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 inability of MVA to undergo productive infection in human and most cells of mammalian origin is the main reason why MVA is regarded as a safe virus vector. In approving the licensing of Imvanex ® as a smallpox vaccine within EU, the EMA Committee for Medicinal Products for Human Use (CHMP) stated, "With regard to safety, the vaccinia virus in Imvanex cannot replicate in human cells and hence is less likely to cause side effects than previous smallpox vaccines. Imvanex would therefore be beneficial for people who cannot be given vaccines containing replicating viruses such as patients with weakened immune system" [97] . The molecular basis for the non-productive infection of human and other mammalian cells by MVA remains unknown. Thus, this creates a major knowledge gap in the hazard characterization of MVA. Until the molecular determinant of the host restriction is identified, it is not a certainty that MVA cannot multiply efficiently in human cells. Earlier suggestions that the absence of host range genes and the presence of six major deletions in the MVA genome may be responsible for the severe host cell defect have been shown to be incorrect as: (i) most of the replication competent VACV host range genes are still intact in MVA [46, 98] ; (ii) marker rescue of non-functional host range genes (KIL and C7L) with functional copies did not restore the host cell tropism of wild-type CVA [45, 98] ; (iii) marker rescue with large fragments of the CVA genome did not restore the wild-type phenotype [99] and (iv) most importantly the sequential introduction of the six major deletions into the CVA genome did not re-create the MVA host restricted phenotype [47] . Thus, the six major deletions and the absence of two VACV host range genes are not essential for the severe host range defect of MVA.