TB Vaccine Research Articles

Leveraging computer-aided design and artificial intelligence to develop a next-generation multi-epitope tuberculosis vaccine candidate

BackgroundTuberculosis (TB) remains a global public health challenge. The existing Bacillus Calmette–Guérin vaccine has limited efficacy in preventing adult pulmonary TB, necessitating the development of new vaccines with improved protective effects. MethodsComputer-aided design and artificial intelligence technologies, combined with bioinformatics and immunoinformatics approaches, were used to design a multi-epitope vaccine (MEV) against TB. Comprehensive bioinformatics analyses were conducted to evaluate the physicochemical properties, spatial structure, immunogenicity, molecular dynamics (MD), and immunological characteristics of the MEV. ResultsWe constructed a MEV, designated ZL12138L, containing 13 helper T lymphocyte epitopes, 12 cytotoxic T lymphocyte epitopes, 8 B-cell epitopes, as well as Toll-like receptor (TLR) agonists and helper peptides. Bioinformatics analyses revealed that ZL12138L should exhibit excellent immunogenicity and antigenicity, with no toxicity or allergenicity, and had potential to induce robust immune responses and high solubility, the immunogenicity score was 4.14449, the antigenicity score was 0.8843, and the immunological score was 0.470. Moreover, ZL12138L showed high population coverage for human leukocyte antigen class I and II alleles, reaching 92.41% and 90.17%, respectively, globally. Molecular docking analysis indicated favorable binding affinity of ZL12138L with TLR-2 and TLR-4, with binding energies of −1173.4 and −1360.5 kcal/mol, respectively. Normal mode analysis and MD simulations indicated the stability and dynamic properties of the vaccine construct. Immune simulation predictions suggested that ZL12138L could effectively activate innate and adaptive immune cells, inducing high levels of Type 1 T helper cell cytokines. ConclusionsThis study provides compelling evidence for ZL12138L as a promising TB vaccine candidate. Future research will focus on experimental validation and further optimization of the vaccine design.

Health and economic impacts of Vaccae vaccination incorporating active case finding in India and South Africa: a modelling study

IntroductionTuberculosis (TB) is a major global health issue, particularly, in India and South Africa. We aim to evaluate the potential of the new TB vaccine, Vaccae, to enhance TB control...

Therapeutic DNA Vaccine Targeting Mycobacterium tuberculosis Persisters Shortens Curative Tuberculosis Treatment.

A TB vaccine shortens curative drug treatment in mice by eliciting strong TB-protective immune responses and induces similar responses in macaques.

Immunogenicity and Protective Efficacy of a Multi-Antigen Mycobacterium tuberculosis Subunit Vaccine in Mice.

There is an urgent need for an effective TB vaccine capable of controlling both acute and chronic Mycobacterium tuberculosis infection in populations with diverse genetic backgrounds. In this study, we characterised the immunogenicity and protective efficacy of a novel protein-in-adjuvant subunit vaccine. The protein component is a fusion protein of three different M. tuberculosis antigens, which we termed CysVac5: CysD, a major component of the M. tuberculosis sulfate activation pathway that is highly expressed during the chronic stage of M. tuberculosis infection, is fused with two major secreted mycobacterial antigens, Ag85B and MPT83. Vaccination of C57BL/6 mice with CysVac5, formulated in a monophosphoryl lipid A (MPLA) and dimethyldioctadecylammonium (DDA) adjuvant combination, resulted in the potent generation of polyfunctional CD4+ T cells secreting multiple cytokines, including IFN-γ, IL-2, TNF and IL-17, against each of the three components of the fusion protein. Furthermore, vaccination with CysVac5-MPLA/DDA conferred significant protection against infection in mouse lungs, which was greater than that afforded by BCG at extended time points post-challenge. The generation of antigen-specific and protective immunity was also observed in CysVac5 vaccinated BALB/c mice, indicating the vaccine could display efficacy across multiple genetic backgrounds. These results indicate that the CysVac5 vaccine has broad immunogenicity, is effective in controlling both acute and chronic phases of M. tuberculosis infection in mice, and warrants further investigation to assess its potential to control pulmonary TB.

