INTERNATIONAL CONGRESS OF
PharmacoGenetics
Optimization Strategies and Expanding Horizons of mRNA Vaccine Technology: Stability, Efficacy, and Beyond
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Shirin Dehghan,1,* Abolfazl Mohammadi,2 Sara parvizifara,3 Zahra Barzagar,4
1. Genetics graduate, Kharazmi University
2. Azad Islamic University, Karaj
3. Department of Biology- Kharazmi University
4. Science teaching- Farhangian University, Zanjan
- Introduction: Messenger RNA (mRNA) vaccines have emerged as a groundbreaking platform in vaccinology, attracting significant global attention after their central role in combating the COVID-19 pandemic. Unlike conventional vaccines that rely on inactivated or attenuated pathogens, mRNA vaccines deliver synthetic strands encoding pathogen-specific antigens directly to host cells, initiating intracellular protein synthesis and eliciting immune responses without exposure to live agents. The rapid development of the Pfizer-BioNTech and Moderna vaccines—achieving ~95% efficacy against symptomatic COVID-19—demonstrated the platform’s unprecedented adaptability to emerging viral threats. Beyond infectious diseases, this technology shows promise in oncology, genetic therapy, and immune modulation.
- Methods: The review integrates data from recent clinical trials, structural biology studies, and molecular design research on mRNA vaccines. Sources include peer-reviewed literature on physicochemical determinants (pH, RNA length, and nucleotide sequence), delivery systems, and safety profiles. Special attention is given to how biochemical parameters influence mRNA stability, translational efficiency, and immunogenicity. Methodological emphasis is placed on correlating in vitro stability assays, computational sequence optimization tools (e.g., LinearDesign, RiboTree), and clinical performance metrics from phase I–III trials.
- Results: Key determinants of mRNA vaccine performance include: 1. pH Stability: Optimal stability is maintained near physiological pH (~7.4). Deviations accelerate RNA hydrolysis and impair protein translation. Buffer systems such as Tris-HCl stabilize pH during storage, while Mg²⁺ and Ca²⁺ ions influence hydrolytic rates. 2. RNA Length: Shorter RNAs degrade more readily, whereas overly long sequences may hinder delivery or trigger unintended immune responses. Poly(A) tails of ~120–150 nucleotides, along with optimized 5′ and 3′ UTRs, enhance stability and protein expression. 3. Sequence Optimization: Incorporating modified nucleosides (e.g., N1-methyl-pseudouridine) reduces innate immune activation and increases translation efficiency. Codon optimization, GC-content balancing, and structural motif refinement improve transcript half-life and ribosome loading efficiency. 4. Structural and Delivery Innovations: Next-generation designs, such as truncated antigen constructs (e.g., mRNA-1283), demonstrate improved thermal stability and storage duration. Circular RNA (circRNA) vaccines, due to their exonuclease resistance, maintain stability for up to 24 weeks at 4 °C. LNP modifications and excipients like sucrose further enhance shelf life. 5. Broader Applications: Personalized cancer vaccines targeting tumor-specific neoantigens, genetic therapies replacing defective proteins or delivering CRISPR/Cas9 components, and tolerogenic vaccines for autoimmune diseases illustrate the platform’s versatility.
- Conclusion: mRNA vaccine technology represents a paradigm shift in preventive and therapeutic medicine. Its speed, flexibility, and capacity for personalization enable rapid responses to pandemics and open new avenues for cancer immunotherapy, genetic disease treatment, and immune modulation. Optimization of pH conditions, RNA length, and nucleotide sequence—combined with advances in delivery and storage—will be critical to achieving maximal efficacy, stability, and global accessibility. Continued integration of computational design, novel biomaterials, and manufacturing innovations promises to expand the impact of mRNA therapeutics in diverse clinical domains.
- Keywords: mRNA vaccine, lipid nanoparticles, pH stability, RNA length
