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

MVA is considered a safe vaccine against smallpox. However, animal studies showed that higher or multiple doses (boosts) are required to obtain the same anti-VACV antibody response as obtained with a single dose of wild-type VACV [167] . Thus, MVA with higher immunogenicity and recombinant MVA vectors that elicit improved immune response against the heterologous antigen but still reduced virulence are needed. VACV encodes several proteins that are involved in evasion of the host immune response [34, 46] . MVA lacks several of these genes and this increases the immunogenicity of the virus [34, 46] . VACV infection in mice and humans induces humoral-(antibody secreting B cells or plasma cells) and cell-mediated (CD4+ and CD8+ T cell) responses. Because VACV is used as a vaccine vector, highly attenuated strains such as MVA have been developed. MVA has retained immune stimulatory properties (see [34] for a recent review). Administration of MVA in animal models leads to the induction of type I and type II interferons (IFNs), pro-inflammatory cytokines and chemokines. All are critical mediators of the host anti-viral response. In addition, virus-specific CD4+ and CD8+ T cell responses are developed, including CD8+ memory T cell response [34, 168, 169] . Despite mutations and major deletions, the MVA genome still encodes several proteins with immunomodulatory functions [46] . Deletion of genes encoding these immunomodulators can increase the immune response to VACV as demonstrated for A41L and B15R genes. Single removal of these genes resulted in increased viral-specific CD8+ T cell response and enhanced protection against challenging with virulent VACV WR in mice [170, 171] . Increased immune responses were also measured after infection with MVA lacking A35R or C12L [87, 88] . These studies suggest that MVA deprived of additional immunomodulatory genes may represent improved vaccine vectors.