Abstract
Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis (Mtb), kills 5,000 people per day globally. Rapid development and spread of various multi drug-resistant strains of Mtb emphasize that an effective vaccine is still the most cost-effectives and efficient way of controlling and eradicating TB. Bacillus Calmette-Guerin (BCG), the only licensed TB vaccine, still remains the most widely administered human vaccine, but is inefficient in protecting from pulmonary TB in adults. The protective immunity afforded by BCG is thought to wane with time and considered to last only through adolescent years. Heterologous boosting of BCG-primed immune responses using a subunit vaccine represents a promising vaccination approach to promote strong cellular responses against Mtb. In our earlier studies, we discovered lipopeptides of ESAT-6 antigen with strong potential as a subunit vaccine candidate. Here, we have investigated that potential as a booster to BCG vaccine in both a pre-exposure preventive vaccine and a post-exposure therapeutic vaccine setting. Surprisingly, our results demonstrated that boosting BCG with subunit vaccine shortly before Mtb challenge did not improve the BCG-primed immunity, whereas the subunit vaccine boost after Mtb challenge markedly improved the quantity and quality of effector T cell responses and significantly reduced Mtb load in lungs, liver and spleen in mice. These studies suggest that ESAT-6 lipopeptide-based subunit vaccine was ineffective in overcoming the apparent immunomodulation induced by BCG vaccine in Mtb uninfected mice, but upon infection, the subunit vaccine is effective in re-educating the protective immunity against Mtb infection. These important results have significant implications in the design and investigation of effective vaccine strategies and immunotherapeutic approaches for individuals who have been pre-immunized with BCG vaccine but still get infected with Mtb.
Highlights
Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis (Mtb), is the leading cause of death due to an infectious disease, claiming ∼2 million lives globally each year [1]
Besides examining the role of LP-Early secreted antigenic target 6 kDa protein (ESAT-6) boost to Bacillus Calmette-Guerin (BCG) vaccine in a conventional manner, we wanted to examine if LPESAT-6 boost will be useful for Mtb infection in the settings where one had been primed with BCG vaccine and yet became infected with Mtb
In schedule A, pre-exposure boost, mice were primed with BCG vaccine (s.c.), followed by LP-ESAT-6±monophosphoryl lipid A (MPL) boost at 14 days, and infection with Mtb subsequently on day 14 after the boost
Summary
Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis (Mtb), is the leading cause of death due to an infectious disease, claiming ∼2 million lives globally each year [1]. One third of the world’s population harbors Mtb in a latent state serving as a large reservoir. These individuals are potentially at risk of developing active disease again and further spreading it to the remaining population [2, 3]. Bacille Calmette-Guerin (BCG), which was developed nearly 100 years ago, is the only available vaccine to prevent TB. BCG remains the most widely administered vaccine around the world and is effective in providing 60–80% protection against childhood and extra-pulmonary forms of TB [4,5,6,7]. BCG affords highly inconsistent and inadequate protection against pulmonary TB and is ineffective when given in adulthood. Improving, boosting or supplementing BCG in different clinical settings appears to be a more logical path for new vaccine/immunotherapy approaches for TB
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