Vaccines to control tuberculosis in cattle.

The age-old cattle disease has resisted rigorous control, but the BCG vaccine may do better.

Rapamycin improves the long-term T-cell memory and protective efficacy of tuberculosis subunit vaccine.

The formation of long-lived T-cell memory is a critical goal of vaccines against intracellular pathogens like Mycobacterium tuberculosis (M. tuberculosis). In this study, to access the adjuvant effect of rapamycin on tuberculosis subunit vaccine, we treated mice with rapamycin during the course of vaccination and then monitored the vaccine-specific long-term memory T cell recall responses and protective ability against mycobacterial organisms. Compared with the mice that received vaccine alone, rapamycin treatment enhanced the vaccine induced long-term IFN-γ and IL-2 recall responses, promoted the development of TCM (central memory) like cells and improved the long-term proliferative ability of lymphocytes. Long-duration (total 53 days) of low-dose rapamycin (75 µg/kg/day) treatment generated stronger vaccine-specific memory T cell responses than short-duration treatment (total 25 days). Moreover, rapamycin improved the vaccine's long-term protective efficacy, which resulted in a better reduction of 0.89-log10 CFU of mycobacterial organisms in the lungs compared with control without rapamycin treatment. These findings suggest that rapamycin may be considered in designing TB subunit vaccine regimens or as potential adjuvant to enhance vaccine-induced T cell memory response and to prolong the longevity of vaccine's protective efficacy.

An Aspiration to Radically Shorten Phase 3 Tuberculosis Vaccine Trials.

A new tuberculosis vaccine is a high priority. However, the classical development pathway is a major deterrent. Most tuberculosis cases arise within 2 years after Mycobacterium tuberculosis exposure, suggesting a 3-year trial period should be possible if sample size is large to maximize the number of early exposures. Increased sample size could be facilitated by working alongside optimized routine services for case ascertainment, with strategies for enhanced case detection and safety monitoring. Shortening enrolment could be achieved by simplifying screening criteria and procedures and strengthening site capacity. Together, these measures could enable radically shortened phase 3 tuberculosis vaccine trials.

Safety and immunogenicity of a thermostable ID93 + GLA-SE tuberculosis vaccine candidate in healthy adults.

Adjuvant-containing subunit vaccines represent a promising approach for protection against tuberculosis (TB), but current candidates require refrigerated storage. Here we present results from a randomized, double-blinded Phase 1 clinical trial (NCT03722472) evaluating the safety, tolerability, and immunogenicity of a thermostable lyophilized single-vial presentation of the ID93 + GLA-SE vaccine candidate compared to the non-thermostable two-vial vaccine presentation in healthy adults. Participants were monitored for primary, secondary, and exploratory endpoints following intramuscular administration of two vaccine doses 56 days apart. Primary endpoints included local and systemic reactogenicity and adverse events. Secondary endpoints included antigen-specific antibody (IgG) and cellular immune responses (cytokine-producing peripheral blood mononuclear cells and T cells). Both vaccine presentations are safe and well tolerated and elicit robust antigen-specific serum antibody and Th1-type cellular immune responses. Compared to the non-thermostable presentation, the thermostable vaccine formulation generates greater serum antibody responses (p < 0.05) and more antibody-secreting cells (p < 0.05). In this work, we show the thermostable ID93 + GLA-SE vaccine candidate is safe and immunogenic in healthy adults.

Cost-effectiveness of routine adolescent vaccination with an M72/AS01E-like tuberculosis vaccine in South Africa and India.

