anti-TB Vaccine Research Articles

Research Progress on Liposome Pulmonary Delivery of Mycobacterium tuberculosis Nucleic Acid Vaccine and Its Mechanism of Action.

Traditional vaccines have played an important role in the prevention and treatment of infectious diseases, but they still have problems such as low immunogenicity, poor stability, and difficulty in inducing lasting immune responses. In recent years, the nucleic acid vaccine has emerged as a relatively cheap and safe new vaccine. Compared with traditional vaccines, nucleic acid vaccine has some unique advantages, such as easy production and storage, scalability, and consistency between batches. However, the direct administration of naked nucleic acid vaccine is not ideal, and safer and more effective vaccine delivery systems are needed. With the rapid development of nanocarrier technology, the combination of gene therapy and nanodelivery systems has broadened the therapeutic application of molecular biology and the medical application of biological nanomaterials. Nanoparticles can be used as potential drug-delivery vehicles for the treatment of hereditary and infectious diseases. In addition, due to the advantages of lung immunity, such as rapid onset of action, good efficacy, and reduced adverse reactions, pulmonary delivery of nucleic acid vaccine has become a hot spot in the field of research. In recent years, lipid nanocarriers have become safe, efficient, and ideal materials for vaccine delivery due to their unique physical and chemical properties, which can effectively reduce the toxic side effects of drugs and achieve the effect of slow release and controlled release, and there have been a large number of studies using lipid nanocarriers to efficiently deliver target components into the body. Based on the delivery of tuberculosis (TB) nucleic acid vaccine by lipid carrier, this article systematically reviews the advantages and mechanism of liposomes as a nucleic acid vaccine delivery carrier, so as to lay a solid foundation for the faster and more effective development of new anti-TB vaccine delivery systems in the future.

Tuberculosis control by novel vaccines development and Indian initiatives

Abstract Pulmonary tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is one of the worst microbial diseases of humankind and an awful societal problem, especially in underdeveloped countries. The enormous TB-infected individuals were in the Southeast Asian Region (46%), about 23% in the African Region, 18% in the West Pacific region, and the rest in other regions. While TB is often effectively treatable, untreated cases can lead to drug-resistant forms that are harder to manage and may kill the infected sooner after the disease flares up. In 2021, approximately 1.6 million individuals succumbed to TB worldwide. Although the Bacillus Calmette–Guérin (BCG) vaccine is currently the only approved anti-TB vaccine, its effectiveness in adolescents and adults is limited. Globally, several vaccines are in the developmental stage. This review narrates the progress made in developing 23 candidate anti-tuberculosis vaccines (including developing more immunogenic and safer recombinant Mtb strains) by different scientific groups worldwide. Additionally, the incidence of TB in India, along with the Indian initiatives and activities in controlling the disease, has been briefly discussed.

A novel multi-component protein vaccine ECP001 containing a protein polypeptide antigen nPstS1 riching in T-cell epitopes showed good immunogenicity and protection in mice.

Tuberculosis (TB) is an infectious disease that seriously affects human health. Until now, the only anti-TB vaccine approved for use is the live attenuated Mycobacterium bovis (M. bovis) vaccine - BCG vaccine, but its protective efficacy is relatively low and does not provide satisfactory protection against TB in adults. Therefore, there is an urgent need for more effective vaccines to reduce the global TB epidemic. In this study, ESAT-6, CFP-10, two antigens full-length and the T-cell epitope polypeptide antigen of PstS1, named nPstS1, were selected to form one multi-component protein antigens, named ECP001, which include two types, one is a mixed protein antigen named ECP001m, the other is a fusion expression protein antigen named ECP001f, as candidates for protein subunit vaccines. were prepared by constructing one novel subunit vaccine by mixing or fusing the three proteins and combining them with aluminum hydroxide adjuvant, and the immunogenicity and protective properties of the vaccine was evaluated in mice. The results showed that ECP001 stimulated mice to produce high titre levels of IgG, IgG1 and IgG2a antibodies; meanwhile, high levels of IFN-γ and a broad range of specific cytokines were secreted by mouse splenocytes; in addition, ECP001 inhibited the proliferation of Mycobacterium tuberculosis in vitro with a capacity comparable to that of BCG. It can be concluded that ECP001 is a novel effective multicomponent subunit vaccine candidate with potential as BCG Initial Immunisation-ECP001 Booster Immunisation or therapeutic vaccine for M. tuberculosis infection.

