Abstract
The ESX systems from Mycobacterium tuberculosis are responsible for the secretion of highly immunogenic proteins of key importance for bacterial survival and growth. The two prototypic proteins, ESAT-6 (EsxA from ESX-1) and TB10.4 (EsxH from ESX-3) share a lot of characteristics regarding genome organization, size, antigenic properties, and vaccine potential but the two molecules clearly have very different roles in bacterial physiology. To further investigate the role of ESAT-6 and TB10.4 as preventive and post-exposure tuberculosis vaccines, we evaluated four different fusion-protein vaccines; H1, H4, H56 and H28, that differ only in these two components. We found that all of these vaccines give rise to protection in a conventional prophylactic vaccination model. In contrast, only the ESAT-6-containing vaccines resulted in significant protection against reactivation, when administered post-exposure. This difference in post-exposure activity did not correlate with a difference in gene expression during infection or a differential magnitude or quality of the vaccine-specific CD4 T cells induced by ESAT-6 versus TB10.4-containing vaccines. The post-exposure effect of the ESAT-6 based vaccines was found to be influenced by the infectious load at the time-point of vaccination and was abolished in chronically infected animals with high bacterial loads at the onset of vaccination. Our data demonstrate that there are specific requirements for the immune system to target an already established tuberculosis infection and that ESAT-6 has a unique potential in post-exposure vaccination strategies.
Highlights
Mycobacterium tuberculosis (M.tb.) remains a major threat to global health with an estimated 2 billion infected
In order to evaluate vaccines for their activity post-exposure in animals infected with M.tb., we developed and characterized an animal model that represents a modification of the previously published Cornell model [4]
The bacterial load was reflected in the IFN-γ response directed to both ESAT-6 and TB10.4 with responses after completed antibiotic treatment below detection levels and highly increased levels as the bacteria resumed growth (Figure 1B)
Summary
Mycobacterium tuberculosis (M.tb.) remains a major threat to global health with an estimated 2 billion infected. The outcome has mostly been disappointing and compared to the numerous reports of vaccines with preventive activity [2,6,7], only very few defined subunit vaccines have been demonstrated to have a significant protective effect in the demanding post-exposure animal model [8,9,10,11]. The reason for this difference is not clear but may relate to the distinct immunological milieu that M.tb. We analyze a series of fusion-protein vaccines that differ only in their ESAT-6 and TB10.4 content and find that whereas both ESAT-6- and TB10.4-containing vaccines had prophylactic activity, only the ESAT-6-containing vaccines resulted in significant protection against relapse when administered post-exposure
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