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Development of a genetically modified Brucella melitensis live vaccine and associated diagnostic assay allowing discrimination between vaccinated and infected sheep

Contract nr: FAIR-CT97-3360
Project nr: 3360
Project type: SC
Starting date: 01/02/1998
Duration: 48 months
Total cost: 1,371,639 EUR
EC Contribution: 1,106,000 EUR
Scientific Officer: Isabel MINGUEZ-TUDELA
Research topic: Animal health

Brucellosis in small ruminants caused by Brucella melitensis is the most widespread form of animal brucellosis in the Mediterranean countries of the European Union (EU). It is mainly sheep brucellosis which is responsible for serious economic losses through the interference with breeding programmes and a reduction in milk yield, and also constitutes a serious hazard to public health, as B. melitensis is highly pathogenic for humans. In the same regions, the ram contagious epididymitis caused by Brucella ovis is also a disease of economic significance. In southern Europe where sheep brucellosis is endemic, efforts are still to be made to reduce the prevalence to a level at which the elimination of infected animals is economically feasible. At this stage, vaccination is the only suitable method for controlling the infection in animals and thus constitutes a real priority. The development of an effective live vaccine allowing discrimination between vaccinated and infected animals is, therefore, highly desirable and justified.

The objective of this project is, therefore, to develop a stable vaccinal strain of B. melitensis which, by virtue of lacking genes encoding specific diagnostic proteins, would induce protection but would not induce anti-body response against the missing proteins. The use of these antigens - produced as recombinant proteins - in new diagnostic tests, would allow the discrimination between vaccinated animals and those which are infected. The critical point for the success of the project is to carefully select the antigens, the genes of which will be deleted from the genome of the vaccinal strain. These antigens should indeed be the best of all possible diagnostic antigens, i.e. they should detect most if not all infected animals and provide negative results with vaccinated and Brucella-free animals.

Recent work on Brucella protein antigens has led to the conclusion that two of them are suitable antigens for the diagnosis of brucellosis in sheep, and that they should facilitate the development of sensitive and specific immunological tests using mixtures of recombinant proteins. Because of their good diagnostic value, these two protein antigens have been selected in this project for developing relevant genetically modified B. melitensis strains. The engineered strains and associated diagnostic assay will be evaluated in mice and sheep. The project should ultimately lead to the development of a diagnostically distinguishable engineered B. melitensis vaccinal strain that would hasten the eradication of this zoonotic disease from the EU and the achievement of a uniform animal health status throughout the Union. This would also promote the control of the animal source of human pathogens.

Current situation/results:
Half of the planned work has now been accomplished and this step is a good opportunity to wonder if the things are heading in the right direction as regard the final perspectives of the programme. If we consider the results obtained during the two first years, we can reasonably answer in the affirmative. The objectives defined for the second year-end of the contract have indeed been achieved as expected, and from the results obtained, some conclusions can be drawn.

1) Although more extensive sensitivity and specificity studies are still needed, the diagnostic assay prototype has already proved, as evaluated on a wider sample of sera, its value for the detection of the field B. melitensis infection in sheep, with sensitivity and specificity respectively equal to 98% and 96%. These values are quite acceptable in the perspective of field use of the new serological assay.
2) As regards their residual virulence and their immunogenicity against both B. melitensis and B. ovis infections, as evaluated in the mouse model, the engineered strains are also acceptable in the perspective of field use as vaccine against sheep brucellosis.

Finally, the acquired results and the relevant milestones achieved augur well for the major step of the programme that will be devoted, in 2000 and 2001, to the evaluation of the engineered B. melitensis strains and the diagnostic assay in sheep.

Jean-Michel VERGER
Institut National de la Recherche Agronomique
Centre de Recherches de Tours
F-37380 Nouzilly
Tel.: +33 2 47 42 78 81
Fax: +33 2 47 42 77 79


    Universidad de Salamanca
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  • Jose Maria BLASCO
    Servicio de Investigación Agroalimentaria de la Diputación General de Aragon
    Carretera De Montañana 176
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  • Eric SAMAN
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    Fax: +32 9 241 09 07

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