Therapeutic Potentials of Immunometabolomic Modulations Induced by Tuberculosis Vaccination.

Metabolomics is emerging as a promising tool to understand the effect of immunometabolism for the development of novel host-directed alternative therapies. Immunometabolism can modulate both innate and adaptive immunity in response to pathogens and vaccinations. For instance, infections can affect lipid and amino acid metabolism while vaccines can trigger bile acid and carbohydrate pathways. Metabolomics as a vaccinomics tool, can provide a broader picture of vaccine-induced biochemical changes and pave a path to potentiate the vaccine efficacy. Its integration with other systems biology tools or treatment modes can enhance the cure, response rate, and control over the emergence of drug-resistant strains. Mycobacterium tuberculosis (Mtb) infection can remodel the host metabolism for its survival, while there are many biochemical pathways that the host adjusts to combat the infection. Similarly, the anti-TB vaccine, Bacillus Calmette-Guerin (BCG), was also found to affect the host metabolic pathways thus modulating immune responses. In this review, we highlight the metabolomic schema of the anti-TB vaccine and its therapeutic applications. Rewiring of immune metabolism upon BCG vaccination induces different signaling pathways which lead to epigenetic modifications underlying trained immunity. Metabolic pathways such as glycolysis, central carbon metabolism, and cholesterol synthesis play an important role in these aspects of immunity. Trained immunity and its applications are increasing day by day and it can be used to develop the next generation of vaccines to treat various other infections and orphan diseases. Our goal is to provide fresh insight into this direction and connect various dots to develop a conceptual framework.

Activation of Nrf2 modulates protective immunity against Mycobacterium tuberculosis infection in THP1-derived macrophages.

Tuberculosis (TB), caused by mycobacterium tuberculosis (M. tuberculosis) infection, is one of the leading causes of death globally and poses a threat to public health. During infection, M. tuberculosis causes redox imbalance and dysfunctions of protective immunity. Transcription factor nuclear factor erythroid 2 (NF-E2)-related factor (Nrf2) is a major modulator of cellular redox homeostasis via transcriptional induction of cytoprotective genes to protect cell against the damage from insults. Thus, we hypothesize that Nrf2 may regulate protective immunity against M. tuberculosis. RNA-seq and immunoblotting results suggested that the expression of Nrf2 protein increased after M. tuberculosis infection, and decreased upon long-term M. tuberculosis infection, while Keap1 protein maintained a low expression level during M. tuberculosis infection. Furthermore, Nrf2 activator sulforaphane (SFN) decreased proinflammatory cytokines production, phagocytosis and host cell apoptosis, while increasing ROS levels and promoting autophagy in THP1 macrophages infected with M. tuberculosis. In addition, SFN-activated Nrf2 augmented bacterial killing by macrophages, which might be due to the regulation of protective immunity via Nrf2. Combined, our results extend the understanding of the complex innate immunity regulation by Nrf2 against mycobacterial infection. Also, these findings suggested that the regulation of Nrf2 signaling cascade could be used as a therapeutic target for the treatment of TB patients and the development of better anti-TB vaccines.

Fusion peptide constructs from antigens of M. tuberculosis producing high T-cell mediated immune response.

Non availability of effective anti-TB vaccine impedes TB control which remains a crucial global health issue. A fusion molecule based on immunogenic antigens specific to different growth phases of Mycobacterium tuberculosis can enhance T-cell responses required for developing a potent vaccine. In this study, six antigens including EspC, TB10.4, HspX, PPE57, CFP21 and Rv1352 were selected for constructing EspC-TB10.4 (bifu25), TnCFP21-Rv1352 (bifu29), HspX-EspC-TB10.4 (trifu37), HspX-TnCFP21-Rv1352 (trifu44) and HspX-EspC-TB10.4-PPE57 (tetrafu56) fusion proteins. Th1-cell epitopes of EspC, PPE57 and Rv1352 antigens were predicted for the first time using different in silico tools. The fusion molecule tetrafu56, which consisted of antigens from both the replicating and the dormant stages of Mtb, induced a release of 397 pg/mL of IFN-γ from PBMCs of the active TB patients. This response was comparable to the response obtained with cocktail of the component antigens (396 pg/mL) as well as to the total of the responses obtained separately for each of its component antigens (388 pg/mL). However, PBMCs from healthy samples in response to tetrafu56 showed IFN-γ release of only 26.0 pg/mL Thus a previous exposure of PBMCs to Mtb antigens in TB plasma samples resulted in 15-fold increase in IFN-γ response to tetrafu56 as compared to the PBMCs from the healthy controls. Hence, most of the T-cell epitopes of the individual antigens seem to be available for T-cell interactions in the form of the fusion. Further investigation in animal models should substantiate the immune efficacy of the fusion molecule. Thus, the fusion tetrafu56 seems to be a potential candidate for developing an effective multistage vaccine against TB.

