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Clinical and Vaccine Immunology, August 2009, p. 1203-1212, Vol. 16, No. 8
1071-412X/09/$08.00+0     doi:10.1128/CVI.00111-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Immunogenicity of Novel DosR Regulon-Encoded Candidate Antigens of Mycobacterium tuberculosis in Three High-Burden Populations in Africa ^,

Gillian F. Black,^1,* Bonnie A. Thiel,^2, Martin O. Ota,³ Shreemanta K. Parida,⁴ Richard Adegbola,³ W. Henry Boom,^2,5 Hazel M. Dockrell,⁶ Kees L. M. C. Franken,⁷ Annemiek H. Friggen,⁷ Philip C. Hill,^3, Michel R. Klein,^7,¶ Maeve K. Lalor,⁶ Harriet Mayanja,⁵ Gary Schoolnik,⁸ Kim Stanley,¹ Karin Weldingh,^9,|| Stefan H. E. Kaufmann,⁴ Gerhard Walzl,¹ Tom H. M. Ottenhoff,⁷ and the GCGH Biomarkers for TB Consortium

Department of Biomedical Sciences, Faculty of Health Sciences, Stellenbosch University, Cape Town, South Africa,¹ Tuberculosis Research Unit, Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals Case Medical Center, Cleveland, Ohio,² Bacterial Diseases Programme, Medical Research Council, P.O. Box 273, Banjul, The Gambia,³ Department of Immunology, Max Planck Institute for Infection Biology, D-10117 Berlin, Germany,⁴ Department of Medicine, Makerere University, Kampala, Uganda,⁵ Department of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London WC1E 7HT, United Kingdom,⁶ Department of Immunohematology and Blood Transfusion, and Department of Infectious Diseases, Leiden University Medical Centre, NL-2300 RC Leiden, The Netherlands,⁷ Department of Microbiology and Immunology, Stanford University, Stanford, California,⁸ Department of Infectious Disease Immunology, Statens Serum Institute, Copenhagen, Denmark⁹

Received 11 March 2009/ Returned for modification 2 April 2009/ Accepted 17 June 2009

Increasing knowledge about DosR regulon-encoded proteins has led us to produce novel Mycobacterium tuberculosis antigens for immunogenicity testing in human populations in three countries in Africa to which tuberculosis (TB) is endemic. A total of 131 tuberculin skin test-positive and/or ESAT-6/CFP10-positive, human immunodeficiency virus-negative adult household contacts of active pulmonary TB cases from South Africa (n = 56), The Gambia (n = 26), and Uganda (n = 49) were tested for gamma interferon responses to 7 classical and 51 DosR regulon-encoded M. tuberculosis recombinant protein antigens. ESAT-6/CFP10 fusion protein evoked responses in >75% of study participants in all three countries. Of the DosR regulon-encoded antigens tested, Rv1733c was the most commonly recognized by participants from both South Africa and Uganda and the third most commonly recognized antigen in The Gambia. The four most frequently recognized DosR regulon-encoded antigens in Uganda (Rv1733c, Rv0081, Rv1735c, and Rv1737c) included the three most immunogenic antigens in South Africa. In contrast, Rv3131 induced the highest percentage of responders in Gambian contacts (38%), compared to only 3.4% of Ugandan contacts and no South African contacts. Appreciable percentages of TB contacts with a high likelihood of latent M. tuberculosis infection responded to several novel DosR regulon-encoded M. tuberculosis proteins. In addition to significant similarities in antigen recognition profiles between the three African population groups, there were also disparities, which may stem from genetic differences between both pathogen and host populations. Our findings have implications for the selection of potential TB vaccine candidates and for determining biosignatures of latent M. tuberculosis infection, active TB disease, and protective immunity.

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* Corresponding author. Mailing address: Department of Biomedical Sciences, Fisan Building, Faculty of Health Sciences, Stellenbosch University, Tygerberg Hospital Campus, Tygerberg, Cape Town 7505, South Africa. Phone: 27 21 938 9069. Fax: 27 21 938 9476. E-mail: gfb{at}sun.ac.za

Published ahead of print on 24 June 2009.

Supplemental material for this article may be found at http://cvi.asm.org/.

Gillian F. Black and Bonnie A. Thiel contributed equally to the preparation of the manuscript.

Present address: Department of Preventive and Social Medicine, University of Otago School of Medicine, Dunedin, New Zealand.

^¶ Present address: National Institute for Public Health and the Environment, Bilthoven, The Netherlands.

^|| Present address: Novo Nordisk, Maaloev, Denmark.

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Clinical and Vaccine Immunology, August 2009, p. 1203-1212, Vol. 16, No. 8
1071-412X/09/$08.00+0     doi:10.1128/CVI.00111-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.