Mapping the existing body of knowledge on new and repurposed TB vaccine implementation: A scoping review.

There is global consensus on the urgent need for a safe and effective TB vaccine for adults and adolescents to improve global TB control, and encouragingly, several promising candidates have advanced to late-stage trials. Significant gaps remain in understanding the critical factors that will facilitate the successful implementation of new and repurposed TB vaccines in low- and middle-income countries (LMICs), once available. By synthesizing the existing body of knowledge, this review offers comprehensive insights into the current state of research on implementation of these adult and adolescent vaccines. This review explores four key dimensions: (1) epidemiological impact, (2) costing, cost-effectiveness, and/or economic impact, (3) acceptability, and the (4) feasibility of implementation; this includes implementation strategies of target populations, and health system capabilities. Results indicate that current research primarily consists of epidemiological and costing/cost-effectiveness/economic studies in India, China, and South Africa, mainly modelling with M72/AS01, BCG revaccination, and hypothetical vaccines. Varying endpoints, vaccine efficacies, and vaccination coverages were used. Globally, new, and repurposed TB vaccines are estimated to save millions of lives. Economically, these vaccines also demonstrate promise with expected cost-effectiveness in most countries. Projected outcomes were dependent on vaccine characteristics, target population, implementation strategy, timing of roll out, TB burden/country context, and vaccination coverage. Potential barriers for vaccine acceptability included TB-related stigma, need for a second dose, and cost, while low pricing, community and civil society engagement and heightened public TB awareness were potential enablers in China, India, and South Africa. Potential implementation strategies considered spanned from mass campaigns to integration within existing vaccine programs and the primary target group studied was the general population, and adults and adolescents. In conclusion, future research must have broader geographical representations to better understand what is needed to inform tailored vaccine programs to accommodate diverse country contexts and population groups to achieve optimal implementation and impact. Furthermore, this review underscores the scarcity of research on acceptability of new and repurposed TB vaccines and their delivery among potential beneficiaries, the most promising implementation strategies, and the health system capabilities necessary for implementation. The absence of this knowledge in these areas emphasizes the crucial need for future research to ensure effective TB vaccine implementation in high burden settings worldwide.

Intravenous Immunization with Triple Auxotrophs of Mycobacterium tuberculosis : A novel vaccine strategy against tuberculosis.

Tuberculosis, caused by Mycobacterium tuberculosis ( Mtb ), remains a leading infectious cause of mortality worldwide despite widespread use of the BCG vaccine and the availability of sterilizing pharmacopoeia. Recent research indicates that the intravenous administration of BCG confers sterilizing immunity against Mtb pulmonary challenge in non-human primates. However, while BCG is relatively safe, complications such as disseminated BCGosis have been observed in immunocompromised individuals. Double auxotrophic mutants of Mtb lacking the ability to synthesize leucine and pantothenate are safe and sterilized in immunocompromised mice and SIV-infected Rhesus macaques. We examined how immunization with a Mtb triple auxotrophic strain, mc 2 7902, which cannot synthesize leucine, pantothenate, and arginine, protects immunocompetent mice from a virulent Mtb infection. The route of immunization was a crucial factor for protection with mc 2 7902 with intravenous immunization being 100 times more effective in protecting immunocompetent mice from Mtb challenge when compared to conventional subcutaneous vaccination with BCG. To further increase the safety of the attenuated auxotroph for vaccine purposes, the type VII secretion system Esx1 responsible for BCG attenuation was deleted in mc 2 7902. When tested by prime-boost immunization of immunocompetent mice followed by aerosol challenge with virulent Mtb , mc 2 7902 Δ esx1 provided similar protection to mc 2 7902. This robust protection against Mtb infection conferred by mc 2 7902 and mc 2 7902 Δ esx1 in a mouse model paves the way for new TB vaccine development using highly attenuated, auxotrophic Mtb strains.

Mycobacterium bovis vaccination and subsequent experimental infection outcomes are associated with changes in vitamin D status in dairy calves.

