A review of the BCG vaccine and other approaches toward tuberculosis eradication

Figures & data

Table 1. Summary of current anti-TB vaccine candidates according to tuberculosis vaccine initiative

Vaccine	Components	Development Status	Studies
Novel anti-TB vaccine
Mycobacterium incidus pranii (MIP)	A nonpathogenic atypical mycobacterium	Phase III	Safe and induced prominent Th1 responses with heat-killed MIP in mice and guinea pigs^Citation45 Enhanced bacterial clearance and improved lung pathology in guinea pig model^Citation46 and advanced pulmonary TB patients^Citation46
Mycobacterium vaccae (M. vaccae)	Heat-killed M. vaccae, a nonpathogenic mycobacterial species	Phase III	Effectively control M. tb infection in animal models^Citation47,Citation48 Failed to provide protective benefits as a single-dose regimen in human trials^Citation49,Citation50 Well-tolerated and immunogenic in three-dose and five-dose regimen in healthy^Citation51 and HIV-infected human^Citation52,Citation53
RhMCV/TB	Recombinant rhesus macaques Cytomegalovirus vectors expressing M. tb antigens	Preclinical	Effective in TB prevention in rhesus macaque model^Citation54
ChadOx1/PPE15	Recombinant chimpanzee Adenoviral vector expressing M. tb antigens	Preclinical	Intranasal administration induced differentiation of lung parenchymal naïve CD4+ and CD8 + T cells to protective phenotype CXCR3+ KLRG1- in mice^Citation55
AEC/BC02	Fusion of Ag85B and ESAT-6/CFP-10 antigens in CpG/aluminum salt-based adjuvant	Phase I	Reduced bacterial load in guinea pig model^Citation56 Dose-dependent potency in stimulation of IFN-y response and effective in latent or active disease^Citation57
H1:IC31	Fusion of ESAT6 and Ag85B antigens in IC31 adjuvant system	Phase I	Safe and immunogenic in murine models^Citation58 Safe in human adults^Citation59,Citation60 and HIV-infected individuals^Citation61 Two low-dose regimens optimally induced polyfunctional CD4 + T cells in healthy adolescents^Citation62
M72/AS01E	Fusion of M. tb32A and M. tb39A antigens in AS01 adjuvant system	Phase II	Safe and immunogenic in BCG-vaccinated infants,^Citation63 healthy HIV-infected^Citation64 and M. tb-infected adults^Citation65 Render 54% protection against reactivation in TB-latent adults^Citation66
RUTI	Polyantigenic liposomal expressing mycobacterial latent antigens	Phase II	Reduce bacterial burden and macrophage infiltration in granulomas, promote strong IFN-y secretion in Th1 immune responses in murine models, and produce a balanced Th1/Th2 response in addition to M. tb antigen-specific IgG antibodies^Citation67–70 Safe and immunogenic in healthy adults^Citation71 Safe and immunogenic with a low dose vaccine in latent TB adults^Citation72
Recombinant BCG strain
BCG-Zmp1	Deletion of zmp1 gene in M. bovis BCG strain	Preclinical	More intense immune responses against M. tb compared to wild-type BCG in mice^Citation73 Safe and immunogenic in guinea pig model^Citation74
SapM:TnBCG	Deletion of SapM gene from parental M. bovis BCG strain	Preclinical	Robust Th1 immune response, decline in bacterial load, and improve long-term survival compared to parental BCG in mice^Citation75
CysVac2	Recombinant BCG expressing Ag85B-CysD fusion protein	Preclinical	Steady reduction in bacterial load in heterologous prime-boost with BCG-CysVac2^Citation76 Robust immunity prior to and after M. Tb exposure with induction of polyfunctional CD4 + T cells^Citation77 Profound Th1 response when CysVac2 formulated with Advax adjuvant^Citation78
VPM1002	Recombinant BCG replacing urease C gene with listeriolysin O	Phase III	Acceptable safety profile in animal models and SCID mice^Citation79,Citation80 Highly efficacious induction of Th1 responses and bacterial burden reduction compared to BCG-control^Citation80–83 Safe and efficacious in prevention of TB in newborns^Citation84
BCG Booster Vaccines
