Abstract
Tuberculosis (TB) is a global pandaemic, partially due to the failure of vaccination approaches. Novel anti-TB vaccines are therefore urgently required. Here we show that aerosol immunization of macaques with the Mtb mutant in SigH (MtbΔsigH) results in significant recruitment of inducible bronchus-associated lymphoid tissue (iBALT) as well as CD4+ and CD8+ T cells expressing activation and proliferation markers to the lungs. Further, the findings indicate that pulmonary vaccination with MtbΔsigH elicited strong central memory CD4+ and CD8+ T-cell responses in the lung. Vaccination with MtbΔsigH results in significant protection against a lethal TB challenge, as evidenced by an approximately three log reduction in bacterial burdens, significantly diminished clinical manifestations and granulomatous pathology and characterized by the presence of profound iBALT. This highly protective response is virtually absent in unvaccinated and BCG-vaccinated animals after challenge. These results suggest that future TB vaccine candidates can be developed on the basis of MtbΔsigH.
Highlights
Tuberculosis (TB) is a global pandaemic, partially due to the failure of vaccination approaches
We have previously established a correlation between the levels of ectopic lymphoid structures known as inducible bronchus-associated lymphoid tissue (iBALT) and the control of Mycobacterium tuberculosis (Mtb) infection in a latent state
Infected macaques had significantly greater levels of iBALT in their lungs during LTBI, and this response was markedly reduced during TB disease31. iBALT was characterized by the presence of CD20 þ B and CXCR5 þ T cells
Summary
Tuberculosis (TB) is a global pandaemic, partially due to the failure of vaccination approaches. Vaccination with MtbDsigH results in significant protection against a lethal TB challenge, as evidenced by an approximately three log reduction in bacterial burdens, significantly diminished clinical manifestations and granulomatous pathology and characterized by the presence of profound iBALT This highly protective response is virtually absent in unvaccinated and BCG-vaccinated animals after challenge. Developing new and efficacious TB vaccines is clearly the most effective intervention for containing the TB pandaemic[3,4,5] To this end, a number of novel candidates are currently being evaluated either as potential replacements for BCG or to boost BCG-generated responses using a variety of approaches[6]. A frontline candidate that attempted to boost existing BCG responses failed to protect a target population against TB in a high-burden setting[7] These results provide further impetus to the objective of replacing BCG with a new live attenuated vaccine. The Mtb mutant in sigE, which is part of the SigH regulon, elicited protection from Mtb infection[19]
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