Every time SARS-CoV-2 – the virus that causes COVID-19 – infects someone it picks up tiny changes in its genetic code as it makes copies of itself. Like all coronaviruses, it uses a type of genetic material called RNA, which is prone to developing errors, or mutations, as the virus replicates inside a person’s cells.
Most of these mutations do not lead to anything – they are evolutionary dead ends. Others don’t alter the virus’s behaviour but are also not harmful to it. If these can spread to other people, they can form new variants of the virus. Using viral genetic data, my colleagues and I have recently described this process. Currently, we know of thousands of slightly different, but genetically distinct lineages of COVID-19 spreading around the world.
Occasionally, however, one of these genetic errors brings about a change that is advantageous to the virus. It might make SARS-CoV-2 better at getting into cells or help it escape the immune system of the person it is infecting. Even more rarely, whole clusters (or ‘constellations’) of mutations can be acquired by the virus during a single infection.
And when viruses with these single or constellations of mutations spread more widely through populations, they may be designated "Variants of Concern". Currently there a handful of these around the world – four of which have been found in the UK.
But while the emergence of these variants is worrying, it is also important to remember that SARS-CoV-2 has been picking up mutations since early in the pandemic.
Shortly after the virus arrived in Europe it picked up a mutation at an important point in its RNA genome. This mutation changed a molecule at a single location on an important part of the virus – its spike protein. This is the protein that studs the outside of SARS-CoV-2 and helps it to infect our cells. It is also the most visible part of the virus to antibodies, an important component of our body’s natural defences, and so a part that our immune systems learn to detect.
This change, known as the D614 mutation, appears to have made the virus more transmissible between individuals. Over the first months of the pandemic, it quickly spread around the world to become the dominant variant of the virus by the summer of 2020.
It showed how a single mutation in the virus’s genome can affect the course of the pandemic. It was a clarifying moment for those of us studying how the virus is evolving over time.
One advantage we have in this pandemic compared to those in the past is the extraordinary amount of genetic sequencing of the virus from samples from infected people. These sequences are being shared all over the world. It has enabled us to track the virus, how it is spreading and spot variants of concern: We have been watching COVID-19’s evolution as it happens.
While it is clear now that the D614G mutation appears to have been an adaptation that allowed the virus to spread more rapidly in the early stages of the pandemic, SARS-CoV-2 had relatively low levels of genetic diversity globally. It was evolving relatively slowly. Part of the reason for this is because, unlike many other RNA viruses, the coronaviruses have a proof-reading mechanism that helps to reduce the number of mutations they pick up. But also, this was a completely new virus that entered a global population with little immunity against it – and so there was little pressure on it to evolve strategies to evade immune attack.
But as the number of people with immunity has grown – at first through natural infections and more recently with vaccinations too – this has put pressure on the virus to change. We are seeing cases of people being reinfected with new variants of SARS-CoV-2. In some parts of the world, such as Manaus, Brazil, where it was estimated three quarters of the population had been infected with the virus by October last year, new variants appear to have caused a resurgence in infections. We are also starting to see the virus develop some ability to escape antibodies from those with natural and vaccine-induced immunity.
This has been most notable in a couple of the emerging “Variants of Concern”. Both the variant B1.351, which was first detected in South Africa, and variant P.1 that was first seen in Brazil, contain mutations that appear to weaken the ability of antibodies to neutralise the virus by binding to it, which would normally prevent it from infecting cells.
Another variant – B1.1.7 – which has been causing concern in the UK since it was first detected in Kent in the autumn of 2020 and has since been reported in 93 other countries, shows less of an ability to escape from antibodies. But it has picked up mutations that allow it to spread faster than the original version of the virus.
Exactly how these variants emerged is still a puzzle. All three carry clusters of mutations – B1.1.7 has 17 mutations on its spike protein, for example, while B1.351 has eight distinctive mutations on the spike. It is quite unusual to get large clusters of mutations like this. There are some suggestions that they may have emerged in people suffering long term infections, perhaps in individuals who are immunocompromised. Unable to fully clear the virus from their bodies, their infections can last several months and in the ongoing battle with their immune systems or the treatment they receive, the virus picks up mutations that give it an advantage. There are also indications that new variants could emerge as the genomes of two different COVID-19 viruses get mixed together while infecting the same person – an event known as recombination.
We will probably never know exactly how the new variants of concern first emerged, but we are now able to watch them as they are spreading and as they continue to change. Already we have spotted a handful of sequences of the B1.1.7 variant in the UK that have picked up a mutation known as E484K. This has been found to reduce the ability of antibodies to target the spike protein in the B1.351 and P.1 variants. While it remains to be seen how far this variant will spread, the ability to track the virus in real time could help us to stay ahead of these changes.
Already vaccine manufacturers are tweaking their vaccines to make them more effective against the current variants. There are also laboratory-based studies that are attempting to identify other mutations that could potentially cause problems in the future. Armed with this information, vaccines could even be prepared in advance, ready to respond to an emerging, rapidly spreading variant.
It is not unlikely that other new variants will emerge in the coming months. Already there are some signs of other potentially troublesome variants emerging in the United States of America. There could even be some already circulating that have yet to be detected in parts of the world where surveillance of the virus is not as sophisticated as it is here in the UK.
It is likely that COVID-19 is going to stick around. My prediction is that as levels of immunity increase – both from natural infection and vaccination – the virus will eventually become globally endemic. It will continue circulating in populations, causing periodic outbreaks much like the four seasonal coronaviruses that are already endemic in humans. How severe infections will be, or the size of outbreaks, is anyone’s guess, and will largely depend on the effectiveness of interventions, including vaccination.
The likelihood is that we are going to have to learn to live with SARS-CoV-2. We can keep an eye on the variants circulating in different parts of the world and update the vaccines accordingly. It might mean getting a booster vaccine once a year or so as the tussle between our immune systems and the virus continues.
One thing is clear though – we have never before been in a situation where we know so much about a virus, can watch it changing and respond to it rapidly. A huge scientific effort has gone into making this possible and it leaves me optimistic that we will get through this.