A New Recombinant BCG Vaccine Induces Specific Th17 and Th1 Effector Cells with Higher Protective Efficacy against Tuberculosis

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.

Protection by novel vaccine candidates, Mycobacterium tuberculosis ΔmosR and ΔechA7, against challenge with a Mycobacterium tuberculosis Beijing strain

“…Not only is Ag85C antigenic, but it is important for monocyte uptake [32]. In fact, an rBCG strain overexpressing both antigens, HspX and Ag85C, has been studied, again improving the efficacy of BCG [33]. We have achieved similar results here without sacrificing the advantages of using an M. tuberculosis background, and plan to assess the specific role these antigens may play in priming the immune response in future studies.…”

Strategies to Improve BCG Vaccine Efficacy

“…Consistent with this idea, priming with rBCG-CMX followed by a booster vaccination with the same strain showed increased efficacy in reducing lung bacterial load in mice [18]. In another study, mice were first primed with BCG and then boosted with liposome-encapsulated α-crystalline 1 (Acr1L), a latency-associated BCG antigen, which enhanced protection against M. tuberculosis infection [19].…”

“…This cocktail of recombinant strains induced a robust Th1 immune response and an increased frequency of IFN-γ-producing CD4 + T-effector memory (T EM ) cells and IL-2-producing CD8 + T-central memory (T CM ) cells, and induced durable protection against M. tuberculosis infection in mice [17]. Yet another group of investigators developed a recombinant BCG vaccine expressing a fusion protein (CMX) composed of the immunodominant T-cell epitopes of Ag85C, MPT51 and HspX [18]. This vaccine strain induced both Th1 and Th17 polarization in mice and reduced the bacterial load and the severity of lung lesions upon M. tuberculosis challenge.…”

Modulation of Macrophage Responses by CMX, a Fusion Protein Composed of Ag85c, MPT51, and HspX from Mycobacterium tuberculosis

“…The rBCG strains were obtained via the electroporation of the BCG-Moreau strain with the pLA71/CMX expression plasmid as described previously (da Costa et al, 2014). …”