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Infection and Immunity, June 2002, p. 3026-3032, Vol. 70, No. 6
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.6.3026-3032.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Correlation of ESAT-6-Specific Gamma Interferon Production with Pathology in Cattle following Mycobacterium bovis BCG Vaccination against Experimental Bovine Tuberculosis

H. Martin Vordermeier,* Mark A. Chambers, Paul J. Cockle, Adam O. Whelan, Jennifer Simmons, and R. Glyn Hewinson

Veterinary Laboratories Agency Weybridge, TB Research Group, New Haw, Addlestone, Surrey KT15 3NB, United Kingdom

Received 27 November 2001/ Returned for modification 8 February 2002/ Accepted 15 March 2002

Vaccine development and the understanding of the pathology of bovine tuberculosis in cattle would be greatly facilitated by the definition of immunological correlates of protection and/or pathology. To address these questions, cattle were vaccinated with Mycobacterium bovis bacillus Calmette-Guérin (BCG) and were then challenged with virulent M. bovis. Applying a semiquantitative pathology-scoring system, we were able to demonstrate that BCG vaccination imparted significant protection by reducing the disease severity on average by 75%. Analysis of cellular immune responses following M. bovis challenge demonstrated that proliferative T-cell and gamma interferon (IFN-{gamma}) responses towards the M. bovis-specific antigen ESAT-6, whose gene is absent from BCG, were generally low in vaccinated animals but were high in all nonvaccinated calves. Importantly, the amount of ESAT-6-specific IFN-{gamma} measured by enzyme-linked immunosorbent assay after M. bovis challenge, but not the frequency of responding cells, correlated positively with the degree of pathology found 18 weeks after infection. Diagnostic reagents based on antigens not present in BCG, like ESAT-6 and CFP-10, were still able to distinguish BCG-vaccinated, diseased animals from BCG-vaccinated animals without signs of disease. In summary, our results suggest that the determination of ESAT-6-specific IFN-{gamma}, while not a direct correlate of protection, constitutes nevertheless a useful prognostic immunological marker predicting both vaccine efficacy and disease severity.

* Corresponding author. Mailing address: VLA Weybridge, TB Research Group, Woodham Ln., New Haw, Addlestone, Surrey KT15 3NB, United Kingdom. Phone: 44 1932 357 884. Fax: 44 1032 357 684. E-mail: mvordermeier.vla{at}gtnet.gov.uk.

Editor: S. H. E. Kaufmann

Infection and Immunity, June 2002, p. 3026-3032, Vol. 70, No. 6
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.6.3026-3032.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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