September 24, 2021

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Overview of the development of mRNA vaccines: Part Five

Overview of the development of mRNA vaccines:

Part Five Effectiveness, Safety and Prospects of mRNA Vaccine

 

 

Overview of the development of mRNA vaccines: Part Five. 

 

Part Five Effectiveness, Safety and Prospects of mRNA Vaccine

 

Effectiveness

mRNA vaccines can induce adaptive immunity in several possible ways:

(1) transfection of somatic cells, such as muscle cells and epidermal cells,

(2) transfection of immune cells residing in the tissue at the injection site,

(3) in the secondary lymph nodes Tissues (including lymph nodes (LN) and spleen) are transfected with immune cells (Figure 1).

 

Overview of the development of mRNA vaccines: Part Five. 

Figure 1 Mode of action of intramuscular injection of mRNA vaccine

 

For injected mRNA vaccines, the main considerations for effectiveness include: the level of antigen expression in professional antigen presenting cells (APC), its carrier efficiency, double-stranded RNA (dsRNA) or pathogen-related molecular patterns in the form of unmodified nucleosides ( PAMP) and the optimization level of RNA sequence (codon usage, G:C content, 5′ and 3′ untranslated regions (UTR), etc.); dendritic cells (DC) mature and migrate to secondary lymphoid tissues, PAMPs enhance this process; the ability of vaccines to activate powerful T follicular helper cells (TFH) and germinal center (GC) B cell responses-this area is still poorly understood. Figure 2 takes intradermal injection as an example to analyze the factors affecting the effectiveness of mRNA vaccine injection.

 

Overview of the development of mRNA vaccines: Part Five. 

Figure 2 Considerations on the effectiveness of direct injection of mRNA vaccines

 

 

Safety

Compared with many current vaccination strategies (such as DNA vaccines), mRNA production is faster, more flexible, and lower in cost, and can be used for precise and individualized treatment. At the same time, mRNA will not be integrated into the host genome, ensuring that Basic security. Compared with the production of most biological products, mRNA manufacturing has advantages. It does not require cell culture; the reaction time is fast and the risk of contamination is lower than that of other complex vaccine production. In addition, the non-integrated nature and transient expression in cells are conducive to the safety of mRNA.

The safety requirements of modern preventive vaccines are very strict, because vaccines are given to healthy people. Since the manufacturing process of mRNA does not require toxic chemicals or cell cultures that may be contaminated by foreign viruses, the production of mRNA avoids other vaccine platforms (including live viruses, viral vectors, inactivated viruses, and subunit protein vaccines). Common risks.

Several different mRNA vaccines have been tested in clinical studies from phase I to phase IIb, and the results show that they are safe and well tolerated. However, recent human trials have shown that there are moderate reactions at the injection site or throughout the body of different mRNA platforms, and severe reactions can occur in rare cases. Potential safety issues that may be evaluated in future preclinical and clinical studies include local and systemic inflammation, the biodistribution and persistence of expressed immunogens, stimulation of autoreactive antibodies, and the potential toxicity of any unnatural nucleotides and delivery system components effect. One thing that may cause people to worry is that some mRNA-based vaccine platforms will induce an effective type I interferon response, which is not only related to inflammation, but may also be related to autoimmunity. Therefore, to identify individuals with increased risk of autoimmune reactions before mRNA vaccination, reasonable preventive measures can be taken.

Another potential safety issue may stem from the presence of extracellular RNA during mRNA vaccination. Naked extracellular RNA has been shown to increase the permeability of tightly packed endothelial cells, which may cause edema. Another study showed that extracellular RNA can promote blood coagulation and pathological thrombosis. Because different mRNA models and delivery systems are used in humans for the first time and tested in a larger patient population, it is necessary to continue to evaluate their safety. In patients with systemic lupus erythematosus and other autoimmune diseases, it has been suggested that the production of anti-auto RNA antibodies may trigger and develop autoimmunity. In addition, the residual risk of toxic side effects associated with delivery compounds, complexing agents, and potential insertion of nucleotides still exists.

Regulatory guidelines for assessing the quality, safety, and effectiveness of RNA-based vaccines for the prevention of infectious diseases are currently being considered. The focus now is to establish a manufacturing process that can provide high-quality and consistent products. Therefore, it is necessary to define some key process steps and acceptance criteria, intermediates, bulk drug (DS) and drug (DP) specifications, for example, according to product yield and allow strict product quantification and characterization (product identification, purity and quality) analysis technology. The quality of mRNA can be assessed using a variety of analytical techniques, such as gel electrophoresis and high-performance liquid chromatography (HPLC), and its identity can be determined using sequencing techniques, such as reverse transcription polymerase chain reaction (RT-PCR) or next-generation sequencing. It must be determined whether there is residual DNA, enzymes and solvents, as well as dsRNA and truncated RNA fragments. In addition, as a general quality control, the presence of endotoxin, overall sterility and mRNA stability must also be evaluated.

 

 

Outlook

The mRNA-based vaccine is a promising new platform with high versatility, effectiveness, simplicity, scalability, low cost and no cold chain potential. Importantly, mRNA-based vaccines may fill the gap between emerging pandemic infectious diseases and rapid, adequate and effective vaccine supplies.

Compared with traditional vaccines, mRNA vaccine technology has great potential. This versatile RNA vaccine platform provides advantages in terms of speed and cost of discovery and development, the probability of success for many targets, and the rapid production of effective vaccines against new threats.

However, it is still too early to fully understand its safety and effectiveness in the human body. The results of two recently announced clinical trials of conventional mRNA vaccines against infectious diseases showed that they were generally well tolerated and immunogenic, but according to the results of animal experiments, the response was milder than expected.

It is necessary to further understand the mechanism of action to understand the impact of the innate immune response generated by the mRNA and delivery system, and to determine how to learn from animal species to transform into humans.

The next 5 years will be very important to the field of mRNA vaccines. The results of human clinical trials will enable people to have a clearer understanding of the true prospects of this technology, and in-depth understanding of the advantages and disadvantages of various mRNA technologies and delivery systems under development.

 

Overview of the development of mRNA vaccines: Part One

Overview of the development of mRNA vaccines: Part Two

Overview of the development of mRNA vaccines: Part Three

Overview of the development of mRNA vaccines: Part Four

Overview of the development of mRNA vaccines: Part Five

 

 

 

 

 

References:

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(source:internet, reference only)


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