An RNAvaccine or mRNA vaccine is a new type of vaccine for providing acquired immunity through an RNA containing vector, such as lipid nanoparticles. Just like normal vaccines, RNA vaccines are intended to induce the production of antibodies which will bind to potential pathogens. The RNA sequence codes for antigens, proteins that are identical or resembling those of the pathogen. Upon the delivery of the vaccine into the body, this sequence is translated by the host cells to produce the encoded antigens, which then stimulate the body’s adaptive immune system to produce antibodies against the pathogen. Another form of the mRNA vaccination is one in which the mRNA encodes for a fully human IgG antibody. In this form, the mRNA codes for antibodies that are identical or resembling those of the antibodies found in a patient with a prior history of potent immunity. Currently, there are no RNA vaccines approved for human use. RNA vaccines offer multiple advantages over DNA vaccines in terms of production, administration, and safety, and have been shown to be promising in clinical trials involving humans. RNA vaccines are also thought to have the potential to be used for cancer in addition to infectious diseases. Multiple companies, including CureVac and Moderna, work in the development of RNA vaccines, and a number of RNA vaccines are under development to combat the COVID-19 pandemic.
Advantages over DNA vaccines
In addition to sharing the advantages of DNA vaccines over protein vaccines, RNA vaccination offers further benefits that make it a more viable alternative to DNA vaccines. Some of these are outlined below.
The mRNA is translated in the cytosol. Therefore there is no need for the RNA to enter the cell nucleus, and the risk of being integrated to the host genome is averted.
Modified nucleosides can be incorporated to mRNA in order to suppress immune response stimulation to avoid immediate degradation and produce a more persistent effect through enhanced translation capacity.
An additional ORF coding for a replication mechanism can be added to amplify antigen translation and therefore immune response, decreasing the amount of starting material needed.
Adverse effects and risks
The mRNA strand in the vaccine may elicit an unintended immune reaction. To minimise this, the mRNA vaccine sequences are designed to mimic those produced by mammalian cells.
A possible concern could be that some mRNA-based vaccine platforms induce potent type I interferon responses, which have been associated not only with inflammation but also potentially with autoimmunity. Thus, identification of individuals at an increased risk of autoimmune reactions before mRNA vaccination may allow reasonable precautions to be taken.
Delivery
The methods of delivery can be broadly classified by whether the RNA transfer to cells happens within or outside the organism.
''Ex vivo''
s are a type of immune cells that display antigens on their surfaces, leading to interactions with T cells to initiate an immune response. DCs can be collected from patients and be programmed with mRNA. Then, they can be re-administered back into patients to create an immune response.
''In vivo''
Since the discovery of in vitro transcribed mRNA expression in vivo following direct administration, in vivo approaches have become more and more attractive. They offer some advantages over ex vivo methods, most significantly by avoiding the cost of harvesting and adapting DCs from patients and by imitating a regular infection. However, there are multiple obstacles for these methods that are yet to be overcome for RNA vaccination to be a potent procedure. Evolutionary mechanisms that prevent the infiltration of unknown nucleic material and promote degradation by RNases should be avoided in order to initiate translation. In addition, the mobility of RNA on its own is completely dependent on regular cell processes because it is too heavy to diffuse, consequently it is bound to be eliminated, halting translation.
The mode of mRNA uptake has been known for over a decade, and the use of RNA as a vaccine tool was discovered in the 1990s in the form of self-amplifying mRNA. It has also emerged that the different routes of injection, such as into the skin, blood or to muscles, resulted in varying levels of mRNA uptake, making the choice of administration route a critical aspect of delivery. Kreiter et al. demonstrated, in comparing different routes, that lymph node injection leads to the largest T cell response. It should be kept in mind that the mechanisms and consequently the evaluation of self-amplifying mRNA could be different, as they are fundamentally different by being a much bigger molecule in size.
Lipid nanoparticles
The idea of encapsulating mRNA in lipid nanoparticles has been attractive for a number of reasons. Principally, the lipid provides a layer of protection against degradation, allowing more robust translational output. In addition, the customization of the lipid outer layer allows the targeting of desired cell types through ligand interactions. However, many studies have also highlighted the difficulty of studying this type of delivery, demonstrating that there is an inconsistency between in vivo and in vitro applications of nanoparticles in terms of cellular intake. The nanoparticles can be administered to the body and transported via multiple routes, such as intravenously or through the lymphatic system.
Viral vectors
In addition to non-viral delivery methods, RNA viruses have been engineered to achieve similar immunological responses. Typical RNA viruses used as vectors include retroviruses, lentiviruses, alphaviruses and rhabdoviruses, each of which can differ in structure and function. Many clinical studies have utilized such viruses to attempt combating a range of diseases in model animals such as mice, chicken and primates.
