How do mRNA vaccines work?
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Our understanding of messenger RNA and ability to study and manipulate it in the lab has come on leaps and bounds since those heady days of the 1960s. But the underlying principle remains the same: mRNA is a transient genetic message that is used by ribosomes as the instructions for making proteins.
So, if you can make an mRNA and you can get it into a cell, then the ribosomes in that cell will make whatever protein that mRNA encodes. And it’s here that we move from the 1960s right up to today, and to the story of mRNA vaccines.
First, let’s take a quick step back and look at what vaccines are and how they work. Cue the training montage...
Vaccines are like a ‘training exercise’ for the immune system. They take many forms, but the basic idea is always the same: give someone a harmless or weakened version of a nasty infectious pathogen like a bacteria or virus, or part of it, known as an antigen.
This antigen triggers an immune response, including the production of special ‘memory’ cells, which remember what that antigen looked like and how to respond to it.
Then when we encounter that pathogen for real, the immune system quickly swings into action to fight off the threat.
Vaccines aren’t perfect - they don’t offer 100% protection against catching a disease and some people aren’t able to have vaccines for health reasons, so we need to have a high proportion of the population vaccinated in order to get sufficient levels of protection to keep the whole community safe from a particular disease.
Over the past 200 years, vaccines have been transformative for public health around the world, saving countless lives, including millions of children. So, when COVID-19 came on the scene, scientists all over the world quickly started the search for a vaccine against this new health threat, and there are currently the best part of 300 different COVID vaccine candidates of various types currently in development, with more than 60 in clinical trials.
Many of these vaccine candidates are made from inactivated or weakened versions of SARS-CoV-2 itself, or other harmless viruses or virus-like particles, or proteins - all obvious kinds of antigens.
The idea behind mRNA vaccines for COVID-19 is simple enough: make an mRNA that encodes an antigen that looks like a protein in SARS-CoV-2, get it into the cells of the body so the ribosomes can make that protein, so that the immune system can be trained to recognise it.
mRNA vaccines might seem a strange, newfangled idea, but they’ve actually been around for decades. So, where did it all start?
The early days of mRNA vaccines
The 1980s was a time when there was a huge amount of excitement around gene therapy, often focused around putting DNA directly into cells or patients. But people were worried that DNA might get incorporated into the genome, causing problems down the road. Because mRNA is far less stable than DNA, is quickly broken down inside cells and can’t be incorporated back into the cell’s genome, it seemed like a much safer option.
The idea of putting mRNA directly into cells to encode replacements for damaged or faulty proteins dates back to 1989, when researchers at a small Californian biotech company, Vical Incorporated, showed that they could smuggle functional mRNA into cells using tiny fatty nanoparticles called liposomes. Then in 1990, researchers at the University of Wisconsin showed that they could inject mRNA into the muscles of mice and it would be translated into proteins.
Building on this idea, others quickly suggested that as well as using mRNA for gene therapy, it might also be useful for vaccination. By 1993, researchers in France had shown that they could provoke an immune response against flu in mice using mRNA packaged inside liposomes.
Watching all of this was a Hungarian researcher named Katalin Karikó, who together with her colleague Drew Weissman at the University of Pennsylvania, were convinced that mRNA-based therapies were the future of medicine. But she struggled to get her research projects to work, and the funding dried up.
Synthetic mRNA just didn’t behave very well - it was unstable and broke down too quickly, before it had a decent chance to be translated into proteins. Worse, putting mRNA into the body ran the risk of triggering a nasty unwanted immune reaction, potentially putting patients in danger.
Just when Karikó had nearly given up hope altogether, and the whole field of mRNA therapeutics was dwindling towards nothing, she and Weissman found the solution to the problem. Instead of using exactly the same four bases normally found in mRNA inside cells - adenine, cytosine, guanine and uracil - they swapped out some of them for slightly modified versions, which could still be read in the same way by ribosomes to make proteins, but didn’t set off an unwanted excessive immune response.
Published in 2005, their discovery transformed mRNA therapeutics from a ‘nice idea but nope’ into a gamechanging medical technology after catching the eye of scientists who would eventually become the founders of the two leading COVID mRNA vaccine companies - BioNTech and Moderna.
Refining mRNA vaccines
Over the following years, scientists refined mRNA vaccine technology, homing in on various modifications to the RNA and delivery mechanisms to make them as effective as possible at triggering a long-lasting immune response.
It’s this last bit - the delivery - that has been a sticking point for a long time, but this has been solved by the development of new polymers and liposome nanoparticles that are incredibly good at smuggling mRNA into cells.
Another thing that’s great about mRNA vaccines is that they’re relatively quick and easy to design and make - and certainly a lot simpler than trying to make a vaccine based on a pathogen itself. As soon as you’ve got the genetic sequence of your pathogen and have picked out the bit you think is going to be the best antigen, you then drop that sequence into your mRNA vaccine template, which has all the bits and bobs that enable it to be read by ribosomes, not be broken down too quickly inside cells, and trigger a protective immune response against the pathogen.
It’s also easy to add a few genetic tweaks here and there to make the antigen even more potent and trigger a better immune response. There are other clever additions like mRNAs that multiply inside cells, known as self-amplifying mRNAs, which would mean that smaller doses are needed.
From there, it’s a case of manufacturing lots of mRNA - something else that has got a lot easier in recent years and is relatively easy to do at large scale nowadays - package it up inside your nanoparticle of choice, and there’s your vaccine - all ready for lab testing and, if that goes well, clinical trials.
