Abstract
Bacille Calmette-Guerin (BCG), an attenuated whole cell vaccine based on Mycobacterium bovis, is the only licensed vaccine against Mycobacterium tuberculosis (Mtb), but its efficacy is suboptimal and it fails to protect against pulmonary tuberculosis. We previously reported that Mtb lacking the virulence genes lprG and rv1410c (ΔLprG) was highly attenuated in immune deficient mice. In this study, we show that attenuated ΔLprG Mtb protects C57BL/6J, Balb/cJ, and C3HeB/FeJ mice against Mtb challenge and is as attenuated as BCG in SCID mice. In C3HeB/FeJ mice, ΔLprG vaccination resulted in innate peripheral cytokine production and induced high polyclonal PPD-specific cytokine-secreting CD4+ T lymphocytes in peripheral blood. The ΔLprG vaccine afforded protective efficacy in the lungs of C3H/FeJ mice following both H37Rv and Erdman aerosolized Mtb challenges. Vaccine efficacy correlated with antigen-specific PD-1-negative CD4+ T lymphocytes as well as with serum IL-17 levels after vaccination. We hypothesize that induction of Th17 cells in lung is critical for vaccine protection, and we show a serum cytokine biomarker for IL-17 shortly after vaccination may predict protective efficacy.
Highlights
Bacille Calmette-Guerin (BCG) is currently the only approved TB vaccine for use in humans
Data in non-human primates (NHP) showing the protective efficacy of prior Mycobacterium tuberculosis (Mtb) infection on preventing subsequent acquisition of Mtb after reexposure [6] coupled with recent clinical safety data on the use of attenuated whole cell Mtb vaccines suggest that the continued development of attenuated Mtb as TB vaccines is warranted [7]
The ΔLprG vaccine protects against Mtb challenge in mice and has a comparable attenuation to BCG
Summary
BCG is currently the only approved TB vaccine for use in humans. While it protects against childhood TB meningitis, it provides only limited protection in adulthood [1]. Any novel vaccination regimen should demonstrate, at a minimum, equivalent protective efficacy as BCG and ideally would surpass the protective benefit provided by BCG vaccination. Data in non-human primates (NHP) showing the protective efficacy of prior Mtb infection on preventing subsequent acquisition of Mtb after reexposure [6] coupled with recent clinical safety data on the use of attenuated whole cell Mtb vaccines suggest that the continued development of attenuated Mtb as TB vaccines is warranted [7]
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