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

Following the discovery in 1982 that VACV can express heterologous genes efficiently in mammalian cells [28, 29] , MVA has undergone rapid development as a virus vector in vaccines against infectious diseases and cancers. The unique characteristics of non-productive infection in human cells [49] , attenuation in vivo [56] , generation of rapid immune responses [63] and the robust activation of the innate immune system [64] have positioned MVA as the virus vector of choice. Although, no vaccine has been licensed for human use, several MVA-vectored vaccines against HIV/AIDS [65] [66] [67] , tuberculosis [68] , malaria [69] [70] [71] , Ebola [72, 73] , influenza [74, 75] and hepatitis B [76] are already in clinical trials, while several candidate vaccines against a plethora of other human diseases are in pre-clinical trials [26, 34, 77] . Apart from human infectious diseases, recombinant MVA vaccines against cancers are in pre-clinical and clinical development [78] [79] [80] [81] . MVA is also an attractive and efficient virus vector for the development of recombinant vaccines against diseases of domesticated animals and wildlife [82] [83] [84] [85] [86] . Although MVA has shown great promise as a vector for recombinant vaccines, there is still the need to improve its efficacy and safety. MVA is further optimized for improved vaccine efficacy by deleting the few intact VACV immunomodulatory genes [87] [88] [89] , insertion of genes that encodes co-stimulatory molecules [90, 91] and more precise regulation of gene expression from endogenous or synthetic promoters [92] [93] [94] . On the contrary, studies aimed at further attenuation of the MVA vector are miniscule probably due to the assumption that the development of MVA has reached a satisfactory level of safety and that additional attenuation may compromise its immunogenicity. The MVA vector is generally believed to pose a very low or negligible risk to humans, animals and the environment [17, 19, 42] . It is claimed that there is overwhelming and indisputable scientific evidence [42] to support this assertion. However, such scientific consensus will be undermined if research on the biosafety and risk characterization of the MVA vector is omitted, not prioritized or remains unpublished. The number of peer reviewed articles published on the two arms of MVA vaccine research being: (i) efficacy (immunogenicity) and (ii) biosafety (environmental risk assessment), was chosen as an indicator of research priority. The object of the PubMed search is "Modified vaccinia virus Ankara" and keyword(s) were appended to the object as prefix or suffix. Each pre-fixed or suffixed object was searched independently and the number of published articles was recorded. PubMed search was conducted on 13 July 2017. When queried with the object "Modified vaccinia virus Ankara" and "Modified vaccinia virus Ankara vaccine" 866 and 800 articles respectively were retrieved. Keywords dealing with the efficacy or immunogenicity of MVA returned higher numbers of published articles (223 to 478), whereas keywords dealing with biosafety or ERA returned very few hits (3 to 16). When the database was queried with the keywords "MVA safety" instead of "MVA biosafety," the number of articles increased from 16 to 183. However, safety studies are not biosafety or environmental risk studies as they are often misconstrued to be. Safety studies deal with potential adverse effects on the patient (direct recipient of the MVA vaccine),