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Messenger RNA (mRNA) vaccines have emerged as a transformative platform in modern vaccinology. mRNA vaccine is a powerful alternative to traditional vaccines due to their high potency, safety, and efficacy, coupled with the ability for rapid clinical development, scalability and cost-effectiveness in manufacturing. Initially conceptualized in the 1970s, the first study about the effectiveness of a mRNA vaccine against influenza was conducted in 1993. Since then, the development of mRNA vaccines has rapidly gained significance, especially in combating the COVID-19 pandemic. Their unprecedented success during the COVID-19 pandemic, as demonstrated by the Pfizer-BioNTech and Moderna vaccines, highlighted their transformative potential. This review provides a comprehensive analysis of the mRNA vaccine technology, detailing the structure of the mRNA vaccine and its mechanism of action in inducing immunity. Advancements in nanotechnology, particularly lipid nanoparticles (LNPs) as delivery vehicles, have revolutionized the field. The manufacturing processes, including upstream production, downstream purification, and formulation are also reviewed. The clinical progress of mRNA vaccines targeting viruses causing infectious diseases is discussed, emphasizing their versatility and therapeutic potential. Despite their success, the mRNA vaccine platform faces several challenges, including improved stability to reduce dependence on cold chain logistics in transport, enhanced delivery mechanisms to target specific tissues or cells, and addressing the risk of rare adverse events. High costs associated with encapsulation in LNPs and the potential for unequal global access further complicate their widespread adoption. As the world continues to confront emerging viral threats, overcoming these challenges will be essential to fully harness the potential of mRNA vaccines. It is anticipated that mRNA vaccines will play a major role in defining and shaping the future of global health.

Influenza remains a significant public health concern, particularly among high-risk populations, due to its capacity to cause annual epidemics and potentially trigger global pandemics. Despite the availability of countermeasures such as vaccines and antiviral treatments, their effectiveness is hindered by factors such as resistance development with manufacturing of the influenza vaccine still heavily relying on decades-old technologies. This review therefore examines the mechanisms by which influenza viruses evade host immunity and evaluates current and emerging approaches to enhance vaccine-mediated protection. Advances targeting the conserved hemagglutinin (HA) stem, incorporating multiple HA subtypes, and the use of adjuvants are discussed, alongside increased attention to neuraminidase (NA) and other viral components as immunogenic targets. Strategic epitope prediction, through glycan masking, evolutionary forecasting, and consensus sequence design, offer promising frameworks for rational vaccine design. Furthermore, delivery platforms, including recombinant protein, mRNA, and conjugate vaccines are explored for their potential to elicit broad and durable immunity. Collectively, these developments highlight a multifaceted approach towards the design of effective interventions against this persistent healthcare challenge.

Triple-negative breast cancer (TNBC) represents a particularly aggressive subtype of breast cancer lacking expression of estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER2), leading to restricted treatment options and unfavorable outcomes and prognosis. This research employs immunoinformatics and reverse vaccinology strategies to develop novel multi-epitope protein and mRNA vaccines targeting TNBC-associated antigens. By using a detailed scoring system, we identified seven extracellular proteins (TROP-2, EpCAM, MUC1, NECTIN4, Folate Receptor α, Mesothelin, α-Lactalbumin) and two intracellular proteins (MAGE-A, NY-ESO-1) as targets for the vaccine. Through a thorough process of predicting and validating epitopes, we discovered 18 MHC-I epitopes, 1 MHC-II epitope, and 2 B-cell epitopes with considerable binding affinity and population coverage (87.75% for the Persian-Iranian cohort), with an emphasis on the MHC-I pathway. The constructed protein vaccine demonstrated favorable physicochemical characteristics, structural stability, non-toxicity, and non-allergenic potential. TLR4 was found to be the primary pattern recognition receptor for adjuvant interaction, and molecular docking illustrated strong binding strength. In constructing the mRNA vaccine, we included N-5′ m7GCap, 5′ UTR, Kozak sequence, signal peptide (tPA), MHC epitopes, linker, MITD sequence, stop codon, 3′ UTR, and poly-A tail. Consequently, the design of the mRNA vaccine integrated optimized codon sequences with relevant regulatory components, achieving a Codon Adaptation Index of 0.93. Furthermore, we propose an innovative four-part mRNA vaccine approach to balance therapeutic effectiveness with clinical practicalities. Both vaccine formulations showed intense immune stimulation in silico, indicating their potential as promising candidates for immunotherapy against TNBC, which will require further experimental exploration.

