This paper presents the biosafety issues and the main lessons learned from the evaluation of the clinical trials with rMVA performed in Belgium. attention. Measures to prevent or manage identified risks are also discussed. Keywords:Biosafety, clinical trials, environmental risk assessment, gene therapy, GMO-based vaccines, MVA-based recombinant vectors. == 1. INTRODUCTION == Poxviruses are considered excellent vector systems candidates for gene delivery without integration into the host genome or for vaccination. This is due to several features including (i) large packaging capacity for recombinant DNA (up to 25 kbp); (ii) precise and controllable recombinant DNA expression regulated by a strong poxviral promoter; (iii) lack of persistence or genomic integration in the host due to their cytoplasmic replication (transient expression); (iv) high immunogenicity as vaccine; and (v) ease of vector and vaccine production [1,2]. Their main disadvantage resides in the development of neutralizing antibodies against the vector after subsequent administrations [3]. To address potential biosafety issues highly attenuated poxvirus strains have been developed, such as, in the orthopox virus (OPV) genus, the modified vaccinia virus Ankara (MVA) strain derived from the chorioallantois vaccinia virus strain Ankara (CVA). The attenuation of MVA is based on serial passages (more then 500) in primary chicken embryo fibroblasts (CEFs), resulting in a genomic loss of approximately 15% compared to the parental CVA strain, reducing its virulence and pathogenesis [4,5]. This SB 271046 Hydrochloride modified MVA is unable to propagate in human or in most mammalian cells. It remains localized in the cytoplasm [6] and there is no evidence for genomic integration. It was originally developed in the 1970s as a vaccine against smallpox and was found to be safer than other replication competent vaccinia strains [7-10]. Since the global eradication of smallpox was certified by a commission of scientists and endorsed by the World Health Organization (WHO) in 1980, this vaccine isnot used anymore. However, with respect to the granting of a marketing authorisation for a new MVA vaccine called Imvanex, the European Medicines Agency (EMA) recommended in May 2013 its use for active immunisation against smallpox in adults” under exceptional circumstances, i.e. to protect populations at risk from bioterrorism [11]. Since the nineties, MVA has been widely tested in clinical trials as recombinant vector for vaccination against various pathogens or as gene delivery vehicle SB 271046 Hydrochloride for gene therapy applications. Although MVA vectors are considered safer than other vaccinia strains, several aspects should be considered carefully when performing the biological risk assessment of MVA and MVA-based vectors [5]. This includes in particular (i) the potential presence in the MVA population of variants able to replicate, (ii) the intrinsic characteristics SB 271046 Hydrochloride of the transgene which may present hazardous properties or change the vector properties, (iii) recombination events with wild type OPV or homologs that could lead to the rescue of parental genes that are interrupted or deleted in MVA or the transfer of the transgene to replication competent OPV. An increasing amount of information is becoming available on biosafety issues associated with MVA and MVA-based vectors, both from the scientific literature and from regulatory dossiers. In Belgium six clinical trials using MVA as vector systems for gene therapy or vaccination have been assessed since 1996. General or regulatory information about these Rabbit polyclonal to Vitamin K-dependent protein C trials (B-GT/11, B-GT/12, B-GT22, B-GT/24 and B-GT/26) are publicly available [12]. This paper presents the main lessons learned from the evaluation of these trials and shows how the information provided by the notifiers and the recommendations proposed by the risk evaluators can contribute to improve the risk assessment and the risk management of such trials. == 2. CRITICAL ISSUES IN THE ENVIRONMENTAL RISK ASSESSMENT OF MVA-BASED CLINICAL TRIALS == == 2.1. Steps in the Environmental Risk Assessment == As detailed in the lead-in article of Baldoet al.the environmental SB 271046 Hydrochloride risk assessment (ERA) focuses on the identification of the characteristics of the genetically modified organism (GMO) and its use which have the potential to cause adverse effects on persons (non-patients) directly exposed to the gene therapy medicinal product, on.