Recombinant BCG: innovations on an old vaccine. Scope of BCG strains and strategies to improve long-lasting memory

Abstract

Bacille Calmette–Guérin (BCG), an attenuated vaccine derived from Mycobacterium bovis, is the current vaccine of choice against tuberculosis (TB). Despite its protection against active TB in children, BCG has failed to protect adults against TB infection and active disease development, especially in developing countries where the disease is endemic. Currently, there is a significant effort toward the development of a new TB vaccine. This review article aims to address publications on recombinant BCG (rBCG) published in the last 5 years, to highlight the strategies used to develop rBCG, with a focus on the criteria used to improve immunological memory and protection compared with BCG. The literature review was done in April 2013, using the key words TB, rBCG vaccine, and memory. This review discusses the BCG strains and strategies currently used for the modification of BCG, including: overexpression of Mycobacterium tuberculosis (Mtb) immunodominant antigens already present in BCG; gene insertion of immunodominant antigens from Mtb absent in the BCG vaccine; combination of introduction and overexpression of genes that are lost during the attenuation process of BCG; BCG modifications for the induction of CD8+ T-cell immune responses and cytokines expressing rBCG. Among the vaccines discussed, VPM1002, also called rBCGΔureC:hly, is currently in human clinical trials. Much progress has been made in the effort to improve BCG, with some promising candidates, but considerable work is still required to address functional long-lasting memory.

Effect of a low dose of BCG-Phipps vaccine on the development of reactivity to tuberculin skin test in neonatal calves and adult cows

“…RD1 is a DNA segment comprising 9.5 kb, which was deleted in all other BCG strains, that encodes T-lymphocyte epitopes such as ESAT-6, CFP-10, Rv3873, and PPE protein among others (Okkels et al, 2003). RD2 is a 10.7 kb DNA segment that encodes many proteins including Mpt-64 and CFP-21 (Joung and Ryoo, 2013) and nRD18 is a 1.5 kb segment containing genes encoding SigI, an alternative RNA polymerase sigma factor that was only lost in the strains BCG Pasteur, Phipps, Frappier, Connaught and Tice (Da Costa et al, 2014).…”

Applications of bacillus Calmette–Guerin and recombinant bacillus Calmette–Guerin in vaccine development and tumor immunotherapy

“…The pore-forming activity of Hly enables L. monocytogenes to escape from the phagosomes of the host cells into the cytoplasm, which is essential for the MHC class I presentation of the L. monocytogenes antigens and the subsequent enhancement of CD8 + T cell stimulation [160]. Constructing rBCG strains that actively secrete Hly while their UreC activity is absent in order to keep the pH optimal for Hly activity allows the rBCG strains to effectively induce apoptosis in infected host cells, and the mycobacterial antigens in the apoptotic bodies can then be taken up by dendritic cells to induce CD8 + T cell response [143;160;162]. This is in contrast to the original BCG bacteria, which are weak apoptosis inducer, and thus only membrane-bound or secreted mycobacterial antigens are presented via the MHC II pathway to elicit CD4 + T cell response.…”

Current efforts and future prospects in the development of live mycobacteria as vaccines

“…As stated in the review by da Costa et al . (71), it is important to determine if the rBCG:AB can also enhance the establishment of functional long lasting memory.…”