Table 13.
The major advantages and disadvantages of the various types of mRNA vaccines.
| Type | Advantages | Disadvantages | |
|---|---|---|---|
| History of mRNA Vaccines | Naked IVT mRNA | - Self-adjuvant potential - Activation of innate and adaptive immunity - Inability to integrate the genome - Inexpensive, simple, reproducible, and fast synthesis procedure - Universal applicability |
- Low transfection efficiency - Intensified and/or boost administrations required - Insufficient for providing complete protective immunity - High type I IFN signaling - Reduced translatability - Optimizations required to reduce immunogenicity (i.e. nucleoside modification and purification from double-stranded RNA) |
| Adjuvant-tethered IVT mRNA | - Enhanced innate immunostimulation - Facilitated transfection of antigen-presenting cells - Low IFN-driven immunogenicity - Ease of production |
- High type I IFN signaling - Reduced translatability - Intricate production to achieve optimal mass ratios of antigen/adjuvant |
|
| RNActive mRNA | - Preserved translatibility - High antigen expression - Enhanced stimulation of innate immunity by TLR7 - Facilitated transfection of antigen-presenting cells - Stronger and more balanced adaptive immunity - Favorable safety profile with low-grade adverse events - Stable at room temperature - Ease of lyophilization for transportation and distribution |
- Inefficient for driving immunogenicity by needle injection | |
| Current status of mRNA Vaccines | Liposome-entrapped IVT mRNA | - Protection of mRNA from degradation - Enhanced internalization by dendritic cells - Easily functionalized with ligands to achieve targeted delivery - Good biocompatibility - Ease of fabrication - Good scalability - Low batch-to-batch variability |
- Unrestricted protein binding - Colloidal instability - Risk of mRNA leakage - Risk of neutralization of cationic liposomes by anionic serum proteins leading to cytotoxicity and reduced efficacy - Difficulty with lyophilization for transportation and distribution |
| LNP-entrapped IVT mRNA | - High encapsulation efficiency - Enhanced mRNA transfection efficiency and antigen presentation - Endosomal escape capacity - Protection of mRNA from degradation - Activation of cellular and humoral immunity - Favorable safety profile with low-grade toxicity - Reliable and reproductive production |
- Risk of low delivery efficiency with cationic lipids - Insufficient information regarding the immunogenicity of lipids used - High frequency and moderate severity of local injection site reactions and systemic adverse events - Short-term and low stability - Difficulty with lyophilization for transportation and distribution |
|
| Polymeric NP-entrapped IVT mRNA | - Enhanced immunogenicity - High stability - Facilitated uptake by dendritic cells - Facilitated intranasal delivery - Activation of dendritic cells maturation and cytolytic T cells - Enhanced safety - Biodegradability - Ease of production |
- Polydispersity - Challenges with metabolism of large molecular weight polymers - Limited animal studies |
|
| Scaffolds for delivery of IVT mRNA | - Slow, local, prolonged release of mRNA - High local transgene expression - Enhanced production of cytotoxic T cells - Biodegradability - Versatile production techniques for different scaffold shapes and porosities |
- Invasive surgical implantation required | |
| Future of mRNA Vaccines | Self-amplifying mRNA | - High level of RNA amplification and transgene expression - Humoral and cellular responses elicited against expressed antigen - Safe due to lack of viral genes for structural protein assembly - No risk of genome integration - Ease of large-scale synthesis for various antigens |
- Prime and/or boost administrations may be required - Delivery via nanocarriers may be required - Insufficient information regarding the immunogenicity of RDRP complex - Insufficient information regarding the safety of prolonged RNA amplification and expression |
| Trans-amplifying mRNA | - High translation efficiency - Enhanced intracellular delivery - Activation of protective immunity at low RNA doses - No interference with cellular translation - Favorable safety profile - Simple, fast, and cost-efficient production - Universal applicability - Ability to optimize each of the two components independently |
- Limited preclinical and clinical data - Insufficient information regarding the safety of sustained trans-replicase activity |
|