Poxviral promoters for improving the immunogenicity of MVA delivered vaccines

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Abstract

<p id="d5087060e130">Modified vaccinia virus Ankara (MVA) is a replication-deficient poxvirus, attenuated in chick embryo fibroblast primary cells. It has been utilised as a viral vector to develop many vaccines against cancer and infectious diseases such as malaria, HIV/AIDS, influenza, and tuberculosis, MERS-CoV, and Ebola virus infection. There is accumulating data from many preclinical and clinical studies that highlights the excellent safety and immunogenicity of MVA. However, due to the complex nature of many pathogens and their pathogenicity, MVA vectored vaccine candidates need to be optimised to improve their immunogenicity. One of the main approaches to improve MVA immunogenicity focuses on optimising poxviral promoters that drive recombinant vaccine antigens, encoded within recombinant MVA vector genome. A number of promoters were described or optimised to improve the development of MVA based vaccines such as p7.5, pF11, and mH5 promoters. This review focuses on poxviral promoters, their optimisation, genetic stability, and clinical use. </p>

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The complete genomic sequence of the modified vaccinia Ankara strain: comparison with other orthopoxviruses.

G Antoine, F Scheiflinger, F Dorner … (1998)

The complete genomic DNA sequence of the highly attenuated vaccinia strain modified vaccinia Ankara (MVA) was determined. The genome of MVA is 178 kb in length, significantly smaller than that of the vaccinia Copenhagen genome, which is 192 kb. The 193 open reading frames (ORFs) mapped in the MVA genome probably correspond to 177 genes, 25 of which are split and/or have suffered mutations resulting in truncated proteins. The left terminal genomic region of MVA contains four large deletions and one large insertion relative to the Copenhagen strain. In addition, many ORFs in this region are fragmented, leaving only eight genes structurally intact and therefore presumably functional. The inserted DNA codes for a cluster of genes that is also found in the vaccinia WR strain and in cowpox virus and includes a highly fragmented gene homologous to the cowpox virus host range gene, providing further evidence that a cowpox-like virus was the ancestor of vaccinia. Surprisingly, the central conserved region of the genome also contains some fragmented genes, including ORF F5L, encoding a major membrane protein, and ORFs F11L and O1L, encoding proteins of 39.7 and 77.6 kDa, respectively. The right terminal genomic region carries three large deletions all classical poxviral immune evasion genes and all ankyrin-like genes located in this region are fragmented except for those encoding the interleukin-1 beta receptor and the 68-kDa ankyrin-like protein B18R. Thus, the attenuated phenotype of MVA is the result of numerous mutations, particularly affecting the host interactive proteins, including the ankyrin-like genes, but also involving some structural proteins.

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Protective Efficacy of Recombinant Modified Vaccinia Virus Ankara Delivering Middle East Respiratory Syndrome Coronavirus Spike Glycoprotein.

Asisa Volz, Alexandra Kupke, Fei Song … (2015)

Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe respiratory disease in humans. We tested a recombinant modified vaccinia virus Ankara (MVA) vaccine expressing full-length MERS-CoV spike (S) glycoprotein by immunizing BALB/c mice with either intramuscular or subcutaneous regimens. In all cases, MVA-MERS-S induced MERS-CoV-specific CD8(+) T cells and virus-neutralizing antibodies. Vaccinated mice were protected against MERS-CoV challenge infection after transduction with the human dipeptidyl peptidase 4 receptor. This MERS-CoV infection model demonstrates the safety and efficacy of the candidate vaccine.

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Compact, synthetic, vaccinia virus early/late promoter for protein expression.

S Chakrabarti, J R Sisler, B Moss (1997)

Vaccinia virus, a member of the poxvirus family, is widely used as a mammalian cell expression vector. Vaccinia virus replicates in the cytoplasm and has its own transcriptional system, making it necessary to use viral promoters. Here, we describe the design, construction and use of a 40-bp synthetic, vaccinia virus promoter with largely overlapping early and late regulatory elements. Convenient plasmid transfer vectors are depicted for expression of one or two genes under control of strong early/late promoters and allowing for thymidine kinase (TK) or antibiotic selection of recombinant viruses.