A Modular Self‐Assembling and Self‐Adjuvanting Multiepitope Peptide Nanoparticle Vaccine Platform to Improve the Efficacy and Immunogenicity of BCG

Small, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 5, 2025

Abstract After more than a century since its initial development, Bacille Calmette‐Guérin (BCG) remains the only licensed vaccine against tuberculosis (TB). Subunit boosters are considered viable strategy to enhance BCG efficacy, which often wanes in adolescence. While many studies on booster subunit vaccines have concentrated recombinant proteins, here we developed novel modular peptide‐based platform that is flexible, cold‐chain independent and customizable diverse circumstances populations. Each individual peptide building block consists of linear arrangement comprising 15‐leucine self‐assembly inducer moiety, Mycobacterium (Mtb) target epitope an human leukocyte antigen E (HLA‐E) binding with each moiety separated by triple lysine spacer. The blocks, any combination, able form multiepitope nanoparticle. Six Mtb epitopes were selected produce self‐assembling self‐adjuvating TB nano‐vaccine candidate PNx6. In vivo vaccination‐challenge experiments demonstrated subcutaneous boost parenteral immunization PNx6 significantly enhanced immunogenicity improved protective efficacy murine model 5‐fold. This study presents evidence purely amphiphilic peptides self‐assemble into nanoparticles appropriate size morphology for vaccination great potential multitude other diseases.

Language: Английский

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Advances in Host–Pathogen Interactions in Tuberculosis: Emerging Strategies for Therapeutic Intervention

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(4), P. 1621 - 1621

Published: Feb. 14, 2025

Tuberculosis (TB) remains one of the most challenging infectious diseases, with Mycobacterium tuberculosis (Mtb) employing sophisticated mechanisms to evade host immunity and establish persistent infections. This review explores recent advances in understanding Mtb's immune evasion strategies; granuloma dynamics; emerging immunotherapeutic approaches. Key findings highlight manipulation autophagy; metabolic reprogramming; cytokine pathways by Mtb sustain its survival within cells. Insights into formation reveal critical role bacterial lipids; modulation; hypoxia-driven dormancy maintaining chronic infection. Innovative therapeutic strategies, including host-directed therapies; epigenetic interventions; immunomodulators, hold promise for improving TB management combating drug-resistant strains. Despite these advancements, significant challenges remain, development effective vaccines; addressing latent TB; ensuring equitable access novel treatments. The integration advanced technologies such as artificial intelligence multi-omics approaches, alongside global collaboration, is essential overcome hurdles. underscores importance a multidisciplinary approach tackling TB, ultimate goal eradicating this health threat.

Language: Английский

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ESAT-6 protein suppresses allograft rejection by inducing CD4+Foxp3+ regulatory T cells through IκBα/cRel pathway

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 15

Published: Jan. 9, 2025

Maintenance immunosuppression is required for suppression of alloimmunity or allograft rejection. However, continuous use immunosuppressants may lead to various side effects, necessitating the alternative immunosuppressive drugs. The early secreted antigenic target 6 kDa (ESAT-6) a virulence factor and immunoregulatory protein mycobacterium tuberculosis (Mtb), which alters host immunity through dually regulating development activation immune cells. ESAT-6 be potential immunosuppressant that could utilized suppress rejection although it remains unknown whether actually regulates alloimmunity. In this study, murine skin heart allotransplantation was performed determine effects on survival. Flow cytometric analyses were conducted quantify CD4+Foxp3+ Tregs, while immunohistochemistry carried out observe immunopathology. Western blotting used detect IĸBα/c-Rel signaling during Treg induction. Finally, CD4+CD25- conventional T cells cultured induce Tregs their proliferation. Here we found significantly extended survival, alleviated CD3+ cell infiltration increased Foxp3+ in an allograft. augmented percentage whereas decreased frequency Th1 CD4+/CD8+ effector spleen lymph nodes (LNs) posttransplantation. also induced from vitro by activating pathway, inhibition c-Rel blocked Moreover, suppressed proliferation absence antigen-presenting (APCs), with increase IL-10 decrease IFN-γ production. On other hand, did not alter DC maturation after allotransplantation. Thus, suppresses inhibits inducing pathway.

Language: Английский

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Novel mRNA vaccines induce potent immunogenicity and afford protection against tuberculosis

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: Feb. 13, 2025

Introduction Mycobacterium tuberculosis ( Mtb ) is the causative agent of (TB), a disease with severe global burden. The intractability has prevented identification clear correlates protection against TB and hindered development novel vaccines that are urgently required. Lipid nanoparticle (LNP)-formulated mRNA highly promising vaccine platform yet to be thoroughly applied TB. Methods We selected five antigens (PPE15, ESAT6, EspC, EsxI, MetE) evaluated their potential as LNP-formulated vaccines, both when each antigen was delivered individually, all were combined in mix regimen (m-Mix). Results Each construct demonstrated unique cellular humoral immunogenicity, m-Mix, well single conferred significant murine challenge model. Whilst potent immune responses maintained boost BCG, there no additional increase efficacy BCG. Combination m-Mix recombinant, replication-deficient chimpanzee adenovirus (ChAdOx1), heterologous prime-boost delivery (C-m-Mix), appeared result increased upon infection, than either alone. Discussion This work warrants further investigation for TB, whilst indicating C-m-Mix progress stages development.

