In recent weeks and months, several highly-transmissible variants of SARS-CoV-2 (the virus that causes COVID-19) have emerged. These variants have mutations in the receptor binding domain (RBD) of the spike protein, which SARS-CoV-2 uses to bind to and infect cells. There has been concern that these and other such variants could have a dramatic, negative impact on the trajectory of the COVID-19 pandemic. However, there are good reasons to be cautiously optimistic.
The variants
The three variants attracting most attention are B.1.1.7 (sometimes referred to as VUI-202012/01 or the UK variant), 501Y.V2 (also known as the South African variant), and B.1.1.248 (often referred to as the Brazilian variant). All three variants appear to be significantly more transmissible than the ‘original’ SARS-CoV-2 variants that have been broad circulation since early last year (for simplicity, throughout the rest of this article I will refer to this initial collection of variants as ‘original SARS-CoV-2’), and there is also some evidence that at least one of the variants might have a modest increase in virulence.
These different variants are characterised by collections of genetic differences relative to the genome of original SARS-CoV-2. Mutations of this kind can be important if they result in a material change in the ability of the immune system to ‘recognise’ and respond to the virus. The vast majority of people that have had and recovered from COVID-19, and those which have been vaccinated against COVID-19 (with one of the approved vaccines, which are generally based on the spike protein of original SARS-CoV-2), develop immunological memory to the virus. When they are first infected with the virus their immune system generates B cells which produce antibodies which bind to the viral proteins, and also T cells which kill cells infected with the virus, thus limiting infection of further cells. These B and T cells are able to recognise and rapidly mount an effective immune response to the virus if they are exposed to it again, preventing symptomatic (re)infection. However, if changes to the virus significantly reduce or prevent recognition of the variant by the immune system, then it might be possible for people to develop COVID-19 despite vaccination or having already had it. Mutations that provide the virus with the ability to evade effective immune responses in this way are sometimes referred to as ‘immune escape’ mutations.
Spike protein mutations
Immunologists are most concerned by mutations to the spike protein of SARS-CoV-2, as it is through this protein that the virus binds to and enters host cells. A sub-region of the spike protein known as the RBD has been shown to be critical for association with the ACE2 receptor on host cells, which is thought to be the key binding event for infection of cells by SARS-CoV-2. Each of the B.1.1.7, 501Y.V2 and B.1.1.248 variants have mutations in the RBD.
B.1.1.7 comprises the mutation N501Y. This is a single change in the amino acid sequence of the RBD relative to original SARS-CoV-2, which may alter binding to ACE2, and which might in turn account for the ~50-70% increase in transmissibility reported for this variant relative to original SARS-CoV-2. However, it has been shown that this change does not significantly affect the ability of antibodies raised in response to the spike protein of original SARS-CoV-2 to recognise the new variant spike protein. This suggests that the emergence of the B.1.1.7 variant will not result in substantial (re)infection of people that have previously had or been vaccinated against COVID-19.
The 501Y.V2 and B.1.1.248 variants also have the N501Y mutation. However, they each also have mutations at two further positions in the RBD, including E484K. These variants present more of a concern than B.1.1.7, as E484K has been shown to be shown to confer at least some degree of immune escape. This change appears to inhibit the ability of antibodies raised against the spike protein of original SARS-CoV-2 to block spike protein:ACE2 interaction, reducing their ability to prevent infection. These data have led some to suggest that the 501Y.V2 and B.1.1.248 variants could result in significant levels of (re)infection of people that have previously had or been vaccinated against COVID-19, and that it might be necessary to produce modified versions of existing approved vaccines designed to cover such variants in order to bring the pandemic under control.
Immune escape variants do not take us back to square one
However, the emergence of variants harbouring the E484K mutation might not be as catastrophic as it may first appear. As yet we only have limited data relating to the ability of immunity elicited by immunisation with the spike protein of, or infection by, original SARS-CoV-2 to recognise and respond to variants comprising the E484K mutation such as 501Y.V2 and B.1.1.248. Most of the results come from laboratory experiments using cells, 501Y.V2 and B.1.1.248 variant viruses and antibody-containing blood samples that cannot easily be extrapolated to the real-world scenario of infection of an individual. We do not know, for example, whether the antibody responses directed against original SARS-CoV-2 spike protein are nevertheless enough to prevent symptomatic infection by 501Y.V2 or B.1.1.248 in most individuals. That is to say, even where there is a considerable reduction in the ability to block infection of cells by the variants as compared to original SARS-CoV-2, the level of inhibition they achieve might still be enough to prevent symptomatic disease, or (more likely still) be effective to reduce the level of infection so as to prevent moderate/severe disease.
