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

Recombination between poxvirus-vectored vaccines and naturally circulating OPVs during co-infection and superinfection of cells/hosts is significant in terms of ERA. This is because recombination has the potential of restoring productive infection of a multiplication-incompetent vaccine-vector as well as generating hybrid viruses with altered host range, cell tropism, transmissibility and virulence. Although recombination is known to occur among replicating poxviruses [141] [142] [143] [144] and is indeed the method for constructing recombinant poxvirus-vectored vaccines [145] , studies aimed at investigating recombination between MVA-vectored vaccines and other OPVs are rare. Previously, we have demonstrated that recombination occurred between an MVA-vectored influenza vaccine and naturally circulating CPXV during co-infection of BHK-21 cells [95] and generated progeny hybrid viruses with parental and non-parental characteristics [95, 96] . Provision of data on the potential for recombination between the MVA-vectored vaccine and wild-type OPVs is not obligatory under Directive 2001/18/EC [14] , which may explain the paucity of data on this issue. At present, the ERA of MVA-vectored vaccine does not evaluate the potential for recombination between the recombinant MVA vaccine and naturally circulating OPVs because the risk of recombination is said to be negligible [19] . Recombination between recombinant MVA vaccines and wild type OPVs is deemed unlikely because MVA does not produce infectious virions in human and most other cells of mammalian origin [50, 52, 99] as well as due to repulsion of superinfecting virions [146] [147] [148] . However, abortive infection and repulsion of superinfecting virions are not sufficient to prevent recombination since recombination requires the presence of homologous DNA only and repulsion of infectious virions is not absolute but leaky [149] . Although, OPV infections are short-lived, DNAemia lasting for up to four weeks has been reported for CPXVs [150] and in this time window, recombination can occur if MVA or recombinant MVA is used to vaccinate such a host. Since DNA replication is not impaired in MVA during non-productive infection of semi-and non-permissive cells, recombination between MVA and wild-type OPVs during co-infection and superinfection cannot be excluded.