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

To examine the potential for recombination in cells in which MVA multiplies poorly, Vero cells were co-infected with MVA-vectored influenza vaccine (MVA-HANP) [151] and a feline CPXV (fCPXV) [119] , infected with MVA-HANP or fCPXV respectively and thereafter superinfected with either fCPXV or MVA-HANP at various times post primary virus infection (ppi). Our results showed that recombination occurred and that 0.5% of the visual plaques in co-infected cells and 0.4% to 7.1% of plaques in superinfected cells expressed the transgene (Figure 3 ). Both the transgene expressing MVA/fCPXV recombinant progenies ( Figure 4 ) and non-transgene expressing MVA/fCPXV recombinants displayed different plaque phenotypes. These results demonstrated that: (i) recombinant MVA vaccine can recombine with naturally circulating OPVs during co-infection and superinfection of mammalian cells that are semi-permissive to MVA and (ii) repulsion of superinfecting virions does not prevent recombination between recombinant MVA and wild-type OPVs. At present, we are extending these experiments to non-permissive cells and to immune-competent and immune-deficient animal models, as well as mapping genome-wide patterns of recombination in the already isolated recombinants. If our results from cell cultures are replicated in intact animal models, the potential for recombination should be examined for each MVA-vectored vaccine for which MAA and clinical trial application is being sought. In addition, the present emphasis on the likelihood or frequency of occurrence but not on the consequences needs a re-examination. Consideration should also be given to the impact or consequences of a presumably rare event like recombination. A rare recombination event may generate progeny hybrid viruses that are more virulent than any of the parental strains. Naturally occurring OPVs like CPXV, MPXV or VACV may become more virulent if they acquire the transgene encoding co-stimulatory molecules from an MVA-vectored vaccine following an unlikely recombination event. Among alphaherpesviruses, recombination between attenuated infectious laryngotracheitis virus vaccine strains resulted in the emergence of virulent field isolates [152] .