Investigations into the role of vitamin D (vitD) in the immune response of cattle are limited. The objectives of this study were therefore to investigate the association between circulating vitD concentration, TB vaccination and Mycobacterium bovis (M. bovis) infection outcomes in 24 dairy calves (<8 weeks old) which were housed throughout and fed a bodyweight-based allowance. The study design incorporated 2 phases: vaccination (experimental wk 0–52) and experimental infection phase (wk 52–65). Vaccinated calves (n = 12) received a subcutaneous injection of a live-attenuated TB strain at wk 0, whereas unvaccinated ones (n = 12) were injected with saline. All animals were infected with 7,600 cfu of M. bovis 52 weeks post-vaccination, and lung and lymph nodes tissues were assessed for pathology following euthanasia after wk 65. Blood samples were taken throughout wk 0–65. Serum 25-hydroxyvitamin D (25(OH)D) concentrations were measured using a commercial ELISA. A mixed-effects linear regression model revealed significantly higher 25(OH)D concentrations in the vaccinates post-infection (wk 65) compared with the non-vaccinates. Linear regression analysis between 25(OH)D concentration and the level of M. bovis-driven pathology revealed a negative linear relationship i.e., higher concentrations were associated with lower pathology scores, irrespective of vaccination status. No correlation was detected between interferon-γ cytokine production and vitD concentration. Overall, the results support a significant role for vitD in the development of effective immunity of cattle against M. bovis. Gaining insight into the interaction between TB vaccination, M. bovis infection and vitD could potentially guide the optimization of vaccination protocols and future TB control strategies.

Global analysis of an age-structured tuberculosis model with an application to Jiangsu, China.

Diagnostic delay for TB infected individuals and the lack of TB vaccines for adults are the main challenges to achieve the goals of WHO by 2050. In order to evaluate the impacts of diagnostic delay and vaccination for adults on prevalence of TB, we propose an age-structured model with latent age and infection age, and we incorporate Mycobacterium TB in the environment and vaccination into the model. Diagnostic delay is indicated by the age of infection before receiving treatment. The threshold dynamics are established in terms of the basic reproduction number . When , the disease-free equilibrium is globally asymptotically stable, which means that TB epidemic will die out; When , the disease-free equilibrium is globally attractive; there exists a unique endemic equilibrium and the endemic equilibrium is globally attractive when . We estimate that the basic reproduction number (95% CI (0.3060, 0.7556)) in Jiangsu Province, which means that TB epidemic will die out. However, we find that the annual number of new TB cases by 2050 is 1,151 (95%CI: (138, 8,014)), which means that it is challenging to achieve the goal of WHO by 2050. To this end, we evaluate the possibility of achieving the goals of WHO if we start vaccinating adults and reduce diagnostic delay in 2025. Our results demonstrate that when the diagnostic delay is reduced from longer than four months to four months, or 20% adults are vaccinated, the goal of WHO in 2050 can be achieved, and 73,137 (95%CI: (23,906, 234,086)) and 54,828 (95%CI: (15,811, 206,468)) individuals will be prevented from being infected from 2025 to 2050, respectively. The modeling approaches and simulation results used in this work can help policymakers design control measures to reduce the prevalence of TB.

New TB vaccine on trial

New TB vaccine on trial

Model-based impact evaluation of new tuberculosis vaccines in aging populations under different modeling scenarios: the case of China.

The slow descent in TB burden, the COVID-19 pandemic, along with the rise of multidrug-resistant strains of Mycobacterium tuberculosis, seriously threaten TB control and the goals of the End TB strategy. To fight back, several vaccine candidates are under development, with some of them undergoing the phases 2B and 3 of the development pipeline. The impact of these vaccines on the general population needs to be addressed using disease-transmission models, and, in a country like China, which last year ranked third in number of cases worldwide, and where the population is aging at a fast pace, the impact of TB vaccination campaigns may depend heavily upon the age of targeted populations, the mechanistic descriptions of the TB vaccines and the coupling between TB dynamics and demographic evolution. In this work, we studied the potential impact of a new TB vaccine in China targeting adolescents (15-19 y.o.) or older adults (60-64 y.o.), according to varying vaccine descriptions that represent reasonable mechanisms of action leading to prevention of disease, or prevention of recurrence, each of them targetting specific routes to TB disease. To measure the influence of the description of the coupling between transmission dynamics and aging in TB transmission models, we explored two different approaches to compute the evolution of the contact matrices, which relate to the spreading among different age strata. Our findings highlight the dependence of model-based impact estimates on vaccine profiles and the chosen modeling approach for describing the evolution of contact matrices. Our results also show, in line with previous modeling works, that older adult vaccination is a suitable option in China to reduce the incidence of TB as long as the vaccine is able to protect already exposed individuals. This study underscores the importance of considering vaccine characteristics and demographic dynamics in shaping TB control strategies. In this sense, older adult vaccination emerges as a promising avenue for mitigating TB transmission in China but also remarks the need for tailored intervention strategies aligned with demographic trends.