The M72/AS01E tuberculosis vaccine showed 50% (95%CI: 2-74%) efficacy in a phase 2B trial in preventing active pulmonary tuberculosis disease, but potential cost-effectiveness of adolescent immunisation is unknown. We estimated the impact and cost-effectiveness of six scenarios of routine adolescent M72/AS01E-like vaccination in South Africa and India. All scenarios suggested an M72/AS01E-like vaccine would be highly (94-100%) cost-effective in South Africa compared to a cost-effectiveness threshold of $2480/disability-adjusted life-year (DALY) averted. For India, a prevention of disease vaccine, effective irrespective of recipient's M. tuberculosis infection status at time of administration, was also highly likely (92-100%) cost-effective at a threshold of $264/DALY averted; however, a prevention of disease vaccine, effective only if the recipient was already infected, had 0-6% probability of cost-effectiveness. In both settings, vaccinating 50% of 18 year-olds was similarly cost-effective to vaccinating 80% of 15 year-olds, and more cost-effective than vaccinating 80% of 10 year-olds. Vaccine trials should include adolescents to ensure vaccines can be delivered to this efficient-to-target population.

Aerosol delivery, but not intramuscular injection, of adenovirus-vectored tuberculosis vaccine induces respiratory-mucosal immunity in humans.

BackgroundAdenovirus-vectored (Ad-vectored) vaccines are typically administered via i.m. injection to humans and are incapable of inducing respiratory mucosal immunity. However, aerosol delivery of Ad-vectored vaccines remains poorly characterized, and its ability to induce mucosal immunity in humans is unknown. This phase Ib trial evaluated the safety and immunogenicity of human serotype-5 Ad-vectored tuberculosis (TB) vaccine (AdHu5Ag85A) delivered to humans via inhaled aerosol or i.m. injection.MethodsThirty-one healthy, previously BCG-vaccinated adults were enrolled. AdHu5Ag85A was administered by single-dose aerosol using Aeroneb Solo Nebulizer or by i.m. injection. The study consisted of the low-dose (LD) aerosol, high-dose (HD) aerosol, and i.m. groups. The adverse events were assessed at various times after vaccination. Immunogenicity data were collected from the peripheral blood and bronchoalveolar lavage samples at baseline, as well as at select time points after vaccination.ResultsThe nebulized aerosol droplets were < 5.39 µm in size. Both LD and HD of AdHu5Ag85A administered by aerosol inhalation and i.m. injection were safe and well tolerated. Both aerosol doses, particularly LD, but not i.m., vaccination markedly induced airway tissue-resident memory CD4+ and CD8+ T cells of polyfunctionality. While as expected, i.m. vaccination induced Ag85A-specific T cell responses in the blood, the LD aerosol vaccination also elicited such T cells in the blood. Furthermore, the LD aerosol vaccination induced persisting transcriptional changes in alveolar macrophages.ConclusionInhaled aerosol delivery of Ad-vectored vaccine is a safe and superior way to elicit respiratory mucosal immunity. This study warrants further development of aerosol vaccine strategies against respiratory pathogens, including TB and COVID-19.Trial registrationClinicalTrial.gov, NCT02337270.FundingThe Canadian Institutes for Health Research (CIHR) and the Natural Sciences and Engineering Research Council of Canada funded this work.

Mucosal Vaccination with Cyclic Dinucleotide Adjuvants Induces Effective T Cell Homing and IL-17-Dependent Protection against Mycobacterium tuberculosis Infection.

Tuberculosis consistently causes more deaths worldwide annually than any other single pathogen, making new effective vaccines an urgent priority for global public health. Among potential adjuvants, STING-activating cyclic dinucleotides (CDNs) uniquely stimulate a cytosolic sensing pathway activated only by pathogens. Recently, we demonstrated that a CDN-adjuvanted protein subunit vaccine robustly protects against tuberculosis infection in mice. In this study, we delineate the mechanistic basis underlying the efficacy of CDN vaccines for tuberculosis. CDN vaccines elicit CD4 T cells that home to lung parenchyma and penetrate into macrophage lesions in the lung. Although CDNs, like other mucosal vaccines, generate B cell-containing lymphoid structures in the lungs, protection is independent of B cells. Mucosal vaccination with a CDN vaccine induces Th1, Th17, and Th1-Th17 cells, and protection is dependent upon both IL-17 and IFN-γ. Single-cell RNA sequencing experiments reveal that vaccination enhances a metabolic state in Th17 cells reflective of activated effector function and implicate expression of Tnfsf8 (CD153) in vaccine-induced protection. Finally, we demonstrate that simply eliciting Th17 cells via mucosal vaccination with any adjuvant is not sufficient for protection. A vaccine adjuvanted with deacylated monophosphoryl lipid A (MPLA) failed to protect against tuberculosis infection when delivered mucosally, despite eliciting Th17 cells, highlighting the unique promise of CDNs as adjuvants for tuberculosis vaccines.

