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EC-sponsored Research on Safety of Genetically Modified Organisms - A Review of Results
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image Monitoring the potential risk linked to the use of modified live viruses for antirabies vaccination of foxes

Background and objectives

In northern countries, sylvatic rabies is a zoonotic disease (a disease whose epidemiology is solely linked to a wildlife reservoir). In Western Europe, the main vector is the red fox (Vulpes vulpes). Here, “vector” refers to the animal host that is most susceptible to rabies in a region at a given time and that is solely responsible for maintaining the infection. The control of the infection within the vector species thus permits overall control of the infection and, most importantly, reduces the risk of transmission to man. In Western Europe, control measures to reduce fox populations were only temporarily effective and did not prevent the disease from spreading. For this reason, other methods such as oral immunisation of foxes needed to be assessed. Research has focused on oral vaccination, the only means allowing the immunisation of a sufficient proportion (75%) of wild foxes, through the distribution of vaccine baits.

Since 1978, several European countries have conducted, at different times, large-scale field trials of oral vaccination of foxes (Vulpes vulpes) against rabies, using the SAD, standard or B19-modified attenuated strains of rabies virus. The use of attenuated strains of rabies virus remains controversial as far as safety and stability are concerned, since these virus strains retain pathogenicity for rodents or other wildlife species and are heat-sensitive. To improve both safety and stability of the vaccine used in the field, a recombinant vaccinia virus expressing the immunogenic G protein of rabies virus has been developed and released in the field. The vaccinia-rabies recombinant virus was called VVTGgRAB. We have studied the safety and efficacy of this recombinant virus in field trials and in vaccination efforts.

image Red fox (Vulpes vulpes).



Approach and methodology

Taking into account all the available experimental data concerning the safety of the VVTGgRAB for target and non target species and its efficacy in foxes, initial limited field trials of fox vaccination were authorised first by the Belgian and then by the French public health authorities. In the Belgian trial (17-18 October, 1987) a total of 250 vaccine baits (chicken heads) were delivered manually on a 6 km2 area situated in the central part of a military zone. With the safety of the VVTGgRAB being confirmed by this small trial, the Belgian authorities agreed to an enlarged open field trial. This was conducted in a 435 km2 area in the southern part of the country, chosen because it has the lowest average human population density in the country (42 inhabitants km-2) as well as high rabies incidence in foxes. Furthermore, the region is characterised by various habitats housing most of the animal species liable to consume bait. Each bait contained a suspension of 108 CCID50 of VVTGgRAB (2.2 ml by volume) within a plastic sachet and 150 mg tetracycline as a long-term biomarker of bait uptake. After the vaccination campaign, 222 dead wild animals belonging to 19 species were collected in the vaccination area. After necropsy, the following tissues were removed: brain for rabies diagnosis, jaws for tetracycline detection and blood for the titration of vaccinia and rabies antibodies.


Main findings and outcome

Following this enlarged trial, three fox-vaccination campaigns using VVTGgRAB were then carried out in Belgium in November 1989, April 1990 and October 1990 in order to check for efficacy in an area of 2200 km2 with a mean baiting density of 15 baits km-2. These campaigns have brought a drastic decrease in the incidence of rabies both in foxes and in domestic animals. The only perceived remaining risk was a recombinant event between the recombinant virus and a wild orthopoxvirus such as cowpox. A serological survey was done on sera collected from foxes and experimental infections of foxes with cowpox were performed in order to assess this perceived risk showing that is was negligible.


Conclusions

All the safety studies during deliberate release trials, done step by step, using the vaccinia-rabies recombinant virus for oral vaccination of foxes against rabies led to the same conclusion: the recombinant vaccinia-rabies virus is perfectly safe and safer than any other attenuated rabies virus strain presently used in the field in Western Europe. The use of the recombinant vaccinia-rabies virus did lead to the elimination of rabies in large areas and, as a consequence a drastic decrease in human post-exposure treatments. Serological surveys and experimental studies in foxes have shown that the risk of recombination between the recombinant vaccinia-rabies virus and wild orthopoxvirus could be considered as nearly nil.

 

Major publications

Brochier B., Kieny M.P., Costy F., Coppens P., Bauduin B., Lecocq J.P., Languet B, Chappuis G., Desmettre P., Afiademanyo K., Libois R., Pastoret P.P., “Large-scale eradication of rabies using recombinant vaccinia-rabies vaccine”.
Nature,
354, 1991, pp. 520-522.

Pastoret P.P., Brochier B., Languet B., Thomas I., Paquot A., Bauduin B., Costy F., Antoine H., Kieny M.P., Lecocq J.P., Debruyn J., Desmettre Ph., “First field trial of fox vaccination against rabies with a vaccinia-rabies recombinant virus”.
Vet. Rec.,
123, 1988, pp. 481-483.

Brochier B., Thomas I., Bauduin B., Leveau T., Pastoret P.P., Languet B., Chappuis G., Desmettre P., Blancou J., Artois M., “Use of vaccinia-rabies recombinant virus for the oral vaccination of foxes against rabies”.
Vaccine,
8, 1990, pp. 101-104.

Boulanger D., Brochier B., Crouch A., Bennett M., Gaskell R.M., Baxby D., Pastoret P.P., “Comparison of the susceptibility of the red fox (Vulpes vulpes) to a vaccinia-rabies recombinant virus and to cowpox virus”.
Vaccine,
13, 1995, pp. 215-219.

Boulanger D., Crouch A., Brochier B., Bennett M., Clément J., Gaskell R.M., Baxby D., Pastoret P.P., “Serological survey for Orthopoxvirus infection of wild mammals in areas where a recombinant vaccinia-rabies virus is used to vaccinate foxes against rabies”.
Vet. Rec., 138, 1996, p. 2.
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imageResearch project
 

Contract number
BAP-0368/0381/0382

Period
January 1989 – December 1990

 
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Partners


P.P. Pastoret
University of Liège (BE)

A. Flamand
CNRS
Gif-sur-Yvette (FR)

J. Blancou
Centre National d’Etudes sur la Rage et la Pathologie des Animaux Sauvages (CNER)
Malzeville (FR)

 
 
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