Pathological and protective roles of dendritic cells in Mycobacterium tuberculosis infection: Interaction between host immune responses and pathogen evasion.

Dendritic cells (DCs) are principal defense components that play multifactorial roles in translating innate immune responses to adaptive immunity in Mycobacterium tuberculosis (Mtb) infections. The heterogeneous nature of DC subsets follows their altered functions by interacting with other immune cells, Mtb, and its products, enhancing host defense mechanisms or facilitating pathogen evasion. Thus, a better understanding of the immune responses initiated, promoted, and amplified or inhibited by DCs in Mtb infection is an essential step in developing anti-tuberculosis (TB) control measures, such as host-directed adjunctive therapy and anti-TB vaccines. This review summarizes the recent advances in salient DC subsets, including their phenotypic classification, cytokine profiles, functional alterations according to disease stages and environments, and consequent TB outcomes. A comprehensive overview of the role of DCs from various perspectives enables a deeper understanding of TB pathogenesis and could be useful in developing DC-based vaccines and immunotherapies.

Reprogramming Mycobacterium tuberculosis CRISPR System for Gene Editing and Genome-wide RNA Interference Screening

Mycobacterium tuberculosis is the causative agent of tuberculosis (TB), which is still the leading cause of mortality from a single infectious disease worldwide. The development of novel anti-TB drugs and vaccines is severely hampered by the complicated and time-consuming genetic manipulation techniques for M. tuberculosis. Here, we harnessed an endogenous type III-A CRISPR/Cas10 system of M. tuberculosis for efficient gene editing and RNA interference (RNAi). This simple and easy method only needs to transform a single mini-CRISPR array plasmid, thus avoiding the introduction of exogenous protein and minimizing proteotoxicity. We demonstrated that M. tuberculosis genes can be efficiently and specifically knocked in/out by this system as confirmed by DNA high-throughput sequencing. This system was further applied to single- and multiple-gene RNAi. Moreover, we successfully performed genome-wide RNAi screening to identify M. tuberculosis genes regulating in vitro and intracellular growth. This system can be extensively used for exploring the functional genomics of M. tuberculosis and facilitate the development of novel anti-TB drugs and vaccines.

A Perspective on the Success and Failure of BCG.

TB continues to be one of the major public health threats. BCG is the only available vaccine against TB and confers significant protection against the childhood disease. However, the protective efficacy of BCG against adult pulmonary TB, which represents a larger burden of disease, is highly variable. It has been suggested that prior exposure to environmental mycobacteria (EMb) mitigates the anti-TB efficacy of BCG by blocking its duplication or masking its immunogenicity. However, its effectiveness against childhood TB and failure of repeated administration to provide additional benefit against pulmonary TB, suggest of some other mechanisms for the variable efficacy of BCG against the pulmonary disease. Importantly, TB is a heterogeneous disease occurring in different forms and having distinct mechanisms of pathogenesis. While inability of the immune system to contain the bacilli is responsible for TB pathogenesis in infants, an aggravated immune response to Mtb has been blamed for the development of adult pulmonary TB. Available data suggest that EMb play a key role in heightening the immune response against Mtb. In this article, differential efficacy of BCG against childhood and adult TB is explained by taking into account the heterogeneity of TB, mechanisms of TB pathogenesis, and the effect of EMb on anti-Mtb immunity. It is believed that a refined understanding of the success and failure of BCG will help in the development of effective anti-TB vaccines.

The contribution of microfluidics to the fight against tuberculosis

Abstract The high mortality associated with tuberculosis brings forward the urgency of developing new therapies and strategies against the disease. With the advance of drug-resistant strains, traditional techniques have proven insufficient to manage the disease appropriately. Microfluidic devices have characteristics that can enhance treatment prescription and significantly advance our knowledge about the disease and its interaction within the human body. In addition, microfluidic systems provide advantages in terms of time and costs, which are particularly important in countries with low income and resources. This review will highlight how microdevices can help bridge the gaps in disease management, including their use for drug testing and development, drug susceptibility, basic research, and novel approaches to anti-TB vaccines and organ-on-chip studies.

