Marvellous Messenger – The Magic of mRNA Vaccines

The human body is constantly encountering agents with the potential to make us ill. Most of the time these pathogens either fail to pass our physical barriers (like skin and mucus) or they lose the arms race with our ever-vigilant immune systems. Sometimes, though, we could do with some extra help - which is where vaccines come in.

The modern concept of "vaccination" originated with Edward Jenner, who showed in 1796 that an extract from a cowpox pustule could protect against smallpox, although the same principle had been used around the world long before that. Jenner's vaccine worked by training the immune system to recognise the smallpox virus by exposing it to the similar, but much less dangerous, cowpox virus. Many of the vaccines we use today utilise the same technique, exposing the body to a weakened or inactivated form of an infectious agent, such as a virus, in order to prime the immune system to fight off the live agent if we encounter it. This allows our bodies to mount a faster immune response, reducing or possibly preventing illness, and potentially stopping the spread of the disease to others.

Vaccination technology has not stood still though, and several of the Covid-19 vaccines that have been developed and approved to date rely on newer approaches that have come of age at just the right time. The most famous example is mRNA vaccine technology, put in the spotlight by the success of the Pfizer/ BioNTech and Moderna Covid-19 vaccines.  This article explores how mRNA vaccines work, how they differ from a more conventional vaccine, and what innovations in mRNA vaccine technology may lie ahead.

The so-called ‘central dogma' of molecular biology is ‘DNA to RNA to Protein'. This highlights the crucial role played by RNA, in particular messenger RNA or mRNA, as an intermediary between the instructions contained within our DNA and the proteins which carry out the various functions of our cells. In response to appropriate signals, a section of DNA (a "gene"), is copied (or "transcribed") into the sequence of a new mRNA molecule. This mRNA can then be read (or "translated") by the machinery in our cells to create a new protein. Viruses, such as the coronavirus responsible for Covid-19, survive by hijacking this process to create their own viral proteins, which are able to create new viruses.

For coronaviruses, a key protein that permits the infection of human cells is the spike protein. This protein is the target of many Covid-19 vaccines. The vaccines teach the immune system to recognise the spike, to target it (for example with antibodies), and so to disrupt its function - slowing or preventing infection.

More traditional vaccines expose the body to viral proteins, such as the spike protein, on the surface of a deactivated virus. The Oxford-AstraZeneca vaccine, which delivers DNA encoding the spike protein to patients, also makes use of an inactivated viral carrier. By contrast, mRNA vaccines work by directly providing our cells with the instructions to make the viral proteins, without the need for any form of viral carrier. The proteins then stimulate an immune response, such as the production of antibodies recognising the spike. An mRNA vaccine is therefore much less complex than vaccines based on viral vectors, as it has fewer, and simpler, components.

This has several advantages over a traditional vaccine. Firstly, it is easier to develop and produce, and has a shorter manufacturing time. This is of particular importance for combating emerging outbreaks of infectious diseases, such as the coronavirus pandemic. mRNA vaccines are also less expensive to manufacture, because they don't involve growing animal cells that are necessary to produce the viruses used in more traditional vaccines . For example, chicken eggs are typically used in the production of flu vaccines. They are also less likely to cause allergic reactions, which can occur in rare cases with traditional vaccines. Finally, perhaps the most exciting advantage of mRNA vaccines is their ability to target infectious diseases for which traditional vaccines are not effective, such as HIV, and even to treat non-infectious diseases, such as cancer.

This new technology did not arrive overnight, though. Several advances had to be made in order for effective mRNA vaccines to be produced. mRNA itself is an unstable molecule, and naked mRNA is quickly degraded by the body. It was therefore necessary first to develop novel methods of delivering the mRNA vaccine to patients. There are two main methods currently available.

The first is direct injection of mRNA. This has required advancements in carrier molecules, such as cationic lipids, which form a protective layer (a liposome) around the mRNA, protecting it from degradation, thereby facilitating delivery to cells. While this method is rapid and cost-effective, carriers which facilitate more precise and efficient delivery to specific cell types are still under development.

The second is ex vivo treatment of dendritic cells. Dendritic cells are one of the key cell types involved in the production of antibodies. Samples of these cells can be taken from patients and exposed to the mRNA vaccine. The dendritic cells will then produce the viral proteins encoded by the mRNA. These will then be presented on the surface of the cells, so that, when the cells are re-infused into the patient, they trigger the production of antibodies against the viral proteins. Ex vivo treatment of dendritic cells with mRNA vaccines has been shown effective at reducing tumour growth in mice, and therefore represents a promising new technology for the treatment of cancer. While this method of mRNA vaccine delivery is more precise and efficient than direct injection, it is costly and labour intensive, and so is not currently in use in patients.

Further, while mRNA vaccines are less likely to cause an adverse response than traditional vaccines, developments still had to be made in order to increase the safety of the vaccines. For example researchers have designed mRNA vaccines which more closely mimic mammalian RNA. This not only reduces the chance of an adverse reaction, but also increases the efficiency of production of the viral proteins within the body, thereby stimulating a more robust immune response against the virus, and providing better protection against infection.

Despite these advances, challenges still remain. For example, because RNA is so unstable, mRNA vaccines must be stored and transported at very low temperatures - the Moderna vaccine must be kept at -20°C and Pfizer originally required storage at -70°C. This presents an administrative challenge to mass vaccinations, particularly in developing countries. Further research is therefore required into carriers and methods of stabilising the mRNA to allow for storage at higher temperatures. Nevertheless it is clear that mRNA vaccines will play a key role in the fight against infectious diseases such as Covid-19, and hopefully also in many more diseases in future.