Novel recombinant BCG expressing perfringolysin O and the over-expression of key immunodominant antigens; pre-clinical characterization, safety and protection against challenge with Mycobacterium tuberculosis

Exploiting the mycobacterial cell wall to design improved vaccines against tuberculosis

“…Now that its safety has been proven (www.clinicaltrials.gov, ID# NCT01113281 and NCT00749034), VPM1002 is currently undergoing phase IIa trials to assess its immunogenicity and safety in the target population [24]. Lastly, the AERAS-422 vaccine, which basically combines concepts underlying VPM1002 and rBCG30 [25], was shown to induce effective protection in preclinical animal models; however, though the phase I clinical trial was stopped because of an adverse effect observed in two participants (www.clinicaltrials.gov ID# NCT01340820). [36] MΦ apoptosis [37] Expression in saprophytic mycobacteria [40] Deletion in BCG [41] Deletion in H37Rv [42] HBHA Bacterial agglutination [45; 46] Dissemination from the primary site of infection [45] Protection in the mouse model of TB [55] Diagnostic marker in QFT-test [59] ESX secretion systems ESX-1: Secretion of ESAT-6 and CFP-10 which are employed in IGRAs to diagnose TB infection [71] Encoded by the RD1 region which loss is the main molecular mechanism of attenuation of BCG [69] …”

Prime-Boost Vaccination with rBCG/rAd35 Enhances CD8+ Cytolytic T-Cell Responses in Lesions from Mycobacterium Tuberculosis-Infected Primates

“…Of note, unlike rodent models of TB, outbreed NHPs develop a human-like TB disease and thus provide a more relevant model to study TB-induced immune responses compared with other experimental animals. A heterologous prime-boost approach was used (9), on the basis of a recombinant BCG (rBCG) expressing the Mtb antigens Ag85A, Ag85B and TB10.4 (10). The novel prototype strain rBCG AFRO-1 also has an insertion of a perfringolysin gene (pfoA) encoding a mutated pore-forming bacterial cytolysin, which permits leakage of antigens from the phagosome to the cytosolic MHC class I pathway (11).…”

“…Thus, rBCG may induce a broader and more potent CTL response than parent BCG, which cannot translocate from the phagosomes to access the cytosol (12). Accordingly, it was recently shown that rBCG AFRO-1 enhanced immune responses and prolonged survival compared with parent BCG upon Mtb challenge in mice and guinea pigs (10).…”

Comparison of BCG prime-DNA booster and rBCG regimens for protection against tuberculosis

“…35,36 Meanwhile, DNA vaccine pE6/85B which consisted of ESAT-6 and Ag85B fusion gene with tpa signal sequence could provide the protection against M. tuberculosis infection in vaccinated mice and be used as an effective booster after BCG immunization, 16 which provided further evidence to support our conclusion. Moreover, there are some rBCG strains, such as rBCG30, 23 rBCG::AB, 24 rBCG::X, 37 rBCG::85B-Rv3425, 38 rBCG UreC: Hly, 28 and AERAS-rBCG, 39 etc, providing stronger and/or longer-lasting protective efficacy than BCG in animal models or in humans. All of these studies indicate that developing more recombinant BCG vaccine candidates mainly depend on the choice of suitable antigens.…”