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EC-sponsored Research on Safety of Genetically Modified Organisms - A Review of Results
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GM technology
for better vaccines


P.P. Pastoret,
Faculty of Veterinary Medicine,
University of Liège (BE)

New biotechnology has had a major impact on the design and development of new medicinal products, especially vaccines. In some cases, use of biotechnology has lead to results which would have been impossible to obtain through classical or conventional routes, for example, defining the complete sequence of human hepatitis C virus, which still cannot be grown in cell culture. Biotechnology has also helped to develop products which are safer than conventional ones; one notable example is the use in humans of growth hormone produced in genetically engineered bacteria instead of natural growth hormone, the use of the latter being responsible for the transmission of Creutzfeldt-Jakob Disease. Another example is the use of a recombinant vaccinia-rabies virus for vaccinating foxes against rabies, which is more efficacious and safer than the conventional attenuated SAD B19 strain. This strain, which is still used, is pathogenic for some non-target mammals and since its safety for man is unknown, people in contact with it must undergo post-exposure anti-rabies treatment.

Medicinal products are among the most stringently regulated products in the market place. They are evaluated for quality and efficacy but, above all, for safety, and if they consist of a genetically modified organism they must comply with specific regulations. If a medicinal product is developed using a biotechnological procedure it must be evaluated at a European level by the relevant scientific committee using the so-called Centralised Procedure: the Committee for Proprietary Medicinal Products (CPMP) deals with human products and the Committee for Veterinary Medicinal Products (CVMP) with products intended for use in animals; both are part of the European Agency for the Evaluation of Medicinal products (EMEA), based in London.

Recombinant pharmaceutical products including genetically modified organisms are often developed primarily for veterinary use, taking advantage of the fact that efficacy and safety can be studied experimentally directly in the target species, and that the environmental impact for non-target species can also be studied experimentally.

DNA vaccination is the new frontier in vaccinology and, thanks to the existence of already available biosafety research results, the Immunological Working Party (IWP) of the CVMP was able to produce guidance notes on DNA vaccines for use by pharmaceutical companies and the relevant competent authorities.

The research projects on vaccine biosafety reported here include five applications of a generic nature and two more focused on specific animal health aspects.

Two serious concerns have been raised concerning the biosafety of conventional or recombinant vaccines for human and animal uses. The first one is the fact that vaccine strains may persist in the vaccinated recipients and, if the target species is a food-producing animal, later on in the food chain. The second one is that administration of a vaccine may trigger long-term adverse effects in normal or immunodeficient recipients. Project BIO4-CT98-0031 showed that those effects could be discarded by using a recombinant alphavirus, namely Semliki Forest Virus (SFV), in mice, chicken and sheep. The vaccine virus does not persist more than seven days after vaccination.

Identification of genes involved in latency and reactivation of Pseudorabies virus (PRV), a herpesvirus primarily infecting pigs, was the subject of project BIOT-CT91-0297. A limited region of the PRV genome (LAP) was identified which appears to be transcribed mostly during the latent stage of the infection. A deletion mutant was produced (from which the putative LAP had been totally deleted) and pigs were infected either with wild type virus or the deleted mutant without showing significant differences.

Another project (BIO4-CT96-0637) was devoted to the immunological biosafety of DNA vaccines. Potential immunological problems associated with this new vaccination technology include unexpected immunopathological reactions or tolerance. The objectives of the project were to investigate circumstances which may lead to an undesirable immune response to a DNA vaccine and to establish an assay for assessing the integration of a plasmid DNA vaccine. These studies have shown that the purity of injected DNA vaccines can affect the inflammatory response and also that the type of vaccination can influence the nature of the response. This kind of work is of primary importance in establishing a scientific basis for proper regulation of DNA vaccines, but also to limit ill-informed opinions impeding clinical trials, which is detrimental both to the vaccine industry and also for human and animal health.

Biosafety of mucosa-specific RNA-vectors expressing foreign antigens and recombinant antibodies for disease prevention was the subject of project BIO4-CT98-0239. This project led to the engineering of the largest RNA-virus genome as an infectious bacterial artificial chromosome, which was a major outcome. Two expression systems for the introduction of genetically modified elements in animals were developed among which was an efficient single genome coronavirus vector expressing foreign genes. The two systems proved to be suitable models to examine biosafety of introduced GMOs.

The last of the generic projects (BIOT-CT91-0286) was related to the safety of genetically engineered retroviruses used for gene transfer. The objective of this project was to accumulate basic information regarding cellular and viral mechanisms involved in modulating the behaviour of retroviral vector systems, in order to construct safe, efficient and targeted retroviral vector systems.

Two projects concerned biosafety aspects of the use of a recombinant vaccinia-rabies virus for wildlife vaccination against rabies (BAP-0368/0381/0382 and BIOT-CT91-0298). The recombinant vaccinia-rabies virus appeared to be perfectly safe and even safer than some attenuated rabies virus strains presently used in the field in Western Europe. The use of this recombinant vaccine did lead to the elimination of rabies in large areas and, as a consequence, to a drastic decrease in the number of human post-exposure treatments.

To conclude, all these projects have contributed to the provision of a sound scientific basis and a more rationale approach to the construction and development of safe GMOs and also towards better regulations for the benefit of both human and animal health.

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