how it works in nature and in the manufacture of vaccines

Vaccines have long been an integral part of public health programs around the world, reducing the spread and severity of infectious diseases. The success of vaccination strategies aimed at protecting children against diseases such as polio, hepatitis B and measles, and adults against influenza and pneumococcal disease, can be observed around the world.

The COVID-19 pandemic has created an urgent need for an effective vaccine. This is where messenger RNA (mRNA) vaccines, which are classified as a next-generation technology, gained prominence. Decades of research and clinical development on synthetic mRNA platforms for cancer treatments and vaccines against infectious diseases like influenza, malaria and rabies have finally paid off as COVID-mRNA vaccines 19 from Moderna and Pfizer / BioNTech have received emergency use authorization. As a result, mRNA technologies have been catapulted into the public spotlight.

Develop synthetic mRNAs in vaccines

Ribonucleic acid (RNA) is a naturally occurring molecule found in all of our cells. There are many types of RNA, each with distinct functions. As the name suggests, mRNA acts as an important messenger in human cells. These molecules carry unique codes that tell our cells what proteins to make and when to make them. The code is copied from a strand of DNA in the nucleus of the cell, in a process called transcription. The mRNA is then transported into the cytoplasm (the solution contained in the cell) where the message is “read” and translated by the cell’s protein production machinery. The result is an important protein, such as an enzyme, antibody, hormone, or structural component of the cell.

Nearly 40 years ago, scientists discovered that they could mimic transcription and produce synthetic mRNA without cells. The process, known as in vitro transcription, can generate many mRNA molecules from a strand of DNA in a test tube. It requires an enzyme (called RNA polymerase) and nucleotides (the molecules that are the building blocks of DNA and RNA). When mixed, the polymerase reads the DNA strand and converts the code into an mRNA strand, binding different nucleotides together in the correct order.

When mRNA transcribed in vitro is introduced into a cell, it is “read” by the cell’s protein production machinery in a manner similar to how natural mRNA works. In principle, the process can be used to generate synthetic mRNA which encodes any protein of interest. In the case of vaccines, mRNA encodes a piece of a viral protein known as an antigen. Once translated, the antigen triggers an immune response to help protect against the virus. MRNA is short lived and does not alter the DNA of the cell. It is therefore safe for the development of vaccines and therapies.

A major advantage of in vitro transcription is that it does not require cells to produce mRNA. It has some manufacturing advantages over other vaccine technologies – fast turnaround times and reduced biosecurity risks, for example. It took just 25 days to manufacture a clinical batch of Moderna’s lipid nanoparticle mRNA vaccine candidate, which in March 2020 became the first COVID-19 vaccine to enter human clinical trials.

Importantly, since in vitro transcription is cell-free, the synthetic mRNA manufacturing pipeline is flexible and new vaccines or therapies can be streamlined in existing facilities. By changing the DNA code, facilities can easily switch from producing one type of mRNA vaccine to another. This not only helps to sustain existing mRNA production facilities, but could prove vital for rapid vaccine responses to new pandemics and emerging disease outbreaks.

How do mRNA vaccines work?

The mRNA vaccines we know today have benefited from many years of research, design and optimization. Understanding how synthetic RNA is recognized in cells has been found to be essential in developing effective vaccines. Typically, the mRNA encodes a known viral antigen. In the case of COVID-19 mRNA vaccines, sequences encoding the SARS-CoV-2 spike protein or the receptor binding domain have been used. These mRNA molecules encoding the antigen are incorporated into very small particles consisting mainly of lipids (fats). The lipid particle has two main functions: it protects mRNA from degradation and helps to transport it into the cell. Once in the cytoplasm, mRNA is translated into an antigen that triggers an immune response.

This process is essentially a training exercise for your immune system, and it normally takes a few weeks for your adaptive immunity to mature and synchronize. MRNA vaccines have been shown to stimulate both arms of the adaptive immune response, which are important in establishing protection. Humoral immunity (B cells) produces antibodies while cellular immunity (T cells) helps detect infected cells. The current COVID-19 mRNA vaccination schedule uses a two-dose (prime-boost) approach, which aims to boost your adaptive immune response against the SARS-CoV-2 virus.

Read more: COVID-19 vaccines produce T-cell immunity that lasts and works against viral variants

Another type of mRNA vaccine, called self-amplifying RNA, may require only one low dose to achieve the same level of protection. In a cell, these self-amplifying RNA vaccines can copy the mRNA code. This means that more antigen can be produced from less RNA. Several COVID-19 RNA vaccines currently in clinical trials explore self-amplifying RNA technologies.

MRNA vaccines beyond COVID-19

It is an exciting time for mRNA technologies. Through the collaborative efforts of governments, funding agencies, universities, biotechnology and pharmaceutical companies, large-scale manufacture of mRNA-based drug products is becoming a reality. The success of Moderna and Pfizer / BioNTech’s COVID-19 vaccines has helped re-energize on-going mRNA research.

Both mRNA and self-amplifying RNA have shown potential as vaccines against multiple infectious diseases, including influenza, respiratory syncytial virus, rabies, Ebola, malaria, and HIV-1. Coupled with therapeutic applications, particularly in immunotherapy for the treatment of cancers, mRNA technologies will continue to improve and develop, being an integral part of future drug development.

At the time of writing this article, Kristie Bloom does not work, consult, own shares or receive funding from any company or organization that would benefit from this article, and has disclosed the following funding associated with his academic appointment: The National Research Foundation (NRF), the Poliomyelitis Research Foundation (PRF) and the South African Medical Research Council (SAMRC).

By Kristie Bloom, Group Leader: Next Generation Vaccines, Antiviral Gene Therapy Research Unit, University of the Witwatersrand