Comparative analysis of genomic characteristics and immune response between Mycobacterium tuberculosis strains cultured continuously for 25 years and H37Rv.

Tuberculosis (TB) continues to pose a significant global health challenge, emphasizing the critical need for effective preventive measures. Although many studies have tried to develop new attenuated vaccines, there is no effective TB vaccine. In this study, we report a novel attenuated Mycobacterium tuberculosis (M. tb) strain, CHVAC-25, cultured continuously for 25 years in the laboratory. CHVAC-25 exhibited significantly reduced virulence compared to both the virulent H37Rv strain in C57BL/6J and severe combined immunodeficiency disease mice. The comparative genomic analysis identified 93 potential absent genomic segments and 65 single nucleotide polymorphic sites across 47 coding genes. Notably, the deletion mutation of ppsC (Rv2933) involved in phthiocerol dimycocerosate synthesis likely contributes to CHVAC-25 virulence attenuation. Furthermore, the comparative analysis of immune responses between H37Rv- and CHVAC-25-infected macrophages showed that CHVAC-25 triggered a robust upregulation of 173 genes, particularly cytokines crucial for combating M. tb infection. Additionally, the survival of CHVAC-25 was significantly reduced compared to H37Rv in macrophages. These findings reiterate the possibility of obtaining attenuated M. tb strains through prolonged laboratory cultivation, echoing the initial conception of H37Ra nearly a century ago. Additionally, the similarity of CHVAC-25 to genotypes associated with attenuated M. tb vaccine positions it as a promising candidate for TB vaccine development.

Development and application of the direct mycobacterial growth inhibition assay: a systematic review.

First described by Wallis et al. in 2001 for the assessment of TB drugs, the direct mycobacterial growth inhibition assay (MGIA) offers a tractable ex vivo tool measuring the combined influences of host immunity, strain virulence and intervention effects. Over the past 13 years, we have led efforts to adapt the direct MGIA for the assessment of TB vaccines including optimisation, harmonisation and validation of BCG vaccine-induced responses as a benchmark, as well as assay transfer to institutes worldwide. We have performed a systematic review on the primary published literature describing the development and applications of the direct MGIA from 2001 to June 2023 in accordance with the PRISMA reporting guidelines. We describe 63 studies in which the direct MGIA has been applied across species for the evaluation of TB drugs and novel TB vaccine candidates, the study of clinical cohorts including those with comorbidities, and to further understanding of potential immune correlates of protection from TB. We provide a comprehensive update on progress of the assay since its conception and critically evaluate current findings and evidence supporting its utility, highlighting priorities for future directions. While further standardisation and validation work is required, significant advancements have been made in the past two decades. The direct MGIA provides a potentially valuable tool for the early evaluation of TB drug and vaccine candidates, clinical cohorts, and immune mechanisms of mycobacterial control. https://www.crd.york.ac.uk/prospero/, identifier CRD42023423491.

