Dr Cristian Segura-Cerda, CIATEJ - VALIDATE Fellow
Evaluation of the efficacy of BCGΔBCG1419c vaccination plus a booster of EsxG/EsxH-derived peptides to prevent tuberculosis progression caused by Mycobacterium tuberculosis strains prevalent in Latin America
Project Aims
The current global burden of tuberculosis makes it necessary to count on an efficacious vaccine that would be able to prevent infection by the harmful bacteria Mycobacterium tuberculosis (M. tuberculosis) and/or its progression to overt disease. An unmet challenge for new vaccines is how they protect against the variety of strains of M. tuberculosis which circulate around the world. In Latin America, two main lineages of M. tuberculosis strains have been recognized to circulate in the continent. These lineages, also present in Europe and Asia, differ in how tuberculosisis presents in the body. Ideally, a new vaccine against tuberculosis should generate protection against a broad variety of M. tuberculosis strains to have the greatest impact on health.
In this project, a vaccination strategy is proposed to improve the protection against this diversity of M. tuberculosis strains. It comprises the administration of the vaccine candidate BCGΔBCG1419c, which has been shown to be effective in reducing progression of tuberculosis in experimental models, particularly by conferring protection against chronic disease. This strain produces more biofilms in vitro than BCG, a form of growth which is common among diverse lineages of M. tuberculosis strains. Intranasal adminstration of EsxG/EsxH-derived peptides is proposed to boost protection. EsxG and EsxH participate in the acquisition of iron and zinc, minerals essential for mycobacterial metabolism. EsxG and EsxH are highly conserved in clinical strains from different lineages. Peptides derived from the structure of EsxG/EsxH have shown to induce higher titers of IgG class antibodies with a direct lysing effect against mycobacteria and to confer protection against tuberculosis in mice. This system has the potential to produce immunity in a systemic and a local way, then providing a broader spectrum of protection against strains which represent the variety of mycobacteria present in Latin America.
Project Outcomes
Most vaccine candidates developed against tuberculosis have the opportunity to work together to induce extended protection against this disease by combining them in prime and booster schemes. By the previous evidence of efficacy of the vaccine candidates BCGΔBCG1419c and H1-TT we hypothesized that the combination of them could produce extended protection against tuberculosis in mice. We performed studies of immunogenicity of this combination of vaccines and studies of its efficacy against M. tuberculosis H37Rv and the hypervirulent clinical strain M. tuberculosis 5186. The results of the project suggest that this combination is immunogenic and efficacious against different stages of tuberculosis in mice and revealing complex effects of combination of vaccines on the development of cellular and humoral responses against mycobacteria. Interestingly, we found deep differences in the protection afforded against the two different strains of Mycobacterium, while a protective effect was seen on H37Rv strain, this was not seen against the clinical strain 5186 which circulates in the south of Mexico, highlighting the importance of developing vaccines which could be efficacious against a broader spectrum of mycobacteria. On the other hand, these studies suggested a connection between immunogenicity, vaccine efficacy and metabolic modulation induced by vaccination, which could be new routes to be considered in the development of vaccines against tuberculosis. In addition, this study also validated cellular blood markers of progression of tuberculosis reported in humans as markers of protection in mice, increasing the opportunities for future developments to be monitored through these biomarkers in oriented to One-Health studies. This study raised new questions to be addressed in future studies: Which is the connection between immunogenicity, vaccine efficacy and metabolic modulation and how could we take advantage of it to develop better vaccines?, is intranasal route of vaccination the better to generate protection against a broader spectrum of mycobacteria?, which aspects of clinical strains are not seen in H37Rv and how it could to alter our perception of vaccine efficacy? There's no doubt our future studies should take action into these interesting questions.
Find out more about Dr Cristian Segura-Cerda here.