Antigen-Specific IFN-γ/IL-17-Co-Producing CD4+ T-Cells Are the Determinants for Protective Efficacy of Tuberculosis Subunit Vaccine.

The antigen-specific Th17 responses in the lungs for improved immunity against Mycobacterium tuberculosis (Mtb) infection are incompletely understood. Tuberculosis (TB) vaccine candidate HSP90-ESAT-6 (E6), given as a Bacillus Calmette-Guérin (BCG)-prime boost regimen, confers superior long-term protection against the hypervirulent Mtb HN878 infection, compared to BCG or BCG-E6. Taking advantage of protective efficacy lead-out, we found that ESAT-6-specific multifunctional CD4+IFN-γ+IL-17+ T-cells optimally correlated with protection level against Mtb infection both pre-and post-challenge. Macrophages treated with the supernatant of re-stimulated lung cells from HSP90-E6-immunised mice significantly restricted Mtb growth, and this phenomenon was abrogated by neutralising anti-IFN-γ and/or anti-IL-17 antibodies. We identified a previously unrecognised role for IFN-γ/IL-17 synergism in linking anti-mycobacterial phagosomal activity to enhance host control against Mtb infection. The implications of our findings highlight the fundamental rationale for why and how Th17 responses are essential in the control of Mtb, and for the development of novel anti-TB subunit vaccines.

Plant-Produced N-glycosylated Ag85A Exhibits Enhanced Vaccine Efficacy Against Mycobacterium tuberculosis HN878 Through Balanced Multifunctional Th1 T Cell Immunity.

Tuberculosis (TB) is one of the deadliest infectious diseases worldwide and is caused by Mycobacterium tuberculosis (Mtb). An effective vaccine to prevent TB is considered the most cost-effective measure for controlling this disease. Many different vaccine antigen (Ag) candidates, including well-known and newly identified Ags, have been evaluated in clinical and preclinical studies. In this study, we took advantage of a plant system of protein expression using Nicotiana benthamiana to produce N-glycosylated antigen 85A (G-Ag85A), which is one of the most well-characterized vaccine Ag candidates in the field of TB vaccines, and compared its immunogenicity and vaccine efficacy with those of nonglycosylated Ag85A (NG-Ag85A) produced with an Escherichia coli system. Notably, G-Ag85A induced a more robust IFN-γ response than NG-Ag85A, which indicated that G-Ag85A is well recognized by the host immune system during Mtb infection. We subsequently compared the vaccine potential of G-Ag85A and NG-Ag85A by evaluating their immunological features and substantial protection efficacies. Interestingly, G-Ag85A yielded moderately enhanced long-term protective efficacy, as measured in terms of bacterial burden and lung inflammation. Strikingly, G-Ag85A-immunized mice showed a more balanced proportion of multifunctional Th1-biased immune responses with sustained IFN-γ response than did NG-Ag85A-immunized mice. Collectively, plant-derived G-Ag85A could induce protective and balanced Th1 responses and confer long-term protection against a hypervirulent Mtb Beijing strain infection, which indicated that plant-produced G-Ag85A might provide an excellent example for the production of an Mtb subunit vaccine Ag and could be an effective platform for the development of anti-TB vaccines.

Mycobacterium tuberculosis Metabolism.

Mycobacterium tuberculosis is the cause of tuberculosis (TB), a disease which continues to overwhelm health systems in endemic regions despite the existence of effective combination chemotherapy and the widespread use of a neonatal anti-TB vaccine. For a professional pathogen, M. tuberculosis retains a surprisingly large proportion of the metabolic repertoire found in nonpathogenic mycobacteria with very different lifestyles. Moreover, evidence that additional functions were acquired during the early evolution of the M. tuberculosis complex suggests the organism has adapted (and augmented) the metabolic pathways of its environmental ancestor to persistence and propagation within its obligate human host. A better understanding of M. tuberculosis pathogenicity, however, requires the elucidation of metabolic functions under disease-relevant conditions, a challenge complicated by limited knowledge of the microenvironments occupied and nutrients accessed by bacilli during host infection, as well as the reliance in experimental mycobacteriology on a restricted number of experimental models with variable relevance to clinical disease. Here, we consider M. tuberculosis metabolism within the framework of an intimate host-pathogen coevolution. Focusing on recent advances in our understanding of mycobacterial metabolic function, we highlight unusual adaptations or departures from the better-characterized model intracellular pathogens. We also discuss the impact of these mycobacterial "innovations" on the susceptibility of M. tuberculosis to existing and experimental anti-TB drugs, as well as strategies for targeting metabolic pathways. Finally, we offer some perspectives on the key gaps in the current knowledge of fundamental mycobacterial metabolism and the lessons which might be learned from other systems.