Moreover, these data do not capture the effects of T cell-mediated immunity. There is a large and growing body of evidence to suggest that T cell responses are an important component of the immune response to SARS-CoV-2 infection. Indeed, earlier on in the pandemic it was proposed that T cell-mediated immunity generated in response to infection with other coronaviruses in circulation (that cause common colds) might account for strikingly low mortality rates observed in some countries. SARS-CoV-2-specific T cells generated in subjects that have had, or which have been vaccinated against, COVID-19 might well be able to prevent development of COVID-19 in those subjects on subsequent exposure to 501Y.V2 or B.1.1.248. Once again, even if they do not prevent the development of symptomatic disease completely, they would be expected to reduce the viral load so as to dramatically reduce the severity of disease.
So, it is very unlikely that the 501Y.V2 and B.1.1.248 variants will enjoy complete immune escape from responses generated in individuals following infection by, or vaccination based on the spike protein of, original SARS-CoV-2. Indeed, we are beginning to see early-stage data that suggest vaccines based on original SARS-CoV-2 confer substantial protection against the development of symptomatic infection by E484K variants. J&J’s vaccine was recently found to be 57% effective to prevent symptomatic COVID-19 in the South African part of its trial, where the 501Y.V2 variant accounts for ~95% of cases (as expected, efficacy was higher in the US part of the trial, where the vast majority of cases are caused by original SARS-CoV-2). Encouragingly, the results also indicated that the vaccine was 89% effective to prevent severe disease in the South African cohort.
Taking a broader view
Central to the wider picture of immunity in an individual is the fact that the adaptive immune system generates specific receptors (in the form of antibodies and T cell receptors) to various different parts of the viral protein(s). We might understandably focus our attention on so-called neutralising antibody responses targeted against the RBD of the spike protein, which block the ability of the virus to bind to and infect cells. However, the role of immunity based on molecules that target other parts of the virus should not be overlooked in considering the complete picture of how the immune system ‘sees’ and responds to SARS-CoV-2. People who have received a COVID-19 vaccine based on the original SARS-CoV-2 spike protein will in general have developed a repertoire of antibody-producing B cells and T cells which recognise regions spanning the full sequence of the spike protein upon which the vaccine is designed, and in this regard it is worth remembering that these variants have only a very small number of changes when viewed in the context of the full protein. For people who have already had COVID-19, their immune system will additionally have developed B and T cells directed against components of SARS-CoV-2 other than the spike protein (e.g. the envelope, membrane and nucleocapsid proteins), which are likewise relatively invariant between the original SARS-CoV-2 and emergent variants.
Taking an even broader view of what the emergence of the 501Y.V2 and B.1.1.248 variants means for the trajectory of the COVID-19 pandemic at a population level, even if some people that have previously had or been vaccinated against COVID-19 are susceptible to re-infection as a consequence of immune evasion through E484K, there is nothing yet to suggest that this would be so common as to cause or sustain significant outbreaks in populations with a high level of immunological experience of original SARS-CoV-2 (as a result of the combination of people having already had COVID-19, or having been vaccinated against it). Even if a proportion of people that have had or been vaccinated against COVID-19 are susceptible to infection by 501Y.V2 and B.1.1.248 variants, this fraction could be too small to support chains of transmission long enough to sustain outbreaks based on the new variants in populations having a high level of immunological experience of original SARS-CoV-2. So high uptake of existing vaccines might well be enough to prevent circulation of the 501Y.V2 and B.1.1.248 variants.
Emergence of further variants?
Finally, some thoughts on the possible emergence of further immune escape variants. Like other coronaviruses, SARS-CoV-2 has a relatively low mutation rate. We have likely seen variants emerge in recent months due to the very large number of infections worldwide. As global vaccination programmes begin to take effect, and we move into the spring and summer months in the northern hemisphere, the number of active SARS-CoV-2 infections will drop, thus limiting the opportunity for new variants to arise. Moreover, and importantly, the virus does not have a bottomless reservoir of mutations to draw from that could result in immune escape without adversely affecting its ability to infect cells and cause disease. Considering the RBD of the spike protein, many of its residues cannot easily be mutated, as they would either significantly reduce or completely prevent binding to ACE2. So it is not correct to assume that we are engaged in an endless arms race with the virus, with new immune escape and equally or more virulent variants constantly arising. In fact, it may be that the B.1.1.7, 501Y.V2 and B.1.1.248 variants are the most effective variants SARS-CoV-2 is likely to be able to produce, having emerged and out-competed less-effective variants, during the time of the very highest levels of infection during the pandemic.
That is to say, we may already have seen the most troubling variants, and as explained above there are good scientific reasons to believe that their emergence might not be as worrying in the long-term as they might at first appear.
