Some oddities of coronavirus mutations

All RNA viruses tend to evolve rapidly; about a million times faster than human genes. Yet for all that, if SARS-CoV-2 stands out at all among them, it is simply because of the markedly slow pace at which it evolves, compared to many of its relatives. For example, it is thought to evolve about five times less rapidly than the biologically related influenza viruses. It has been postulated by Nextstrain, an open-source project that tracks the evolution of pathogens in real time, and other sources as well, that SARS-CoV-2 is accumulating an average of about two mutations per month.

By Dr B. J. C. Perera

MBBS(Cey), DCH(Cey), DCH(Eng), MD(Paed), MRCP(UK), FRCP(Edin), FRCP(Lon), FRCPCH(UK), FSLCPaed, FCCP, Hony FRCPCH(UK), Hony. FCGP(SL) 

Specialist Consultant Paediatrician

There is a lot of talk as well as considerable uncertainty and apprehension associated with the spectacle of natural and spontaneous changes or ‘mutations’, as they are called, in the SARS-CoV-2 virus that causes COVID-19. These trepidations are currently apparent, not only among people but also in the medical circles as well. We have all read several accounts of patients who recovered from Covid-19 only to be infected with SARS-CoV-2 again later, allegedly by a different “strain” of the virus. In late August 2020, came news about the world’s first “documented” or “confirmed” case of reinfection with SARS-CoV-2: a man from Hong Kong, diagnosed in March, had contracted “a new virus variant” circulating in Western Europe during the summer. The very next day, news broke out that two people in Europe also appeared to have been reinfected. After that, it was a story about the first American case of the kind, involving a patient in Nevada, who was said to have suffered worse symptoms the second time around. The preprint study which had not been peer-reviewed, on which those reports were based, seems to no longer be available in the global scientific literature.

Yet, for all that, all this talk about newly mutated, perhaps even more virulent forms of SARS-CoV-2, is most definitely igniting and sparking fear and sowing confusion. The vital question is whether there could be either an increase, or for that matter even a decrease, in the severity of the illness caused by these mutant viruses.

For one thing, it is important to keep in mind that isolated cases of reinfection also happen with other viruses. That fact should not necessarily be alarming. Reinfection usually tells us something only about how the human immune system works. On just the face of it, that occurrence is not definitive evidence that a virus does always change in ways that make it more dangerous. Of course, it is well-known that viruses routinely mutate. However, perhaps more importantly, quite a lot of these changes and modifications to their basic structure are bad for the virus itself or even fatal to the virus, according to some scientific studies. Only a minority of mutations are neutral, and only just a tiny minority of mutations are beneficial to the virus itself. The word “mutation” may sound ominous, but it is a rather boring and well-recognised fact of viral life and its implications may not always be all that malevolent for humans.

Yes, of course, the SARS-CoV-2 is mutating, too. One might justifiably ask “So what?”. The million-dollar question is whether it has become more virulent or more infectious than it was when it was first detected in Wuhan in December 2019? The current evidence suggests that it has not been proven to be more virulent. So what indeed?

Like the viruses that give us influenza or measles, SARS-CoV-2 has a genetic code made up of ribonucleic acid (RNA). But RNA is highly mutable, and since SARS-CoV-2 infects us by using our body’s cells to replicate itself again and again, every time its genome is copied, there is a real chance that an error might creep in. That is the unavoidable basic progress of the life-cycle of the virus. Most mutations actually get lost rather quickly, either by chance, or because they damage some part of the main structure or the functions of the virus. Only a small proportion end up spreading widely or lasting for long periods of time. Mutation may be the fuel of evolution but, especially for an RNA virus, it also is just business as usual. Mutations may not always make the virus comply with the celebrated theory of Charles Darwin of survival of the fittest.

All RNA viruses tend to evolve rapidly; about a million times faster than human genes. Yet for all that, if SARS-CoV-2 stands out at all among them, it is simply because of the markedly slow pace at which it evolves, compared to many of its relatives. For example, it is thought to evolve about five times less rapidly than the biologically related influenza viruses. It has been postulated by Nextstrain, an open-source project that tracks the evolution of pathogens in real time, and other sources as well, that SARS-CoV-2 is accumulating an average of about two mutations per month.