BCG Vaccination Prevents Reactivation of Latent Lymphatic Murine Tuberculosis Independently of CD4+ T Cells.

Tuberculosis (TB) is a major global public health problem causing significant mortality and morbidity. In addition to ~10.4 million cases of active TB annually, it is estimated that about two billion people are latently infected with Mycobacterium tuberculosis (Mtb), the causative agent of TB. Reactivation of latent Mtb infection is the leading cause of death in patients with immunodeficiency virus (HIV) infection. The low efficiency of the only licensed anti-TB vaccine, Bacille Calmette–Guérin (BCG) to reduce pulmonary TB in adults contributes to this problem. Here we investigated if vaccination with conventional BCG or the genetically modified experimental BCGΔBCG1419c strain can prevent reactivation of latent lymphatic TB in a mouse model of induced reactivation, following the depletion of CD4+ T cells, as it occurs in HIV+ individuals. Vaccination with conventional BCG or BCGΔBCG1419c prevented reactivation of Mtb from the infected lymph node and the systemic spread of Mtb to spleen and lung. Prevention of reactivation was independent of vaccination route and was accompanied by reduced levels of circulating inflammatory cytokines and the absence of lung pathology. Our results demonstrate that vaccine-induced CD4+ T cells are not essential to prevent reactivation of latent lymphatic murine TB, and highlight the need to better understand how non-CD4+ immune cell populations participate in protective immune responses to control latent TB.

Epitope and affinity determination of recombinant Mycobacterium tuberculosis Ag85B antigen towards anti-Ag85 antibodies using proteolytic affinity-mass spectrometry and biosensor analysis.

Tuberculosis (TB) is the first cause of death from infectious diseases worldwide. Only a single anti-TB vaccine is currently available for clinical use, but its efficacy is not achieved with certainty. The aim of this work is to provide a basis for the rational design of a neo-glycoconjugate vaccine against TB. Structural characterization of recombinant antigenic proteins from Mycobacterium tuberculosis (MTB) Ag85B (rAg85B, variants, and semi-synthetic glycoconjugates) was initially carried out. Identification of antibody epitope analyses by proteolytic affinity-mass spectrometry and surface plasmon resonance (SPR) biosensor analyses were performed in order to qualitatively identify and quantitatively characterize interaction structures of the antigens with antibodies from different sources. A commercial monoclonal antibody and polyclonal antibodies from different sources (patients with active TB, vaccinated individuals, and a healthy control) were employed to analyze antigen-antibody interactions. These combined approaches provided the identification of different assembled epitope regions on the recombinant MTB antigens, their affinity binding constants in the interactions with specific antibodies, and revealed the importance of protection from excessive glycosylation. The identified epitope peptides should constitute a suitable basis for the design of new specific target vaccines. Graphical abstract ᅟ.

Characterising antibody avidity in individuals of varied Mycobacterium tuberculosis infection status using surface plasmon resonance

