host against the encoded antigen that is at least 30% of total CD8 T cells.
10. The method of claim 1 comprising administering at least four immunizations of a recombinant MVA to the host.
11. The method of claim 10 , wherein the host is a human.
12. The method of claim 11 , wherein the host is a human.
13. A kit comprising a recombinant MVA vector comprising a VACV early/late hybrid promoter linked to a nucleotide sequence encoding an antigen and instructions to administer the recombinant MVA in at least three administrations to a host, wherein the recombinant MVA expresses in HeLa cells a level of the encoded antigen in the presence of 40 μg/ml AraC that is greater than the level of the encoded antigen in the absence of AraC.
14. The kit of claim 13 , wherein the early/late hybrid promoter comprises an ATI late promoter linked to at least 5 copies of an optimized p7.5 early promoter element.
15. The kit of claim 13 , wherein the early/late hybrid promoter comprises the nucleotide sequence of SEQ ID NO: 1.
16. A recombinant MVA comprising an early/late hybrid promoter linked to a nucleotide sequence encoding an antigen,
wherein the early/late hybrid promoter comprises an ATI late promoter linked to at least 5 copies of an p7.5 early promoter element,
wherein the recombinant MVA expresses in HeLa cells a level of the encoded antigen in the presence of in the presence of 40 μg/ml AraC that is greater than the level of the encoded antigen in the absence of AraC.