Tuberculosis (TB), caused by Mycobacterium tuberculosis , remains a major global health burden due to latent infection, multidrug resistance, and the limited efficacy of the BCG vaccine. To address this challenge, we computationally designed and evaluated a circular mRNA-based multi-epitope vaccine candidate, TZ1391. Five experimentally validated M. tuberculosis antigens (ESAT-6, CFP-10, Ag85B, PPE18, and HspX) were used to predict immunodominant cytotoxic T lymphocyte (CTL), helper T lymphocyte (HTL), and B-cell epitopes. Three vaccine constructs (MTB-C1, MTB-C2, and MTB-C3) were assembled by integrating 20 CTL, 20 HTL, and 20 B-cell epitopes with appropriate linkers, PADRE sequence, and innate immune adjuvants. Structural modeling using AlphaFold2 and GalaxyRefine confirmed stable, native-like conformations for all constructs, with MTB-C3 showing the highest structural quality (GDT-HA = 0.8782; RMSD = 0.646 Å) and the greatest number of stabilizing disulfide bonds. Molecular docking against TLR3, TLR4, and TLR8 identified two top-performing candidates. MTB-C3 exhibited the strongest interaction with TLR3, achieving the lowest HDock score (− 480.53) and highest confidence score (0.9987), while MTB-C2 showed optimal binding to TLR4 (ClusPro score − 1488.6; confidence 0.9700). Despite favorable TLR4 engagement by MTB-C2, MTB-C3 was prioritized as the lead candidate (TZ1391) due to its superior structural stability, reduced conformational fluctuations during molecular dynamics simulations, and stronger TLR3 binding free energy (ΔG_bind = − 173.25 ± 7.9 kcal/mol). Immune simulations further predicted that TZ1391 elicits a robust Th1-biased response, characterized by sustained IgG production, strong IFN-γ and IL-2 induction, and durable immune memory. Overall, the strong TLR3-mediated interaction, combined with enhanced structural stability and favorable immunogenic profiles, establishes TZ1391 as a promising multi-epitope vaccine candidate for further experimental validation against tuberculosis. Graphical abstract

Background: Latent tuberculosis infection (LTBI) is the principal reservoir for active tuberculosis, with >85% of cases attributable to reactivation. Bacillus Calmette-Guérin fails to block this transition, leaving a critical gap in prevention. Methods: An immunoinformatics/reverse-vaccinology pipeline was applied to seven dormancy-related antigens retrieved from Mycobrowser. T-cell epitopes were predicted with NetMHCI/IIpan-4.1 and B-cell epitopes with ABCpred; antigenicity, allergenicity, and toxicity were evaluated with VaxiJen, AllerTOP, and ToxinPred. Secondary/tertiary structures were modeled with PSIPRED and AlphaFold-3; docking to Toll-like receptors (TLR) 2/4 and 100 ns molecular dynamics simulations assessed complex stability. Immune responses were simulated with C-ImmSim, and the mRNA sequence was human-codon-optimized using ExpOptimizer. Results: The resulting construct, RP14914P, encodes 14 cytotoxic T lymphocyte, 9 helper T lymphocyte, and 14 B-cell epitopes within an 866-aa, 90.4 kDa polypeptide. Antigenicity score = 0.7797, immunogenicity score = 8.58629. and no toxicity or allergenicity was predicted. Physicochemical analysis: instability index = 28.65, and solubility = 0.513. Estimated population coverage is 82.35% and 99.67% for Human Leukocyte Antigen (HLA)-I and HLA-II globally. Docking energies: −1477.8 kcal/mol (TLR2) and −1480.1 kcal/mol (TLR4). Molecular dynamics trajectories confirm stable binding. Immune simulation predicts potent activation of Natural Killer cells, macrophages, and dendritic cells, Th1 polarization, high interferon-γ/interleukin-2 secretion, and durable memory. Conclusions: In silico analyses predict that RP14914P exhibits favorable immunogenicity, safety, and broad population coverage, suggesting its potential as a promising mRNA vaccine candidate to prevent LTBI reactivation. However, these computational predictions require thorough experimental validation to confirm the vaccine’s immunogenicity and protective efficacy.

The landscape of cancer immunotherapy has been redefined by mRNA vaccines as rapid clinically viable strategies that help induce potent, tumor-specific immune responses. This review highlights the current advances in mRNA engineering and antigen design to establish an integrated immunological framework for cancer vaccine development. Achieving durable clinical benefit requires more than antigen expression. Effective vaccines need precise epitope selection, optimized delivery systems, and rigorous immune monitoring. The field is shifting from merely inducing immune responses to focusing more on the biochemistry and molecular design principles that combine magnitude, polyfunctionality, and longevity to overcome tumor-induced immune suppression. We examine an integrated immunological framework for mRNA cancer vaccine development, examining how rational molecular engineering of vaccine components, from nucleoside modifications and codon optimization to untranslated regions and linker sequences, shapes immunogenicity and therapeutic efficacy. Future directions will depend on balancing combinatorial strategies combining vaccination with immune checkpoint inhibitors and adoptive cell therapies.