There is increasing evidence supporting a role for antibodies in protection against tuberculosis (TB), with functional antibodies being described in the latent state of TB infection. Antibody avidity is an important determinant of antibody-mediated protection. This study characterised the avidity of antibodies against Ag85A, an immunodominant Mycobacterium tuberculosis (M.tb) antigen and constituent of several anti-TB vaccine candidates, in individuals of varied M.tb infection status. Avidity of Ag85A specific antibodies was measured in 30 uninfected controls, 34 individuals with latent TB infection (LTBI) and 75 active pulmonary TB (APTB) cases, employing the more commonly used chaotrope-based dissociation assays, and surface plasmon resonance (SPR). Chaotrope-based assays indicated that APTB was associated with a higher antibody avidity index compared to uninfected controls [adjusted geometric mean ratio (GMR): 1.641, 95% confidence interval (CI): 1.153, 2.337, p = 0.006, q = 0.018] and to individuals with LTBI [adjusted GMR: 1.604, 95% CI: 1.282, 2.006, p < 0.001, q <0.001]. SPR assays showed that APTB was associated with slower dissociation rates, an indication of higher avidity, compared to uninfected controls (adjusted GMR: 0.796, 95% CI: 0.681, 0.932, p = 0.004, q = 0.012) and there was also weak evidence of more avid antibodies in the LTBI compared to the uninfected controls (adjusted GMR: 0.871, 95% CI: 0.763, 0.994, p = 0.041, q = 0.123). We found no statistically significant differences in anti-Ag85A antibody avidity between the APTB and LTBI groups. This study shows that antibodies of increased avidity are generated against a principle vaccine antigen in M.tb infected individuals. It would be important to determine whether TB vaccines are able to elicit a similar response. Additionally, more research is needed to determine whether antibody avidity is important in protection against infection and disease.

Measuring autophagy level along with vaccine reactive IFN-+CD4+ Th1 cells may be a promising approach to understand effi cacy of anti TB vaccine(s)

Autophagy is a homeostatic process in the eukaryotic cells which contributes towards degradation of unwanted cellular constituents, killing of the invading intracellular microbes and generation of cell mediated immunity (CMI).

Tuberculosis and its Treatment: An Overview.

Tuberculosis (TB) is a primordial infectious disease that mainly affects the lungs. M. tuberculosis (Mycobacterium tuberculosis) is the etiological agent of TB and currently more than one-third of the world population is suffering from TB. For the treatment of TB, administration of multiple antibiotics such as isoniazid, rifampicin, pyrazinamide and ethambutol is required for a long period of time to kill bacteria. However, antibiotic resistance is an emerging problem in multiple drug-resistant tuberculosis (MDR-TB) infections. World Health Organization (WHO) has developed a novel strategy called DOTS (directly observed treatment, short-course), in which specific combination of anti-TB drugs is given to control TB. In this review article we have focused on the comprehensive management of TB and have provided the valuable information about first and second line anti-TB drugs, DOTS and novel drug delivery systems to be used against M. tuberculosis. Important aspects related to new anti-TB drugs and vaccines in various stages of clinical development are also covered in this article.

Animal Models for Tuberculosis in Translational and Precision Medicine.

Tuberculosis (TB) is a health threat to the global population. Anti-TB drugs and vaccines are key approaches for TB prevention and control. TB animal models are basic tools for developing biomarkers of diagnosis, drugs for therapy, vaccines for prevention and researching pathogenic mechanisms for identification of targets; thus, they serve as the cornerstone of comparative medicine, translational medicine, and precision medicine. In this review, we discuss the current use of TB animal models and their problems, as well as offering perspectives on the future of these models.

Sendai Virus Mucosal Vaccination Establishes Lung-Resident Memory CD8 T Cell Immunity and Boosts BCG-Primed Protection against TB in Mice

Accumulating evidence has shown the protective role of CD8+ T cells in vaccine-induced immunity against Mycobacterium tuberculosis (Mtb) despite controversy over their role in natural immunity. However, the current vaccine BCG is unable to induce sufficient CD8+ T cell responses, especially in the lung. Sendai virus, a respiratory RNA virus, is here engineered firstly as a novel recombinant anti-TB vaccine (SeV85AB) that encodes Mtb immuno-dominant antigens, Ag85A and Ag85B. A single mucosal vaccination elicited potent antigen-specific T cell responses and a degree of protection against Mtb challenge similar to the effect of BCG in mice. Depletion of CD8+ T cells abrogated the protective immunity afforded by SeV85AB vaccination. Interestingly, only SeV85AB vaccination induced high levels of lung-resident memory CD8+ T (TRM) cells, and this led to a rapid and strong recall of antigen-specific CD8+ T cell responses against Mtb challenge infection. Furthermore, when used in a BCG prime-SeV85AB boost strategy, SeV85AB vaccine significantly enhanced protection above that seen after BCG vaccination alone. Our findings suggest that CD8+ TRM cells that arise in lungs responding to this mucosal vaccination might help to protect against TB, and SeV85AB holds notable promise to improve BCG’s protective efficacy in a prime-boost immunization regimen.