When translated to real time, it means that the forms of the virus circulating today are only about 15 accumulated mutations or so, different from the first version traced to the outbreak in Wuhan in China. This really is a tiny number when one considers the fact that the SARS-CoV-2 genome consists of about 30,000 nucleotide components. The implication is that the viral versions that are prevalent today are at least 99.9 per cent the same as the original index strain from Wuhan. If one were to say it in a more simplified way, for an RNA virus, SARS-CoV-2 is in the slowest lane of evolution.

In fact, from a purely scientific perspective, all these discussions of SARS-CoV-2 having developed into however many different “strains” is misleading. Scientists tend to reserve the word ‘strain’ for versions of a virus that differs from the original in major biological ways. SARS-CoV-2’s different forms are very similar; and technically, it is far better to label them as “variants”.

The coronavirus’s sluggish pace of mutation is good news for us. That is because a virus that evolved more rapidly would have a greater chance of outrunning any vaccines or drugs developed to counter it. Having said that, have even the small mutations so far changed SARS-CoV-2 in any important ways? For example, has it become more deadly? The answer might surprise many. Up to the present time, there is no evidence to suggest that any newer or mutated forms of SARS-CoV-2 have become more virulent or more lethal; nor for that matter, that it has become less so as well.

For example, a recent preprint paper (i.e. not yet peer-reviewed) by Erik Volz, of Imperial College, London, UK, and other co-workers, including members of the Covid-19 Genomics UK Consortium which analysed 25,000 whole genome SARS-CoV-2 sequences collected in the United Kingdom, found that one particular mutation in the virus, known as D614G, had not increased mortality in patients. There has been much discussion over whether the D614G mutation, which affects the so-called spike protein of the virus, has made SARS-CoV-2 more infectious. In a very broad sense this appears to be so and that contention has led to some of the affected countries to which it has spread, taking drastic steps in locking-down certain areas.

The spike protein sits on the surface of the coronavirus, and that really matters because it’s the part of the virus that attaches itself to the host’s cells. “D614G” is an abbreviation for a change at position 614 of the spike protein. The D614G mutation, which probably initially arose in China, first appeared to become more and more frequent in the outbreak in northern Italy in February. The G614 form of the virus has since spread all over the world and has become the dominant variant. The D614G mutation does seem to have increased the infectivity of the coronavirus, at least in cells grown in laboratories, according to a recent paper by the computational biologist Bette Korber and others, published in the journal ‘Cell’. Apparently based partly on this and some other studies as well, health authorities in various countries have claimed that the G614 form of the coronavirus may be 10 times more infectious than the version first detected in Wuhan.

The more recent UK variant, commonly known as B-1.1.7, is definitely a more contagious variant of the coronavirus. It first emerged in the U.K. in late 2020. It has 23 accumulated mutations. It has acquired 17 of these at once, a feat that has not been seen before. Of particular concern to scientists are eight mutations that affect the gene for a spike protein on the surface of coronaviruses. The worries are the results of the fact that the viruses use the spike protein to grab onto human cells. This mutant strain too appeared to spread faster than other variants in the United Kingdom but has not shown itself to cause more severe disease.

These scientific details could have an abiding effect on the future of this capricious and miserable virus that causes COVID-19. A pandemic virus may disappear from the scene due to one or more of three reasons. The first of these is the notion that a virus that is capable of taking lives would kill a significant number of affected people but those who manage to recover will have some degree of immunity against the very same virus. So, reinfections may be naturally prevented following the first infection with the virus, provided of course that the patient survives the initial onslaught. The second factor is that the virus may induce extensive immunity in a populace, the so-called ‘herd immunity’, either through widespread infection of a large proportion of the population or a similar scenario being enacted through vaccination against the virus. The end result of this is to produce a rather resistant population against the effects of the virus. The third possibility is that repeated mutations would lead to converting the virus into a much less troublesome and less virulent form that it ceases to be a major medical problem and converts the blight into an insignificant and toothless type of an entity. Such impotent strains might even be able to completely overwhelm the more virulent types, with tremendously beneficial implications for the whole of humanity.

These are thought to be at least some of the mechanisms through which the Spanish Flu of 1918 disappeared within a year or so. It was destined never to return in the same life-threatening format for a period of over 100 years or so, right up to the present time.

It has been said that hope springs eternal in the human breast. We do hope and even pray that through some of these postulated mechanisms, the inhabitants of Mother Earth would be spared further turmoil, intense suffering and absolute mayhem that has been their lot for the last year or so, through the doings of this dastardly blight of a nasty coronavirus. We have suffered immeasurably. It is about time that we got a decent break in this fight.