Hazard Characterization of Modified Vaccinia Virus Ankara Vector: What Are the Knowledge Gaps?

Okeke, Malachy I.; Okoli, Arinze S.; Diaz, Diana; Offor, Collins; Oludotun, Taiwo G.; Tryland, Morten; Bøhn, Thomas; Moens, Ugo

The immunogenicity of MVA cannot only be altered by deletion of immunomodulatory genes, but also by posttranslational modifications of viral structural proteins. Rojas and colleagues found that the glycosylation state of VACV particles had an impact on the immune response [177] . VACV naturally activates Toll-like receptor 2 (TLR2), associated with induction of anti-viral neutralizing antibody response. Deglycosylation of the virus particle blocked TLR2 activation and greatly reduced the production of anti-viral antibodies, but did not affect infectivity. Glycosylated MVA should be used to increase the immune response and cause better protection against poxvirus infection. Vaccination with VACV strains that can multiply in patients with glycosylation defects may result in poorer immune response and poorer protection against poxvirus infection. Strategies used to improve the immunogenicity of (recombinant) MVA besides deletion of immunomodulatory genes include immunization with prime/boost with other viruses or DNA vectors, insertion of genes encoding co-stimulatory molecules (e.g., interleukins, IFNγ), increased expression of the foreign antigen (e.g., promoter strength, codon optimization, terminal signal peptide) and adjuvant (e.g., Glucopyranosyl Lipid A, MF59) (reviewed in [91] . Thus, modulating the expression of MVA genes in these manners can improve the immunogenicity of MVA vaccines and activate immune responses to heterologous antigens. However, the effect of these strategies on the biosafety of MVA including its attenuation, multiplication incompetence, cell and tissue tropism, genome stability, biodistribution and shedding is mostly not investigated.