BCG-mediated protection against M. tuberculosis is sustained post-malaria infection independent of parasite virulence.

Tuberculosis (TB) and malaria remain serious threats to global health. Bacillus Calmette-Guerin (BCG), the only licensed vaccine against TB protects against severe disseminated forms of TB in infants but shows poor efficacy against pulmonary TB in adults. Co-infections have been reported as one of the factors implicated in vaccine inefficacy. Given the geographical overlap of malaria and TB in areas where BCG vaccination is routinely administered, we hypothesized that virulence-dependent co-infection with Plasmodium species could alter the BCG-specific immune responses thus resulting in failure to protect against Mycobacterium tuberculosis. We compared virulent Plasmodium berghei and non-virulent Plasmodium chabaudi, their effects on B cells, effector and memory T cells, and the outcome on BCG-induced efficacy against M. tuberculosis infection. We demonstrate that malaria co-infection modulates both B- and T-cell immune responses but does not significantly alter the ability of the BCG vaccine to inhibit the growth of M. tuberculosis irrespective of parasite virulence. This malaria-driven immune regulation may have serious consequences in the early clinical trials of novel vaccines, which rely on vaccine-specific T-cell responses to screen novel vaccines for progression to the more costly vaccine efficacy trials.

Designing of a Chimeric Vaccine Using EIS (Rv2416c) Protein Against Mycobacterium tuberculosis H37Rv: an Immunoinformatics Approach.

Mycobacterium tuberculosis (Mtb) is a respiratory pathogen that causes tuberculosis (TB). There are a large number of proteins that are involved in the pathogenesis of TB. Stimulating the immune response against TB is very important to clear the pathogens from host. In the present study, an immunoinformatics conduit is used for designing an epitope based chimeric vaccine against TB. Enhanced intracellular survival (EIS) protein from Mtb is used for designing the chimeric vaccine. One B cell epitope, 8 cytotoxic T lymphocyte (CTL), and 6 helper T lymphocyte (HTL) epitopes were predicted based on the MHC allele binding, immunogenicity, antigenicity, allergenicity, toxicity and IFN epitopes. The selected epitopes were used for chimeric vaccine designing. Furthermore, 3D structure elucidation, structural refinement and validation of the designed chimeric vaccine were carried out. The 3D structure was used for protein-protein docking studies with Toll-like receptor 4 (TLR-4), followed by molecular dynamic simulation (MDS) and the interaction between the chimeric vaccine and TLR-4 complex was verified.

A Phase I/II randomized trial of H56:IC31 vaccination and adjunctive cyclooxygenase-2-inhibitor treatment in tuberculosis patients.

Host-directed-therapy strategies are warranted to fight tuberculosis. Here we assess the safety and immunogenicity of adjunctive vaccination with the H56:IC31 candidate and cyclooxygenase-2-inhibitor treatment (etoricoxib) in pulmonary and extra-pulmonary tuberculosis patients in a randomized open-label phase I/II clinical trial (TBCOX2, NCT02503839). A total of 222 patients were screened, 51 enrolled and randomized; 13 in the etoricoxib-group, 14 in the H56:IC31-group, 12 in the etoricoxib+H56:IC31-group and 12 controls. Three Serious Adverse Events were reported in the etoricoxib-groups; two urticarial rash and one possible disease progression, no Serious Adverse Events were vaccine related. H56:IC31 induces robust expansion of antigen-specific T-cells analyzed by fluorospot and flow cytometry, and higher proportion of seroconversions. Etoricoxib reduced H56:IC31-induced T-cell responses. Here, we show the first clinical data that H56:IC31 vaccination is safe and immunogenic in tuberculosis patients, supporting further studies of H56:IC31 as a host-directed-therapy strategy. Although etoricoxib appears safe, our data do not support therapy with adjunctive cyclooxygenase-2-inhibitors.

