BCG as a Vector for Novel Recombinant Vaccines against Infectious Diseases and Cancers

Bacillus Calmette-Guérin (BCG) has been widely used globally as a prophylactic vaccine to protect against tuberculosis (TB) for about a century [...].

and boosted with MVA-Gag than in those receiving the MVA-Gag boost alone [12]. rBCG expressing the HIVACAT T-cell immunogen (HTI), when delivered in combination with chimpanzee adenovirus (ChAd)Ox1.HTI in mice, induced HIV-1-specific T-cell responses [15]. Furthermore, priming with rBCG doubled the magnitude of the T-cell response in comparison with ChAdOx1.HTI alone while maintaining its breadth [15].
Several recently published reports have suggested the protective effect of BCG vaccine against the development of corona virus disease (COVID)-19 and death [16][17][18]. However, other reports do not support this suggestion [19,20]. It is quite unlikely that BCG by itself can provide substantial protection against SARS-CoV-2 infection solely due to its activation of innate immunity. However, rBCG strains expressing spike protein of SARS-CoV-2 may provide a high degree of protection against COVID-19 due to the activation of both innate and virus-specific adaptive immune responses [21]. The high level of safety records of BCG in healthy humans, its potent adjuvant activity, non-requirement of a cold chain and low cost for manufacturing the vaccine makes rBCG an interesting candidate for protection against COVID-19 [21].
Mice immunized with a rBCG expressing gp63 antigen of Leishmania were protected against challenges with Leishmania promastigotes [22] and Leishmania major [23]. Similarly, immunization of mice with a rBCG strain expressing four antigens of Trypanosoma cruzi resulted into the induction of parasite antigen-specific T helper (Th1) and Th17 cytokine responses and provided significant protection against challenge with the parasites with a low degree of cardiac lesions 120 days after infection [24].
A host of cancers have been targeted for immunotherapy using rBCG [25]. VPM1002BC is a live rBCG prepared by insertion of listerolysin gene from Listeria monocytogenes into the urease c gene of BCG. The intravesical application of VPM1002BC in patients with non-muscle invasive bladder cancer was found safe and well tolerated by patients and resulted in the induction of Th1-type immune response [26].
A rBCG strain expressing the detoxified S1 pertussis toxin (rBCG-S1PT) proved more effective than wildtype BCG (WT-BCG) in increasing survival time in an experimental mouse model of bladder cancer. Furthermore, human peripheral blood leukocytes stimulated with rBCG-S1PT produced increased levels of IL-6, IL-8, and IL-10; enhanced the expression of CD25 and CD69 on human CD4 + T cells; and induced higher cytotoxicity to MB49 bladder cancer cells than WT-BCG [27].
Two rBCG strains expressing Streptococcal inhibitor of complement (Sic) [rBCG-Sic], and d-alanyl carrier protein ligase (dltA) [rBCG-Sic] were tested in a growth inhibition assay using two bladder cancer cell lines (5637, T24). The growth inhibitory effects of rBCGs on bladder cancer cells were significantly enhanced as compared to WT-BCG. After 8 h of infection, the levels of internalization were higher in rBCG-infected bladder cancer cells than in BCG-infected cells, and cells infected with rBCGs showed increased release of antitumor cytokines, such as IL-6/12, TNF-α, and INF-γ, resulting in inhibition of bacterial killing and immune modulation via antimicrobial peptides [28].
The immunization of mice with a rBCG strain, expressing human granulocyte macrophage colony stimulating factor (hGM-CSF) gene and the Epstein-Barr virus gene BZLF1, induced antigen-specific antibodies. The specific cytotoxic effects of the spleen cells from the rBCG group on Epstein-Barr virus-positive tumor cells were significantly higher than the cytotoxic effects of the control group cells. Morphological observations of the tumor sections from the rBCG-immunized mice showed the infiltration of CD4 + T and CD8 + T lymphocytes into the tumor tissues. The average tumor volume in the rBCG group was less than the average tumor volume in the control group [29].
rBCG strains expressing single mycobacterial protein antigens have shown efficacy in enhancing cytotoxicity on superficial bladder cancers in vitro and orthotopic murine bladder models [29]. Furthermore, rBCG strains expressing multiple mycobacterial antigens induced predominantly Th1-type immune responses, inhibited tumor growth, and prolonged the survival of mice with bladder tumor [29]. Several rBCG strains have been constructed that secrete cytokines with anti-tumor activity, e.g., IL-2, Il-12 IL-18 and IFN-α. IL-2-based rBCG strains have shown that, relative to BCG alone, IL-2 secreting rBCG strains can improve antigen-specific proliferation, induce a more favorable IFN-γ:IL-4 ratio, elicit higher levels of Th1 cytokines, and enhance antitumor cytotoxicity [30]. The IL-18-secreting rBCG strain induced increased secretion of IFN-γ and GM-CSF, decreased production of IL-10, increased cellular proliferation, induced higher production of IFN-γ-secreting cells in mouse splenocytes and enhanced BCG-induced macrophage cytotoxicity against murine bladder tumor cells in a dose-dependent manner [31]. IFN-α-secreting rBCG strains were more effective than WT-BCG in inducing IFN-γ production from peripheral blood mononuclear cells (PBMC) and inducing PBMC cytotoxicity against bladder cancer cell lines in vitro [32].

Conflicts of Interest:
The author declares no conflict of interest.