Tuberculosis vaccine with high predicted population coverage and compatibility with modern diagnostics

Posted on by

PNAS – Proceedings of the National Academy of Sciences of the United States
of America
http://www.pnas.org/content/early/recent
(Accessed 11 January 2014)

Tuberculosis vaccine with high predicted population coverage and compatibility with modern diagnostics
Niels Peter H. Knudsena, Sara Nørskov-Lauritsena,1, Gregory M. Dolganovb, Gary K. Schoolnikb, Thomas Lindenstrøma, Peter Andersena, Else Marie Aggera,2, and Claus Aagaarda,2
Author Affiliations
Edited by Barry R. Bloom, Harvard School of Public Health, Boston, MA, and approved December 4, 2013 (received for review August 7, 2013)
http://www.pnas.org/content/early/2014/01/03/1314973111.abstract

Significance
Despite the availability of a number of antibiotics and extensive use of the live vaccine bacillus Calmette–Guérin, tuberculosis remains a major global health problem. Antigen 85 is by far the most popular antigen in current clinical trials vaccines. However, a recent failure of a virus-based vaccine expressing antigen 85 emphasizes the continued need for identifying antigens, testing their protective efficacy, and learning from this process to develop a protective vaccine. The H65 vaccine demonstrates that it is possible to develop antigen 85-free vaccines that does not interfere with current immune-based diagnostic assays.

Abstract
A central goal in vaccine research is the identification of relevant antigens. The Mycobacterium tuberculosis chromosome encodes 23 early secretory antigenic target (ESAT-6) family members that mostly are localized as gene pairs. In proximity to five of the gene pairs are ESX secretion systems involved in the secretion of the ESAT-6 family proteins. Here, we performed a detailed and systematic investigation of the vaccine potential of five possible Esx dimer substrates, one for each of the five ESX systems. On the basis of gene transcription during infection, immunogenicity, and protective capacity in a mouse aerosol challenge model, we identified the ESX dimer substrates EsxD-EsxC, ExsG-EsxH, and ExsW-EsxV as the most promising vaccine candidates and combined them in a fusion protein, H65. Vaccination with H65 gave protection at the level of bacillus Calmette–Guérin, and the fusion protein exhibited high predicted population coverage in high endemic regions. H65 thus constitutes a promising vaccine candidate devoid of antigen 85 and fully compatible with current ESAT-6 and culture filtrate protein 10-based diagnostics.