Advancing Adjuvants for Mycobacterium tuberculosis Therapeutics.

Tuberculosis (TB) remains one of the leading causes of death worldwide due to a single infectious disease agent. BCG, the only licensed vaccine against TB, offers limited protection against pulmonary disease in children and adults. TB vaccine research has recently been reinvigorated by new data suggesting alternative administration of BCG induces protection and a subunit/adjuvant vaccine that provides close to 50% protection. These results demonstrate the need for generating adjuvants in order to develop the next generation of TB vaccines. However, development of TB-targeted adjuvants is lacking. To help meet this need, NIAID convened a workshop in 2020 titled "Advancing Vaccine Adjuvants for Mycobacterium tuberculosis Therapeutics". In this review, we present the four areas identified in the workshop as necessary for advancing TB adjuvants: 1) correlates of protective immunity, 2) targeting specific immune cells, 3) immune evasion mechanisms, and 4) animal models. We will discuss each of these four areas in detail and summarize what is known and what we can advance on in order to help develop more efficacious TB vaccines.

An integrated computational framework to design a multi-epitopes vaccine against Mycobacterium tuberculosis.

Tuberculosis (TB) is a highly contagious disease that mostly affects the lungs and is caused by a bacterial pathogen, Mycobacterium tuberculosis. The associated mortality rate of TB is much higher compared to any other disease and the situation is more worrisome by the rapid emergence of drug resistant strains. Bacillus Calmette-Guerin (BCG) is the only licensed attenuated vaccine available for use in humans however, many countries have stopped its use as it fails to confer protective immunity. Therefore, urgent efforts are required to identify new and safe vaccine candidates that are not only provide high immune protection but also have broad spectrum applicability. Considering this, herein, I performed an extensive computational vaccine analysis to investigate 200 complete sequenced genomes of M. tuberculosis to identify core vaccine candidates that harbor safe, antigenic, non-toxic, and non-allergic epitopes. To overcome literature reported limitations of epitope-based vaccines, I carried out additional analysis by designing a multi-epitopes vaccine to achieve maximum protective immunity as well as to make experimental follow up studies easy by selecting a vaccine that can be easily analyzed because of its favorable physiochemical profile. Based on these analyses, I identified two potential vaccine proteins that fulfill all required vaccine properties. These two vaccine proteins are diacylglycerol acyltransferase and ESAT-6-like protein. Epitopes: DSGGYNANS from diacylglycerol acyltransferase and AGVQYSRAD, ADEEQQQAL, and VSRADEEQQ from ESAT-6-like protein were found to cover all necessary parameters and thus used in a multi-epitope vaccine construct. The designed vaccine is depicting a high binding affinity for different immune receptors and shows stable dynamics and rigorous van der Waals and electrostatic binding energies. The vaccine also simulates profound primary, secondary, tertiary immunoglobulin production as well as high interleukins and interferons count. In summary, the designed vaccine is ideal to be evaluated experimentally to decipher its real biological efficacy in controlling drug resistant infections of M. tuberculosis.

An Escherichia coli carrier vaccine with surface-displayed protein MAP3061c elicits protective immunity against Mycobacterium paratuberculosis in mice.