Identification of differentially recognized T cell epitopes in the spectrum of tuberculosis infection

There is still incomplete knowledge of which Mycobacterium tuberculosis (Mtb) antigens can trigger distinct T cell responses at different stages of infection. Here, a proteome-wide screen of 20,610 Mtb-derived peptides in 21 patients mid-treatment for active tuberculosis (ATB) reveals IFNγ-specific T cell responses against 137 unique epitopes. Of these, 16% are recognized by two or more participants and predominantly derived from cell wall and cell processes antigens. There is differential recognition of antigens, including TB vaccine candidate antigens, between ATB participants and interferon-gamma release assay (IGRA + /−) individuals. We developed an ATB-specific peptide pool (ATB116) consisting of epitopes exclusively recognized by ATB participants. This pool can distinguish patients with pulmonary ATB from IGRA + /− individuals from various geographical locations, with a sensitivity of over 60% and a specificity exceeding 80%. This proteome-wide screen of T cell reactivity identified infection stage-specific epitopes and antigens for potential use in diagnostics and measuring Mtb-specific immune responses.

Harnessing bioinformatics for the development of a promising multi-epitope vaccine against tuberculosis: The ZL9810L vaccine

BackgroundTuberculosis (TB) is a global infectious disease posing a serious threat to human health, caused by Mycobacterium tuberculosis (MTB) infection. Although vaccination is the most effective way to prevent and control TB, the existing Bacillus Calmette–Guérin (BCG) vaccine exhibits limited protective efficacy in adult pulmonary TB. Therefore, developing a novel TB vaccine is an urgent need. MethodsThis study designed a novel multi-epitope vaccine (MEV) to combat MTB infection, utilizing bioinformatics and immunoinformatics approaches. Dominant epitopes of helper T lymphocytes (HTL), cytotoxic T lymphocytes (CTL), and B lymphocytes were selected from antigens of MTB to construct the MEV. To enhance the targeting and immunogenicity of the vaccine, toll like receptor (TLR) agonists and PADRE helper peptides were incorporated into the design. In addition, comprehensive predictions have been made on the physicochemical properties, three-dimensional structure, spatial conformation, and molecular interactions with TLRs of MEVs. These evaluations also extend to the exploration of their immunological characteristics. ResultsA novel MEV named ZL9810L was successfully constructed, based on 8 HTL epitopes, 9 CTL epitopes, 10 B lymphocyte epitopes, Toll-like receptor agonists, and auxiliary peptides. Bioinformatics analysis demonstrated that the ZL9810L vaccine has excellent immunogenicity and antigenicity, non-toxicity, and non-sensitization capability, capable of significantly inducing a strong immune response and solubility, with scores of 2.21451, 0.8913, and 0.455 respectively. Moreover, the global population coverage of HLA class I and II allele genes by the ZL9810L vaccine reached 72.89 % and 81.49 %, respectively. Molecular docking analysis indicated good binding capacities of the ZL9810L vaccine to TLR2 and TLR4 receptors, with binding energies of −1028.5 kcal/mol and −1018.8 kcal/mol respectively. Immune simulation predicted that the vaccine could effectively activate innate and adaptive immune cells, including NK cells, macrophages, B lymphocytes, and T lymphocytes. ConclusionAs a candidate for a novel TB vaccine, the ZL9810L vaccine exhibits significant immunogenicity and antigenicity, with no toxicity or allergenicity. The ZL9810L vaccine designed in this study provides a new vaccine candidate for TB control and prevention.

Host and pathogen genetic diversity shape vaccine-mediated protection to Mycobacterium tuberculosis.

To investigate how host and pathogen diversity govern immunity against Mycobacterium tuberculosis (Mtb), we performed a large-scale screen of vaccine-mediated protection against aerosol Mtb infection using three inbred mouse strains [C57BL/6 (B6), C3HeB/FeJ (C3H), Balb/c x 129/SvJ (C129F1)] and three Mtb strains (H37Rv, CDC1551, SA161) representing two lineages and distinct virulence properties. We compared three protective modalities, all of which involve inoculation with live mycobacteria: Bacillus Calmette-Guérin (BCG), the only approved TB vaccine, delivered either subcutaneously or intravenously, and concomitant Mtb infection (CoMtb), a model of pre-existing immunity in which a low-level Mtb infection is established in the cervical lymph node following intradermal inoculation. We examined lung bacterial burdens at early (Day 28) and late (Day 98) time points after aerosol Mtb challenge and histopathology at Day 98. We observed substantial heterogeneity in the reduction of bacterial load afforded by these modalities at Day 28 across the combinations and noted a strong positive correlation between bacterial burden in unvaccinated mice and the degree of protection afforded by vaccination. Although we observed variation in the degree of reduction in bacterial burdens across the nine mouse/bacterium strain combinations, virtually all protective modalities performed similarly for a given strain-strain combination. We also noted dramatic variation in histopathology changes driven by both host and bacterial genetic backgrounds. Vaccination improved pathology scores for all infections except CDC1551. However, the most dramatic impact of vaccination on lesion development occurred for the C3H-SA161 combination, where vaccination entirely abrogated the development of the large necrotic lesions that arise in unvaccinated mice. In conclusion, we find that substantial TB heterogeneity can be recapitulated by introducing variability in both host and bacterial genetics, resulting in changes in vaccine-mediated protection as measured both by bacterial burden as well as histopathology. These differences can be harnessed in future studies to identify immune correlates of vaccine efficacy.