BCG revaccination	Wild-type M. bovis BCG strain	Phase II	Increase magnitude of a robust CD4 + T cells response with no significant affect to the response rate of CD4 + T cells in homologous BCG prime-boost regimen^Citation85 Confer 45.4% efficacy against M. tb infection in BCG-primed group^Citation86 No additional benefits upon homologous BCG prime boost in two large-scale randomized trials^Citation87,Citation88
Ad5Ag85A	Adenovirus type 5 expressing Ag85A antigen	Phase I	Superior efficacy of heterologous BCG-prime Ad5Ag85A-boost regimen among mice,^Citation89 cattle,^Citation89 and goat^Citation90 Greater degree of protection against TB seen in bovine model^Citation91 Administered intranasally, elicited significant T cells responses in the lung with better protection following pulmonary challenge^Citation92
Ad5-CEAB	Adenovirus type 5 expressing CFP10, ESAT6, Ag85A, and Ag85B antigen in a mixture rather a fusion protein	Unknown	Antigen-specific T cell responses were significantly amplified in heterologous prime-boost regimen^Citation93
Ad35-TBS (AERAS-402)	Adenovirus type 35 expressing Ag85A, Ag85B, and TB10.4 antigens	Unknown	Strong CD8+ and CD4 + T-cell response in a dose-dependent manner in murine model^Citation94 Heterologous prime-boost regimen greatly induces multifunctional CD4+ and CD8 + T cells^Citation95
GaM. tbVac	Fusion of Ag85A and ESAt6-CFp10 with dextran-binding domain fixated on dextran and mixed with a dextran core/CpG ODN adjuvant system	Phase I	Heterologous prime-boost regimen considerably enhanced antigen-specific responses and reduced bacterial burden compared to BCG alone and homologous GaM. tbVac-GaM. tbvac regimen^Citation96 Safe and efficacious as a heterologous prime-boost regimen in human adults^Citation97
H4:IC31 (AERAS-404)	Fusion of TB10.4 and Ag85B in IC31 adjuvant system	Unknown	Safe and protective against M. tb challenge in murine model^Citation98 Safe and optimal responses at low dose in human model^Citation99,Citation100
H56:IC31	Fusion of Ag85B, ESAT-6, and Rv2660c in IC31 adjuvant system	Phase II	Safe and effectively reduce bacterial burden in BCG-primed mice^Citation101 and nonhuman primates^Citation102,Citation103 Induce polyfunctional CD4 + T cell responses at low dose^Citation104 Induce robust immune responses with three doses of H56:IC31 in QFT-negative individuals whereas no additional benefits were seen from the third dose in QFT-positive individuals^Citation105
ID93/GLA-SE	Fusion of Rv1813, Rv2608, Rv3619, and Rv3620, combined with glucopyranosyl lipid adjuvant in oil-in-water stable emulsion	Phase I	Heterologous BCG-prime ID93/GLA-SE-boost regimen enhanced survival in guinea pig model^Citation106,Citation107 and against a virulent MTb strain in the mouse model^Citation108 Induced polyfunctional CD4 + T cells double expressing either cytokines CD154+ IFN-y+ or CD154+ TNF-a+ in mice^Citation109 and TB naïve human^Citation110 Tuberculin Skin Test is not compromised in ID93/GLA-SE vaccinated animals^Citation111
DAR-901	Inactivated M. tb SRL172 strain	Phase II	Safe and immunogenic with superior protection compared to BCG alone in BCG-DAR-901-vaccinated mice^Citation112 and human adults^Citation113,Citation114
MTBVAC	Live-attenuated M. tb with deletion of virulence factors, fadD26 and phoP	Phase II	Safe in SCID mice and guinea pigs^Citation115 No effect on growth and development in newborn mice^Citation116 Similar safety profile to BCG in adults and infants^Citation117 Reduce bacterial burden and enhance survival in mice,^Citation118 goats,^Citation119 and nonhuman primate^Citation120 Greater multifunctional CD4 + T cell responses with acceptable safety profile in humans^Citation121 BCG-prime M. TBVAC-boost regimen confers greater protection in guinea pigs compared to BCG alone^Citation122 Intranasal administration of heat-killed M. TBVAC induce profound humoral and cellular responses systemically and locally in BCG-prime animals^Citation123

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