Language: Английский

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In Silico Targeting and Immunological Profiling of PpiA in Mycobacterium tuberculosis: A Computational Approach

Pathogens, Journal Year: 2025, Volume and Issue: 14(4), P. 370 - 370

Published: April 9, 2025

Tuberculosis (TB) remains a leading cause of mortality, with drug resistance highlighting the need for new vaccine targets. Peptidyl-prolyl isomerase A (PpiA), conserved Mycobacterium tuberculosis (Mtb) protein, plays role in bacterial stress adaptation and immune evasion, making it potential target immunotherapy. This study uses computational methods to assess PpiA’s antigenicity, structural integrity, immunogenic potential. The PpiA sequence was retrieved from NCBI analyzed antigenicity allergenicity using VaxiJen, AllerTOP, AllergenFP. Physicochemical properties were evaluated ProtParam, models generated through PSIPRED SWISS-MODEL. Structural validation performed MolProbity, QMEANDisCo, ProSA-Web. B-cell epitopes predicted BepiPred 2.0 IEDB, while T-cell mapped via IEDB’s MHC-I MHC-II tools. Epitope conservation across Mtb strains confirmed ConSurf. Results indicate is highly antigenic, non-allergenic, stable, several identified both B- T-cells. supports as promising TB development.

Language: Английский

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Advancement in diagnostic approaches for latent tuberculosis: distinguishing recent from remote infections

One Health Outlook, Journal Year: 2025, Volume and Issue: 7(1)

Published: April 9, 2025

Tuberculosis (TB) remains as a significant global health threat to date, with latent TB infection (LTBI) serving major reservoir for future active disease cases. A practical approach an effective control and eradication of hence, requires explicit identification infected patient whom are at high risk progressing from TB, particularly in those recently individuals. Current diagnostic tools however, including Tuberculin Skin Test Interferon-Gamma Release Assays, still lacking their ability critically distinguish between recent remote infections, leading insufficiency optimizing targeted preventive treatment strategies. This review examines the limitations current explores novel biomarkers enhance distinction within timeline LTBI diagnostics. Advancement immune profiling, dormancy antigen, along molecular transcriptomic approaches holds great promise develop better accuracy differentiate thereby interventions improve These underscores need further research into these emerging facilitate public strategies contribute united efforts End Strategy.

Language: Английский

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Advances in electrochemical biosensors for the diagnosis of tuberculosis: Perspectives for control and eradication of the disease

Microchemical Journal, Journal Year: 2025, Volume and Issue: unknown, P. 113622 - 113622

Published: April 1, 2025

Language: Английский

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Therapeutic DNA Vaccine Targeting Mycobacterium tuberculosis Persisters Shortens Curative Tuberculosis Treatment

Published: Sept. 7, 2024

Abstract Mycobacterium tuberculosis ( Mtb) is one of the leading infectious causes death worldwide. There no available licensed therapeutic vaccine that shortens active (TB) disease drug treatment and prevents relapse, despite World Health Organization’s calls. Here, we show an intranasal DNA containing a fusion stringent response rel Mtb gene with encoding immature dendritic cell-targeting chemokine, MIP-3α/CCL20, duration curative TB in immunocompetent mice. Compared to first-line regimen for drug-susceptible alone, our novel adjunctive induced greater Rel -specific T-cell responses associated optimal control spleen, blood, lungs, mediastinal lymph nodes, bronchoalveolar lavage (BAL) fluid. These were sustained, if not augmented, over time. It also triggered more effective cell recruitment, activation, colocalization T cells, implying enhanced crosstalk between innate adaptive immunity. Moreover, it potentiated 6-month drug-resistant regimen, rendering across regimens, showed promising results CD4+ knockout mice, perhaps due Rel-specific CD8+ responses. Notably, was immunogenic nonhuman primates, gold standard animal model studies, eliciting antigen-specific blood BAL fluid analogous those observed protected Our findings have critical implications clinical development immunocompromised populations may serve as defining immunological correlates vaccine-induced protection. One sentence summary A mice by strong TB-protective immune induces similar macaques.

Language: Английский

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A modular self-assembling and self-adjuvanting multiepitope peptide nanoparticle vaccine platform to improve the efficacy and immunogenicity of BCG

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 5, 2024

Abstract After more than a century since its initial development, Bacille Calmette-Guérin (BCG) remains the only licensed vaccine against tuberculosis (TB). Subunit boosters are considered viable strategy to enhance BCG efficacy, which often wanes in adolescence. While many studies on booster subunit vaccines have concentrated recombinant proteins, here we developed novel modular peptide-based platform that is flexible, cold-chain independent and customizable diverse circumstances populations. Each individual peptide building block consists of linear arrangement comprising 15-leucine self-assembly inducer moiety, Mycobacterium (Mtb) target epitope an HLA-E binding with each moiety separated by triple lysine spacer. The blocks, any combination, were able form multiepitope nanoparticle. Six Mtb epitopes selected produce self-assembling self-adjuvanting TB nano-vaccine candidate PNx6. In vivo vaccination-challenge experiments demonstrated subcutaneous boost parenteral immunization PNx6 significantly enhanced immunogenicity improved protective efficacy murine model 5-fold. Our study present evidence purely amphiphilic peptides self-assemble into nanoparticles appropriate size morphology for vaccination great potential multitude other diseases.

Language: Английский

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Host Immune Pathways to Mycobacterium tuberculosis Infection

Journal of Bacteriology and Virology, Journal Year: 2024, Volume and Issue: 54(3), P. 167 - 190

Published: Sept. 30, 2024

Language: Английский

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