Reply to McShane.

Reply to McShane.

The TB Vaccine Accelerator Council: harnessing the power of vaccines to end the tuberculosis epidemic

The TB Vaccine Accelerator Council: harnessing the power of vaccines to end the tuberculosis epidemic

The Use of Particulate Systems for Tuberculosis Prophylaxis and Treatment: Opportunities and Challenges.

The use of particles to develop vaccines and treatments for a wide variety of diseases has increased, and their success has been demonstrated in preclinical investigations. Accurately targeting cells and minimizing doses and adverse side effects, while inducing an adequate biological response, are important advantages that particulate systems offer. The most used particulate systems are liposomes and their derivatives, immunostimulatory complexes, virus-like particles, and organic or inorganic nano- and microparticles. Most of these systems have been proven using therapeutic or prophylactic approaches to control tuberculosis, one of the most important infectious diseases worldwide. This article reviews the progress and current state of the use of particles for the administration of TB vaccines and treatments in vitro and in vivo, with a special emphasis on polymeric particles. In addition, we discuss the challenges and benefits of using these particulate systems to provide researchers with an overview of the most promising strategies in current preclinical trials, offering a perspective on their progress to clinical trials.

Is neglect of self-clearance biasing TB vaccine impact estimates?

BackgroundMathematical modelling has been used extensively to estimate the potential impact of new tuberculosis vaccines, with the majority of existing models assuming that individuals with Mycobacterium tuberculosis (Mtb) infection remain...

No impact of helminth coinfection in patients with smear positive tuberculosis on immunoglobulin levels using a novel method measuring Mycobacterium tuberculosis-specific antibodies

Helminth/tuberculosis (TB)-coinfection can reduce cell-mediated immunity against Mycobacterium tuberculosis (Mtb) and increase disease severity, although the effects are highly helminth species dependent. Mtb have long been ranked as the number one single infectious agent claiming the most lives. The only licensed vaccine for TB (BCG) offers highly variable protection against TB, and almost no protection against transmission of Mtb. In recent few years the identification of naturally occurring antibodies in humans that are protective during Mtb infection has reignited the interest in adaptive humoral immunity against TB and its possible implementation in novel TB vaccine design. The effects of helminth/TB coinfection on the humoral response against Mtb during active pulmonary TB are however still unclear, and specifically the effect by globally prevalent helminth species such as Ascaris lumbricoides, Strongyloides stercoralis, Ancylostoma duodenale, Trichuris trichiura. Plasma samples from smear positive TB patients were used to measure both total and Mtb-specific antibody responses in a Peruvian endemic setting where these helminths are dominating. Mtb-specific antibodies were detected by a novel approach coating ELISA-plates with a Mtb cell-membrane fraction (CDC1551) that contains a broad range of Mtb surface proteins. Compared to controls without helminths or TB, helminth/TB coinfected patients had high levels of Mtb-specific IgG (including an IgG1 and IgG2 subclass response) and IgM, which were similarly increased in TB patients without helminth infection. These data, indicate that helminth/TB coinfected have a sustained humoral response against Mtb at the level of active TB only. More studies on the species-specific impact of helminths on the adaptive humoral response against Mtb using a larger sample size, and in relation to TB disease severity, are needed.