Abstract
Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb) that is a major public health problem. The vaccine used for TB prevention is Mycobacterium bovis bacillus Calmette-Guérin (BCG), which provides variable efficacy in protecting against pulmonary TB among adults. Consequently, several groups have pursued the development of a new vaccine with a superior protective capacity to that of BCG. Here we constructed a new recombinant BCG (rBCG) vaccine expressing a fusion protein (CMX) composed of immune dominant epitopes from Ag85C, MPT51, and HspX and evaluated its immunogenicity and protection in a murine model of infection. The stability of the vaccine in vivo was maintained for up to 20 days post-vaccination. rBCG-CMX was efficiently phagocytized by peritoneal macrophages and induced nitric oxide (NO) production. Following mouse immunization, this vaccine induced a specific immune response in cells from lungs and spleen to the fusion protein and to each of the component recombinant proteins by themselves. Vaccinated mice presented higher amounts of Th1, Th17, and polyfunctional specific T cells. rBCG-CMX vaccination reduced the extension of lung lesions caused by challenge with Mtb as well as the lung bacterial load. In addition, when this vaccine was used in a prime-boost strategy together with rCMX, the lung bacterial load was lower than the result observed by BCG vaccination. This study describes the creation of a new promising vaccine for TB that we hope will be used in further studies to address its safety before proceeding to clinical trials.
Highlights
Tuberculosis (TB) is a public health problem causing 8.6 million new cases and 1.3 million deaths annually [1]
IFNc is crucial for the immune response to Mycobacterium tuberculosis (Mtb), studies have shown this cytokine is not a surrogate marker of the protection conferred by Bacillus Calmette-Guerin (BCG) [12,11]
Different strategies are being used by the groups modifying BCG, such as the expression of immunodominant Mtb antigens [15], the association of re-introduction and super-expression of antigens lost during the process of BCG attenuation [16], the development of recombinant BCG (rBCG) expressing cytokines and Mtb proteins [17], and the heterologous expression of proteins in rBCG to induce CD8+ T lymphocytes [18]
Summary
Tuberculosis (TB) is a public health problem causing 8.6 million new cases and 1.3 million deaths annually [1]. The causative agent of TB is Mycobacterium tuberculosis (Mtb), an intracellular pathogen that after infecting the host can either cause active disease or remain latent In this context, it is estimated that one third of the world population is latently infected with Mtb, of which approximately 10% will develop active disease [2,1]. IFNc is crucial for the immune response to Mtb, studies have shown this cytokine is not a surrogate marker of the protection conferred by BCG [12,11]. To address this matter, several groups have been working on the development of protein subunit vaccines, new adjuvants, attenuated/auxotrophic Mtb strains, and recombinant BCG (rBCG) vaccines, among other approaches [13,14]. Different strategies are being used by the groups modifying BCG, such as the expression of immunodominant Mtb antigens [15], the association of re-introduction and super-expression of antigens lost during the process of BCG attenuation [16], the development of rBCG expressing cytokines and Mtb proteins [17], and the heterologous expression of proteins in rBCG to induce CD8+ T lymphocytes [18]
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