As a result, immunologists were getting pretty excited about the potential for mRNA vaccines to transform the future of immunisation and global health, even before the current pandemic. A 2018 review described them as a ‘new era in vaccinology’, hailing their potential as a “promising alternative to conventional vaccine approaches because of their high potency, capacity for rapid development and potential for low-cost manufacture and safe administration.”
mRNA vaccines have been tested in clinical trials against at least four infectious diseases - rabies, flu, cytomegalovirus, and Zika - as well as for treating various types of cancer by stimulating the immune system, although the Pfizer/BioNTech and Moderna COVID vaccines are the first to make it into widespread use.
So - what got these vaccines over the line so fast?
mRNA COVID-19 vaccines
For any new vaccine, the first challenge is to decide on the best antigen that’s most likely to provoke a memorable immune response. Based on previous work with similar viruses, the spiky molecule studding the outside of the SARS-CoV-2 coronavirus, known - obviously enough - as the spike protein emerged as the leading antigen.
For making an mRNA vaccine, the next obvious problem is getting hold of the genetic sequence encoding that spike. Thanks to the urgency of scientific research into the emerging pandemic, the genetic code of the SARS-CoV-2 virus was deciphered at breakneck speed.
The first version of the virus genome was made freely available to researchers all over the world by Chinese scientists as soon as the 10th of January 2020. Within a matter of days, the teams at BioNtech, Moderna and other companies had designed their vaccines and were starting to take them through lab testing. Following promising results and good safety profiles, early stage clinical trials followed shortly after, with both companies beginning large-scale trials in late July 2020.
Both vaccines showed high levels of protection against COVID-19, providing enough data on safety and effectiveness to convince regulators in various countries that they were ready for public rollout. On 8th December 2020, 90-year-old Margaret Keenan from Coventry became the first person in the UK to receive a COVID-19 vaccine on the NHS, kicking off the biggest mass vaccination programme ever undertaken in the country.
It’s going to take a fair old while to vaccinate everyone - and even longer to get the whole world vaccinated - but for now we can allow ourselves to think that there might be light at the end of the tunnel.
The need for speed
The Pfizer and Moderna vaccines have now been authorised for emergency use in the US, and the vaccines are also being rolled out in a number of other countries. Other types of vaccine are hot on their heels, including the virus-based AstraZeneca/Oxford University jab, now being rolled out in the UK, and vaccines developed in Russia, China and India.
Given that it takes years, if not decades, to bring new vaccines to market, there’s understandable suspicion about the speed at which COVID-19 vaccines have been developed, trialled and approved.
Rather than skimping on safety, there are many places where time has been saved simply by reducing the delays that normally hamper vaccine research. Unprecedented amounts of money and humanpower have been thrown at the problem, combined with the fact that the frontrunner mRNA and viral vaccines are built on tried and tested platform technology that has been in development and testing for years.
Scientists moved swiftly from one phase of research to the next without having to apply for further funding and wait for it to arrive, and there’s been a large number of willing participants for clinical trials at a time when the prevalence of the disease is very high, meaning that trials have hit their statistical targets quickly.
From what we know so far, both of the mRNA vaccines that are being rolled out for COVID-19 seem to be safe and effective. Yes, we don’t have long-term data on safety, because we can’t bend the fabric of space-time, but from what we know so far - and based on previous clinical trials - the long-term safety appears to be good.
And no - even though mRNA is technically genetic code, it won’t alter your DNA. This is an understandable fear: as we discussed in episode 3 of our very first season, there are some RNA-based retroviruses that can integrate themselves into the genome, including HIV. But although the mRNA vaccines do encode a small bit of the coronavirus, there’s no chance that they can incorporate themselves into our DNA or make new virus.
The vaccine mRNA breaks down within a couple of days inside cells and doesn’t have the right kind of ‘molecular passcode’ that would enable it to even enter the nucleus. And even if it could get in there, it also doesn’t bring along the reverse transcriptase enzyme that retroviruses like HIV rely on to integrate into DNA.
With any vaccine there will be side effects and risks, but this has to be balanced against the risk of the disease itself - and we know that COVID-19 kills around one in every hundred people infected in wealthier countries, depending on age and underlying health. And around one in twenty people who fall ill with COVID-19 will experience symptoms for 8 weeks or more, with many tens of thousands likely to suffer long-term health issues.
Personally speaking, I can’t wait for myself and my loved ones to get our COVID jabs so life can start to get back to some semblance of normality. We’ve still got a long way to go before the pandemic is under control, but it feels like the end might be in sight.
I’m also excited to see what the future holds for mRNA vaccines for other diseases that cause so much death and misery around the world, now we’ve had such a dramatic proof of principle that they can work and the speed at which they can be developed.
There are still some technical issues to be ironed out with mRNA vaccines more generally, such as the low temperatures that are needed to store and transport them, which makes things tricky for use in countries without good cold chains and health infrastructure, but they hold great promise for global health.
We can think of mRNA vaccines as a kind of ‘plug and play’ platform technology: once you have the genetic sequence of any pathogen, away you go. There are plenty of other diseases that could benefit from this approach.
As we look forward to a year in which hopefully we start to get COVID-19 under control, I want to offer my heartfelt thanks to all the scientists who have worked so hard for so long- whether you’re vaccine researchers, geneticists, immunologists, public health specialists and all the rest, and to all the incredible healthcare workers and carers on the frontlines. Thank you.
References:
MedPage Today - Want to Know More About mRNA Before Your COVID Jab?
NanoToday - Three decades of messenger RNA vaccine development
Nature Reviews Drug Discovery - mRNA vaccines — a new era in vaccinology
STAT - The story of mRNA: How a once-dismissed idea became a leading technology in the Covid vaccine race
ZOE COVID Symptom Study - How have COVID-19 vaccines been developed so fast?