Johne's disease, or paratuberculosis, is a chronic granulomatous enteritis of ruminants caused by Mycobacterium avium subsp. paratuberculosis (MAP). This disease occurs worldwide and results in considerable economic losses in the livestock industry. There are no effective treatments for Johne's disease, so there is an urgent need to develop an efficient, economical, and stable vaccine for MAP control. Here, a live Escherichia coli (E. coli) surface display vaccine harboring the MAP3061c gene was developed through an ice nucleation protein (INP) surface display system. The experimental data demonstrated that MAP3061c has strong immunogenicity and that the surface displayed vaccine can stimulate mice to produce high levels of antibodies. Both CD4+ and CD8+ T cell counts as well as several cytokines - including IFN-γ, IL-4, IL-10, IL-17A and IL-23 - were significantly increased in the display vaccine group. Post-vaccination challenge with MAP in mice resulted in improved fitness of the mice as demonstrated by a lack of weight loss. Pathological results revealed that the surface display vaccine could reduce the degree of pathological damage and slowed the course of disease. Taken together, our data suggests that the E. coli carrier vaccine with surface-displayed MAP3061c elicits protective immunity against MAP, providing new insights into the development of a MAP vaccine.

A Mycobacterium tuberculosis-specific subunit vaccine that provides synergistic immunity upon co-administration with Bacillus Calmette-Guérin.

Given the encouraging clinical results of both candidate subunit vaccines and revaccination with Bacillus Calmette-Guérin (BCG) against tuberculosis (TB), there is support for combining BCG and subunit vaccination for increased efficacy. BCG and Mycobacterium tuberculosis (Mtb) share ~98% of their genome and current subunit vaccines are almost exclusively designed as BCG boosters. The goal of this study is to design a TB subunit vaccine composed of antigens not shared with BCG and explore the advantages of this design in a BCG + subunit co-administration vaccine strategy. Eight protective antigens are selected to create an Mtb-specific subunit vaccine, named H107. Whereas traditional vaccines containing BCG-shared antigens exhibit in vivo cross-reactivity to BCG, H107 shows no cross-reactivity and does not inhibit BCG colonization. Instead, co-administering H107 with BCG leads to increased adaptive responses against both H107 and BCG. Importantly, rather than expanding BCG-primed T cells, H107 broadens the overall vaccine repertoire with new T cell clones and introduces 'adjuvant-imprinted' qualities including Th17 responses and less-differentiated Th1 cells. Collectively, these features of H107 are associated with a substantial increase in long-term protection.

Edoardo Maragliano (1849-1940) and the immunogenicity of the tubercle bacillus: the pathway of a great italian physician.

Edoardo Maragliano (1849-1940) was an Italian physician; he played a central role in medicine's "renaissance" in Italy and Europe. After beginning his academic career as a professor of pathology, he became full professor of internal medicine in 1881. While he studied all fields of internal medicine, his research focused mainly on tuberculosis. Thanks to his experiments in the medical clinic, Maragliano announced the possibility of immunization against Mycobacterium tuberculosis. Although criticized for using an inactivated vaccine, Maragliano continued to advocate vaccination with any type of vaccine. Maragliano keenly contributed to the still ongoing process of understanding the difficult interaction between Mycobacterium tuberculosis and the infected host.

A recombinant bovine adenoviral mucosal vaccine expressing mycobacterial antigen-85B generates robust protection against tuberculosis in mice.

Although the BCG vaccine offers partial protection, tuberculosis remains a leading cause of infectious disease death, killing ∼1.5 million people annually. We developed mucosal vaccines expressing the autophagy-inducing peptide C5 and mycobacterial Ag85B-p25 epitope using replication-defective human adenovirus (HAdv85C5) and bovine adenovirus (BAdv85C5) vectors. BAdv85C5-infected dendritic cells (DCs) expressed a robust transcriptome of genes regulating antigen processing compared to HAdv85C5-infected DCs. BAdv85C5-infected DCs showed enhanced galectin-3/8 and autophagy-dependent in vitro Ag85B-p25 epitope presentation to CD4 T cells. BCG-vaccinated mice were intranasally boosted using HAdv85C5 or BAdv85C5 followed by infection using aerosolized Mycobacterium tuberculosis (Mtb). BAdv85C5 protected mice against tuberculosis both as a booster after BCG vaccine (>1.4-log10 reduction in Mtb lung burden) and as a single intranasal dose (>0.5-log10 reduction). Protection was associated with robust CD4 and CD8 effector (TEM), central memory (TCM), and CD103+/CD69+ lung-resident memory (TRM) T cell expansion, revealing BAdv85C5 as a promising mucosal vaccine for tuberculosis.

