Modified orthopoxvirus vectors

A nucleic acid comprising a recombinant orthopoxvirus genome, wherein the genome comprise deletions in each of the following 23 genes:

• C2L, C1L, N1L, N2L, M1L, M2L, K1L, K2L, K3L, K4L, KSL, K6L, K7R, F1L, F2L, F3L, B14R, B15R, B16R, B17L, B18R, B19R, and B20R and further comprises deletions in each of the following 9 genes:
• B21R, B22R, B23R, B24R, B25R, B26R, B27R, B28R, and B29R;
• and
• wherein the nucleic acid further comprises:
• (i) a transgene encoding a tumor-associated antigen;
• (ii) a transgene encoding an immune checkpoint inhibitor;
• (iii) a transgene encoding an interleukin (IL);
• (iv) a transgene encoding an interferon (IFN);
• (v) a transgene encoding a TNF superfamily member protein;
• (vi) a transgene encoding a cytokine;
• or (vii) any combination thereof.