PE/PPE proteins and TCR-recognized immunoreactive peptides are suggested as promising vaccine components against tuberculosis and the designed MEV with the C-terminal fragment of CPE may represent a potential candidate for future development as a mucosal vaccine against M. tuberculosis.
Abstract
Mycobacterium tuberculosis infects one-fourth of the global population, and current challenges such as latent infections, multidrug-resistant strains, and the limited efficacy of the BCG vaccine emphasize the urgent need for next-generation vaccines. This study aimed to introduce novel vaccine candidates, immunoreactive epitopes, and a novel multi-epitope vaccine (MEV). New immunogenic targets were identified based on different characteristics, including subcellular localization, antigenicity, non-similarity to the host proteome, sequence conservation, prevalence, and B-cell and T-cell epitopes. In the next step, IFN-γ releasing immunoreactive epitopes with a high similarity to TCR-interacting epitopes were identified. The MEV was generated using shortlisted epitopes and the C-terminal fragment of Clostridium perfringens enterotoxin (CPE). Finally, the interactions of MEV epitopes with human MHC I and MHC II alleles were investigated. In the first step, a total of seven proteins with desired immunogenic properties were introduced as novel immunogenic targets. Comparison of surface-exposed proteins to 4718 immunoreactive linear B-cell epitopes of M. tuberculosis resulted in identification of 719 non-redundant immunoreactive epitopes. Finally, seven immunoreactive, IFN-γ releasing epitopes with significant homology to TCR binding epitopes were employed to design a MEV. This MEV showed desirable structural and immunogenic properties. Moreover, it revealed promising interactions with human MHC I and MHC II alleles in molecular docking. This study suggests PE/PPE proteins and TCR-recognized immunoreactive peptides as promising vaccine components against tuberculosis. In addition, the designed MEV with the C-terminal fragment of CPE may represent a potential candidate for future development as a mucosal vaccine against M. tuberculosis.
A computationally validated multi-epitope peptide vaccine construct with strong immunogenicity were generated, but validation through the in-vitro and in-vivo study of the developed vaccine is essential to assess its efficacy and immunogenicity profile.
Abebe Tesfaye Gessese, M. Kinde, Tegegne Eshetu et al.· Scientific Reports· 0 citations
Among infectious diseases, tuberculosis is the biggest cause of death worldwide. Thus, controlling TB, a global epidemic, is a major public health concern on a worldwide scale. According to epidemiological modelling, a new vaccination that can prevent TB, especially in adults and adolescents, is necessary to control the disease’s spread, even while medication therapies for the disease are still improving. The development of novel vaccines with broader applicability and improved, long-lasting effectiveness becomes increasingly crucial as strains resistant to various drugs emerge. This work designed a multi-epitope subunit vaccine (MESV) candidateusing immunoinformatic approaches that targets five virulence-associated proteins, Rv0227c, Rv0584, Lipoprotein LprA, Phospholipase C, and Antigen 85 C. Antigenicity, non-allergenicity, and non-toxicity were the criteria used to identify and filter potential CTL, HTL, and B-cell epitopes. High-affinity epitopes connected with suitable spacers and an adjuvant for improved immunogenicity were included in the carried-out vaccine formulation. Validation and structural modelling verified the MESV’s quality and stability. TLR2 and TLR4 receptors have strong interactions, which were further demonstrated through molecular docking, and molecular dynamics simulations showed low fluctuations and good structural stability. Further, the MMPBSA analysis was introduced to determine the binding affinity of the vaccine construct, and a more pronounced binding affinity was established by the designed vaccine with TLR4. Increased cytokine release, memory cell development, and the developed MESV candidateare viable options warranting further experimental validation, as it may elicit potent humoral and cellular immune responses against M. tuberculosis.
Swagat Ranjan Maharana, S. Khan, Kiran Mahapatra et al.· Scientific Reports· 0 citations
These computational results suggest that the construct has the potential to induce effective immunity against WELV, however further experimental validations in future have to be performed in order to confirm its efficacy against the pathogen.
