key: cord-0707063-69ba1xup authors: Mustafa, Abu Salim title: BCG as a Vector for Novel Recombinant Vaccines against Infectious Diseases and Cancers date: 2020-12-04 journal: Vaccines (Basel) DOI: 10.3390/vaccines8040736 sha: 902fc383608a6607231af2d21733fd7faf79e13e doc_id: 707063 cord_uid: 69ba1xup 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] . Funding: This research was funded by Kuwait University, Research Sector grant nos. MI02/12, SRUL02/13 and GM01/15. The author declares no conflict of interest. BCG pros and cons and new/improved vaccines for tuberculosis Variable virulence and efficacy of BCG vaccine strains in mice and correlation with genome polymorphisms Report on BCG vaccine use for protection against mycobacterial infections including tuberculosis, leprosy, and other nontuberculous mycobacteria (NTM) infections BCG: A vaccine with multiple faces Proteomic analysis of antigen 60 complex of M. bovis Bacillus Calmette-Guérin reveals presence of extracellular vesicle proteins and predicted functional interactions Cellular immune responses to recombinant Mycobacterium bovis BCG constructs expressing major antigens of region of difference 1 of Mycobacterium tuberculosis Multi-subunit BCG booster vaccine GamTBvac: Assessment of immunogenicity and protective efficacy in murine and guinea pig TB models Recombinant bacille Calmette-Guerin coexpressing Ag85b, CFP10, and interleukin-12 elicits effective protection against Mycobacterium tuberculosis First-in-human trials of GamTBvac, a recombinant subunit tuberculosis vaccine candidate: Safety and immunogenicity assessment An overview of the development of new vaccines for tuberculosis Advances and challenges in recombinant Mycobacterium bovis BCG-based HIV vaccine development: Lessons learned The use of directed evolution to create a stable and immunogenic recombinant BCG expressing a modified HIV-1 Gag antigen Development of a live recombinant BCG expressing human immunodeficiency virus type 1 (HIV-1) Gag using a pMyong2 vector system: Potential use as a novel HIV-1 vaccine Priming with recombinant BCG expressing novel HIV-1 conserved mosaic immunogens and boosting with recombinant ChAdOx1 is safe, stable, and elicits HIV-1-specific T-cell responses in BALB/c mice Recombinant BCG expressing HTI prime and recombinant ChAdOx1 boost is safe and elicits HIV-1-specific T-cell responses in BALB/c mice Can BCG vaccine protect against COVID-19 via trained immunity and tolerogenesis? Bioessays 2020, e2000200 Is BCG associated with reduced incidence of COVID-19? A meta-regression of global data from 160 countries Association between live childhood vaccines and COVID-19 outcomes: A national-level analysis The influence of vaccination against tuberculosis with the Bacillus-Calmette-Guérin(BCG) vaccine on COVID-19 incidence and mortality-Review of the literature Protection against SARS-CoV-2 by BCG vaccination is not supported by epidemiological analyses New disease old vaccine: Is recombinant BCG vaccine an answer for COVID-19? Effective immunization against cutaneous leishmaniasis with recombinant bacille Calmette-Guérin expressing the Leishmania surface proteinase gp63 Recombinant BCG expressing the Leishmania surface antigen Gp63 induces protective immunity against Leishmania major infection in BALB/c mice Recombinant Mycobacterium bovis BCG is a promising platform to develop vaccines against Trypansoma cruzi infection Applications of bacillus Calmette-Guerin and recombinant bacillus Calmette-Guerin in vaccine development and tumor immunotherapy Results of the phase I open label clinical trial SAKK 06/14 assessing safety of intravesical instillation of VPM1002BC, a recombinant mycobacterium Bacillus Calmette Guérin (BCG), in patients with non-muscle invasive bladder cancer and previous failure of conventional BCG therapy In vitro evidence of human immune responsiveness shows the improved potential of a recombinant BCG strain for bladder cancer treatment The immunotherapeutic effects of recombinant Bacillus Calmette-Guérin resistant to antimicrobial peptides on bladder cancer cells Novel immunotherapeutic approaches to the treatment of urothelial carcinoma. Ther Manipulation of immune responses to Mycobacterium bovis by vaccination with IL-2-and IL-18-secreting recombinant bacillus Calmette Guerin Recombinant Mycobacterium bovis bacillus Calmette-Guérin (BCG) expressing mouse IL-18 augments Th1 immunity and macrophage cytotoxicity Antitumor effects of human interferon-alpha 2b secreted by recombinant bacillus Calmette-Guérin vaccine on bladder cancer cells