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13 maltatoday | WEDNESDAY • 27 JANUARY 2021 OPINION Ed Feil Ed Feil is Professor of Microbial Evolution at The Milner Centre for Evolution, University of Bath • theconversation.com WHEN supplies of oxygen at hospitals in Manaus, Brazil, recently ran out, the air- force was called in for emergency evacua- tions while healthcare workers frantically tried to save lives with manual ventilation. For those that could not be saved, there was only morphine and a final hand- squeeze. As calamitous as the situation is for those affected, the devastating surge in COVID cases in Manaus over the last few weeks has set alarm bells ringing ever more loud- ly for governments and agencies around the world struggling to manage the pan- demic. Cases continue to surge in the UK and South Africa and, as in Manaus, they appear to be mainly due to the emergence of new variants of the coronavirus. Three variants causing concern The naming of these "variants of con- cern" – as scientists refer to them – is somewhat muddled. For simplicity, they are referred to here as the Brazilian, South African and UK variant. All have emerged recently, and all have picked up several mutations that mark a distinct shift in the evolution of the virus. Similar variants are almost certainly out there spreading un- der the radar. More are likely to evolve. Despite arising independently on three different continents, the three variants share striking similarities. Each has picked up several mutations over a short time, with many in the gene providing the in- structions to make the virus's spike pro- tein. The spike protein is where the key bat- tles between human and virus are being waged, including the vaccines. It is the key to how the virus interacts with the human body, both regarding the immune response and in binding to and entering human airway cells. Not only have several mutations affect- ed this protein, but identical mutations have cropped up independently both in the variants of concern and in other viral lineages. In effect, the virus has repeated- ly stumbled across the same evolutionary solutions to specific challenges. This phe- nomenon is known as evolutionary con- vergence (consider the independent evo- lution of wings in bats, birds and insects). Understanding how these mutations might affect the coronavirus's behaviour at the molecular level is difficult. Work to bridge the gap between each variant's "genotype" (the mutations) and its "phe- notype" (how quickly it spreads) is being ramped up in the UK and elsewhere, but will require a sustained multidisciplinary effort. Constellations of mutations The task is made more difficult because several mutations have accumulated in these variants (so-called constellations). The UK variant, for example, has 23 sepa- rate mutations, representing a remarkable evolutionary jump with no known inter- mediate variants (like there are "missing links" in the evolutionary chain). Although not all the mutations are thought to be important, the effect of any individual mutation might be changed by the presence of other mutations (an effect called epistasis). This greatly complicates the problem of figuring out precisely what these mutations are doing and of assessing the risk of newly emerging variants from the sequence data alone. Despite these complexities, a combina- tion of computational analysis and labora- tory experiments have yielded valuable ev- idence of the effect of these mutations. For example, one mutation found in all three variants is N501Y. The name refers to an alteration in the spike protein, where the type of amino-acid molecule located in position 501 has changed from asparagine (N) to tyrosine (Y). Position 501 is on the receptor-binding domain – part of the spike protein that at- taches to a particular receptor (ACE2) on cells in the human body – and this change appears to strengthen the binding between the virus and human cells. Yet for reasons that remain unclear, the effect of N501Y is greatly amplified when combined with other mutations. Other mutations in the spike protein of- fer the virus some protection from the im- mune response. Examples include E484K (found in the Brazilian and South African variants, but not the UK variant), and a mutation in the UK variant in which two amino acids are deleted (del69-70) and which is repeatedly found in combination with mutations in the receptor-binding domain. Selection pressure Specific evolutionary challenges and se- lection pressures that favour the survival of some variants of the virus over others may be driving the emergence of the var- iants of concern. This would help to ex- plain why they acquire several mutations so quickly, or why these variants are start- ing to emerge now. A plausible explanation for the emer- gence of the UK variant is that it arose in a single chronically infected person with a weakened immune system who was be- ing treated with convalescent plasma (an- tibodies from a recovered patient). This would have given a strong advantage to any variant that could resist the therapeu- tic antibodies. But it remains a theory. A second possibility relates to the emer- gence of the Brazilian variant. The cur- rent wave of infection in Manaus is only the latest COVID disaster to hit this city. Previous waves may have led to 76% of the population being infected. The resulting high level of immunity in the population may have given an advantage to mutations in the spike protein. Although these variants are causing con- cern, we should remain confident that the vaccines will ultimately prove successful in ending the pandemic and allow a return to normality. There is currently no evidence that the vaccines are less effective against the new variants. While it remains impossible to be certain whether, or how, the virus will make further evolutionary jumps when confronted by the vaccines, modifications to vaccine design should ensure that we stay one step ahead. Coronavirus variants: how did they evolve and what do they mean? None of the coronavirus variants has been shown to 'escape' the vaccine