An immunoinformatics approach to design a multi-epitope vaccine against Mycobacterium tuberculosis exploiting secreted exosome proteins.

Tuberculosis is one the oldest known affliction of mankind caused by the pathogen Mycobacterium tuberculosis. Till date, there is no absolute single treatment available to deal with the pathogen, which has acquired a great potential to develop drug resistance rapidly. BCG is the only anti-tuberculosis vaccine available till date which displays limited global efficacy due to genetic variation and concurrent pathogen infections. Extracellular vesicles or exosomes vesicle (EVs) lie at the frontier cellular talk between pathogen and the host, and therefore play a significant role in establishing pathogenesis. In the present study, an in-silico approach has been adopted to construct a multi-epitope vaccine from selected immunogenic EVs proteins to elicit a cellular as well as a humoral immune response. Our designed vaccine has wide population coverage and can effectively compensate for the genetic variation among different populations. For maximum efficacy and minimum adverse effects possibilities the antigenic, non-allergenic and non-toxic B-cell, HTL and CTL epitopes from experimentally proven EVs proteins were selected for the vaccine construct. TLR4 agonist RpfE served as an adjuvant for the vaccine construct. The vaccine construct structure was modelled, refined and docked on TLR4 immune receptor. The designed vaccine construct displayed safe usage and exhibits a high probability to elicit the critical immune regulators, like B cells, T-cells and memory cells as displayed by the in-silico immunization assays. Therefore, it can be further corroborated using in vitro and in vivo assays to fulfil the global need for a more efficacious anti-tuberculosis vaccine.

Immunoinformatics analysis of antigenic epitopes and designing of a multi-epitope peptide vaccine from putative nitro-reductases of Mycobacterium tuberculosis DosR.

Mycobacterium tuberculosis (Mtb) resides in alveolar macrophages as a non-dividing and dormant state causing latent tuberculosis. Currently, no vaccine is available against the latent tuberculosis. Latent Mtb expresses ~48 genes under the control of DosR regulon. Among these, putative nitroreductases have significantly high expression levels, help Mtb to cope up with nitrogen stresses and possess antigenic properties. In the current study, immunoinformatics methodologies are applied to predict promiscuous antigenic T-cell epitopes from putative nitro-reductases of the DosR regulon. The promiscuous antigenic T-cell epitopes prediction was performed on the basis of their potential to induce an immune response and forming a stable interaction with the HLA alleles. The highest antigenic promiscuous epitopes were assembled for designing an in-silico vaccine construct. A TLR-2 agonist Phenol-soluble modulin alpha 4 was exploited as an adjuvant. Molecular docking and Molecular Dynamics Simulations were used to predict the stability of vaccine construct with the immune receptor. The predicted promiscuous epitopes may be helpful in the construction of a subunit vaccine against latent tuberculosis, which can also be administered along with the BCG to increase its efficacy. Experimental validation is a prerequisite for the in-silico designed vaccine construct against TB infection.

A 2-Dose AERAS-402 Regimen Boosts CD8+ Polyfunctionality in HIV-Negative, BCG-Vaccinated Recipients.

