mRNA Vaccines - Why Are They Preferred Over Conventional Vaccines?

 by Christine Zhou

mRNA in vitro transcription, innate and adaptive immunity activation

Vaccines are biological preparations that stimulate the immune system to produce a protective immune response against specific pathogens, preventing or reducing the severity of infectious diseases in the future.

Conventional vaccines typically involve the use of inactivated or weakened forms of the pathogen to stimulate the immune response. Scientists first identify the pathogen responsible for a particular condition and cultivate it in the lab. Then the pathogen is treated by either chemical, heat, radiation or UV light for inactivation, which disrupts its genetic material to stop them from replicating and causing the disease while remaining the antigen on their membrane surface. Hence the prepared pathogen is used as the basis for the vaccine, which is then injected into the recipient. Once in the body, the immune system can recognise the antigen as foreign invaders and generate antibodies along with the memory cells. These memory cells remember this pathogen and are able to respond rapidly when the disease-causing pathogen with the same antigen infects. Although conventional vaccines have a long history of success in preventing and controlling infectious diseases, it has several disadvantages. For example, developing and manufacturing conventional vaccines can be time-consuming, culturing pathogens in the lab introduces the risk of contamination, and the vaccines may still cause mild infections or allergic reactions in patients.

In contrast, mRNA vaccines can be developed more quickly than conventional vaccines since culturing live pathogens is not needed, and the genetic sequence of the pathogen can be readily determined using advanced sequencing technologies. It is also easy to tweak RNA sequences to adapt to the rapidly-mutating pathogens. These allow for a faster response to emerging infectious diseases, making the mRNA vaccine valuable during pandemics. Moreover, allergic reactions are extremely rare, making it a safer vaccine. 

In order to create an mRNA vaccine, scientists first identify a key antigen associated with the target pathogen and then the mRNA sequence that codes for that antigen is determined by gene sequencing, via the route of synthesising cDNA by reverse transcription, using PCR to amplify these cDNA and sequencing of them. After attaining the mRNA sequence, the mRNAs are produced by transcription from the cDNA templates and act as a basis of the vaccine. Afterwards, delivering them into the cells could be challenging, because the RNA sequences and secondary structures may be recognised and destroyed by the innate immune system as soon as they are injected into the body. However, these limitations can be overcome by optimising the codons, using modified nucleosides to avoid recognition as they mimic the naturally occurring nucleosides in cellular RNA, and packaging RNA into protective lipid nanoparticles for shielding the enzymes in the extracellular environment from the mRNA to prolong its stability and ensure it to reach its target cells. 

Once inside the body cells, the mRNA is translated into the antigen, which is then displayed on the cell surface where it can be recognised by the immune system. Some mRNA vaccines also contain additional mRNA coding for an enzyme, RdRp, that can generate multiple copies of the antigen-encoding mRNA after being translated in the host cells. This essentially amplifies the production of antigen from a small amount of vaccine, making the vaccine more effective. These vaccines are called self-amplifying vaccines. As RNA molecules do not enter the nuclei of host cells, the possibility of integrating into the cell genome is low. The RNA strands are usually degraded by cellular enzymes once the protein is made. The immune system recognises the antigen as foreign and starts to produce antibodies even though it is harmless. After the initial immune response, memory cells are generated, and they can remember this antigen and are ready to respond rapidly if the individual is exposed to the actual pathogen in the future.

mRNA holds great potential for the future of healthcare. Beyond mRNA vaccines, mRNAs could also have potential use in cancer treatments, rare genetic disorders, and autoimmune diseases.