Kadhirmathiyan Velumani, Sarumathi Umapathi, B. Shanmugaraj· Human Immunology· 0 citations
Background Tuberculosis remains a leading global infectious killer, with BCG offering inconsistent adult protection and rising drug-resistant strains demanding novel vaccine strategies. We report the first multi-epitope vaccine construct simultaneously targeting three previously unexplored Mycobacterium tuberculosis virulence proteins; EccB3, MycP, and polyketide synthase which collectively govern nutrient acquisition, ESX secretion integrity, and innate immune evasion. Methods Using a reverse vaccinology pipeline, B-cell, CTL, and HTL epitopes were predicted, filtered for allergenicity, toxicity, and IFN-γ induction, then assembled into an 823-residue chimeric construct incorporating beta-defensin and PADRE adjuvants with AAY/GPGPG linkers, covering ∼90% global HLA diversity. The construct underwent AlphaFold structure prediction, 3DRefine refinement, disulfide engineering, PROCHECK/ProSA validation, ClusPro 2.0 docking against TLR1/TLR2, and C-IMMSIM immune simulation. Results The construct (82.3 kDa, instability index 32.48) showed strong structural quality (94.7% favoured Ramachandran residues), stable TLR1/TLR2 binding (weighted energy: −1,371.0 kcal/mol), and robust in silico immune responses and durable memory cell formation following booster simulation. Conclusion This computationally validated construct represents a promising multi-target TB vaccine candidate warranting experimental advancement.
Community-acquired pneumonia (CAP) remains a major global health concern.
Mycoplasma pneumoniae
(
M. pneumoniae
) and
Chlamydia pneumoniae
(
C. pneumoniae
) are important atypical CAP pathogens, and reported coinfection may complicate diagnosis and management. However, no licensed vaccine simultaneously targeting both pathogens is currently available. In this context, mRNA-based multi-epitope vaccines represent a promising platform for bivalent vaccine design because they allow the integration of multiple epitopes into a single construct and may support both humoral and cellular immune responses. This study aimed to design bivalent multi-epitope mRNA vaccine candidates against
M. pneumoniae
and
C. pneumoniae
using an immunoinformatics-based strategy.
Conserved cytotoxic T-lymphocyte (CTL), helper T-lymphocyte (HTL), and linear B lymphocyte (LBL) epitopes were screened from selected antigenic proteins. Two constructs, MCV1 and MCV2, were assembled with distinct N-terminal immunostimulatory or helper-epitope modules and evaluated for antigenicity, safety, physicochemical and structural properties, receptor docking, three independent 100-ns molecular dynamics simulations, replicate-level MM-PBSA, immune simulation, population coverage, human codon optimization, and RNA secondary structure.
A total of 11 CTL, 5 HTL, and 14 LBL epitopes with ≥ 90% conservancy among the analyzed strain sequences were selected. Both core constructs were predicted to be antigenic, non-toxic, non-allergenic, and structurally acceptable. HADDOCK refinement yielded cluster-level scores of − 394.3 ± 7.3 for MCV1–TLR2 and − 399.0 ± 5.5 for the exploratory MCV2–TLR4 complex. Across three independent trajectories, MM-PBSA total binding free energies were − 125.19 ± 20.13 and − 126.87 ± 12.73 kcal/mol, respectively. C-ImmSim generated modeled profiles involving humoral and cellular immune components, and the estimated global population coverage was 97.90%. Human codon optimization yielded codon adaptation index values of 0.92 and 0.91 and GC contents of 61.06% and 60.94% for MCV1 and MCV2, respectively.
In this in silico study, two bivalent multi-epitope mRNA vaccine candidates against
M. pneumoniae
and
C. pneumoniae
were computationally prioritized. These findings provide a theoretical basis for subsequent experimental validation, while in vitro and in vivo studies are still required to verify their actual immunogenicity, protective efficacy, and safety.
Xuan Wu, Yizhong Xu, Weiwei Zhao et al.· BMC Microbiology· 0 citations
The rationally designed multi-epitope vaccine demonstrates robust theoretical potential to elicit comprehensive, long-lasting immunity in humans, although its safety and effectiveness require additional experimental validation.
Chenchen Yi, Yu Shen, Ye Luo et al.· Frontiers in Cellular and In...· 0 citations
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