Despite the widespread use of BCG, tuberculosis (TB) remains a global threat. Existing vaccine candidates in clinical trials are designed to replace or boost BCG which does not provide satisfying long-term protection. AERAS-402 is a replication-deficient Ad35 vaccine encoding a fusion protein of the M. tuberculosis (Mtb) antigens 85A, 85B, and TB10.4. The present phase I trial assessed the safety and immunogenicity of AERAS-402 in participants living in India - a highly TB-endemic area. Healthy male participants aged 18-45 years with a negative QuantiFERON-TB Gold in-tube test (QFT) were recruited. Enrolled participants (n=12) were randomized 2:1 to receive two intramuscular injections of either AERAS-402 (3 x 1010 viral particles [vp]); (n=8) or placebo (n=4) on study days 0 and 28. Safety and immunogenicity parameters were evaluated for up to 182 days post the second injection. Immunogenicity was assessed by a flow cytometry-based intracellular cytokine staining (ICS) assay and transcriptional profiling. The latter was examined using dual-color-Reverse-Transcriptase-Multiplex-Ligation-dependent-Probe-Amplification (dc-RT MLPA) assay. AERAS-402 was well tolerated, and no vaccine-related serious adverse events were recorded. The vaccine-induced CD8+ T-cell responses were dominated by cells co-expressing IFN-γ, TNF-α, and IL-2 ("polyfunctional" cells) and were more robust than CD4+ T-cell responses. Five genes (CXCL10, GNLY, IFI35, IL1B and PTPRCv2) were differentially expressed between the AERAS-402-group and the placebo group, suggesting vaccine-induced responses. Further, compared to pre-vaccination, three genes (CLEC7A, PTPRCv1 and TAGAP) were consistently up-regulated following two doses of vaccination in the AERAS-402-group. No safety concerns were observed for AERAS-402 in healthy Indian adult males. The vaccine-induced predominantly polyfunctional CD8+ T cells in response to Ag85B, humoral immunity, and altered gene expression profiles in peripheral blood mononuclear cells (PBMCs) indicative of activation of various immunologically relevant biological pathways.

Prevalence of Mycobacterium tuberculosis infection as measured by the QuantiFERON-TB Gold assay and ESAT-6 free IGRA among adolescents in Mwanza, Tanzania.

BACKGROUND: The prevalence of latent tuberculosis infection (LTBI) is vastly higher than that of tuberculosis (TB) disease and this enormous reservoir of individuals with LTBI impacts the global TB control strategy. Adolescents are at greatest risk of TB infection and are thus an ideal target population for a potential effective TB vaccine to be added to the current BCG programme as it could reduce the number of latent infections and consequently the number of adults with TB disease. However, LTBI rates are often unknown for this population. This study aims to estimate the magnitude of LTBI and to determine if Tanzanian adolescents would be a good population for a prevention of TB infection trial. METHODS: This was a descriptive cross-sectional study that recruited 193 adolescents aged 12 and 16 years from government schools and directly from the community in Mwanza Region, Tanzania. Socio-demographic characteristics were collected for all enrolled participants. Blood was drawn and tested using QuantiFERON-TB Gold In-Tube (QFT-GIT), and Early Secretory Antigenic Target-6-Free Interferon-gamma Release Assay (ESAT-6 free IGRA). Concordance between QFT-GIT and ESAT-6 free IGRA was evaluated using the McNemar's test. RESULTS: Overall estimates of LTBI prevalence were 19.2% [95%CI, 14.1; 25.2] and 18.6% [95%CI, 13.6; 24.6] as measured by QFT-GIT IGRA and ESAT-6 free IGRA, respectively. The 16-year-old cohort had a higher LTBI prevalence (23.7% [95%CI, 16.1; 32.9]) as compared to 12-year-old cohort (14.6% [95%CI, 8.6; 22.7]) as measured by QFT-GIT IGRA. When measured by ESAT-6 Free IGRA, LTBI prevalence was 24.7% (95%CI, 16.9; 34.0) for the 16-year-old cohort and 12.5% (95%CI, 7.0; 20.3) among the 12-year-old cohort. According to both tests the prevalence of TB infection and the corresponding annual risk of tuberculosis infection (ARTI) and force of infection were high and increased with age. Of all enrolled participants, 97.4% had concordant results for QFT-GIT IGRA and ESAT-6 free IGRA (p = 0.65). CONCLUSIONS: The prevalence of LTBI and the associated ARTI and force of infection among adolescents is high and increases with age in Mwanza Region. There was a high concordance between the QFT-GIT and the novel ESAT-6 free IGRA assays. These findings suggest Mwanza is a promising area to conduct novel TB vaccine research prevention of infection (POI) studies targeting adolescents.